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Captopril

Pronunciation

Pronunciation

(KAP toe pril)

Index Terms

  • Capoten

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 12.5 mg, 25 mg, 50 mg, 100 mg

Pharmacologic Category

  • Angiotensin-Converting Enzyme (ACE) Inhibitor
  • Antihypertensive

Pharmacology

Competitive inhibitor of angiotensin-converting enzyme (ACE); prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion

Absorption

60% to 75%; rapid

Distribution

Vdss: 0.7 L/kg (Duchin 1982)

Metabolism

50% metabolized

Excretion

Urine (>95%) within 24 hours (40% to 50% as unchanged drug)

Onset of Action

Within 15 minutes; Peak effect: Blood pressure reduction: 1 to 1.5 hours after dose; Maximum effect: Antihypertensive: 60-90 minutes; may require several weeks of therapy before full hypotensive effect is seen

Time to Peak

Within 1-2 hours

Duration of Action

Dose related, may require several weeks of therapy before full hypotensive effect

Half-Life Elimination

Infants with CHF: 3.3 hours; range: 1.2-12.4 hours (Pereira 1991)

Children: 1.5 hours; range: 0.98-2.3 hours (Levy 1991)

Adults: Healthy volunteers: ~1.7 hours (Duchin 1982). In two studies, patients with chronic renal failure demonstrated approximately 2-fold longer half-lives as compared to normal subjects (Giudicelli 1984; Onoyama 1981). Half-life was up to 21 hours in patients with severe renal impairment and up to 32 hours in patients on chronic hemodialysis in another study (Duchin 1984)

Protein Binding

25% to 30%

Use: Labeled Indications

Diabetic nephropathy: Treatment of diabetic nephropathy (proteinuria more than 500 mg daily) in patients with type 1 insulin-dependent diabetes mellitus and retinopathy

Heart failure: Treatment of congestive heart failure

Hypertension: Management of hypertension

Left ventricular dysfunction after myocardial infarction: To improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction of 40% or less, and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients.

Guideline recommendations:

Heart failure: The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2013 heart failure guidelines recommend the use of angiotensin-converting enzyme (ACE) inhibitors, along with other guideline directed medical therapies, to prevent heart failure in patients with a reduced ejection fraction who have a history of myocardial infarction (stage B heart failure), to prevent heart failure in any patient with a reduced ejection fraction (stage B heart failure), or to treat those with heart failure and reduced ejection fraction (stage C heart failure) (Yancy, 2013).

Hypertension: The 2014 guideline for the management of high blood pressure in adults (Eighth Joint National Committee [JNC 8]) recommends initiation of pharmacologic treatment to lower blood pressure for the following patients:

• Patients ≥60 years of age with systolic blood pressure (SBP) ≥150 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg. Goal of therapy is SBP <150 mm Hg and DBP <90 mm Hg.

• Patients <60 years of age with SBP ≥140 mm Hg or DBP is ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with diabetes and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

• Patients ≥18 years of age with chronic kidney disease (CKD) and SBP ≥140 mm Hg or DBP ≥90 mm Hg. Goal of therapy is SBP <140 mm Hg and DBP <90 mm Hg.

Chronic kidney disease (CKD) and hypertension: Regardless of race or diabetes status, the use of an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) as initial therapy is recommended to improve kidney outcomes. In the general nonblack population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic, calcium channel blocker, ACEI, or ARB. In the general black population (without CKD) including those with diabetes, initial antihypertensive treatment should consist of a thiazide-type diuretic or a calcium channel blocker instead of an ACEI or ARB.

Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with CAD recommends the use of an ACE inhibitor (or an ARB) as part of a regimen in patients with hypertension and chronic stable angina if there is prior MI, LV systolic dysfunction, diabetes mellitus, or CKD. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).

STEMI: The 2013 American College of Cardiology Foundation/American Heart Association guidelines for the management of patients with ST-elevation myocardial infarction (STEMI) states that an ACE inhibitor (eg, captopril) should be initiated within the first 24 hours after STEMI in patients with anterior MI, heart failure, or left ventricular ejection fraction ≤40%. It is also reasonable to initiate an ACE inhibitor in all patients with STEMI (ACCF/AHA [O'Gara, 2013]).

Use: Unlabeled

To delay the progression of nephropathy and reduce risks of cardiovascular events in hypertensive patients with type 1 or 2 diabetes mellitus; treatment of hypertensive crisis, diagnosis of anatomic renal artery stenosis, hypertension secondary to scleroderma renal crisis; diagnosis of aldosteronism, Bartter's syndrome, postmyocardial infarction for prevention of ventricular failure; increase circulation in Raynaud's phenomenon, hypertension secondary to Takayasu's disease

Contraindications

Hypersensitivity to captopril, any other ACE inhibitor, or any component of the formulation; angioedema related to previous treatment with an ACE inhibitor; concomitant use with aliskiren in patients with diabetes mellitus

Dosage

Note: Titrate dose according to patient's response; use lowest effective dose.

Children ≤1 year and Adolescents ≤17 years: Hypertension: Oral: Initial: 0.3 to 0.5 mg/kg/dose every 8 hours; titrate upward to maximum of 6 mg/kg/day in 2 to 4 divided doses (NHBPEP, 2004; NHLBI, 2011); maximum daily dose: 450 mg daily.

Adults:

Acute hypertension (urgency/emergency): Oral, sublingual: 25 mg, may repeat as needed; consider alternative therapy if blood pressure is nonresponsive within 20 to 30 minutes (Angeli, 1991; Castro del Castillo, 1988; Ceyhan, 1990; Damasceno, 1997; Tschollar, 1985). Note: May be given sublingually, but therapeutic advantage has not been demonstrated over oral administration (Karakilic, 2012).

Heart failure with reduced ejection fraction (HFrEF) (ACCF/AHA [Yancy, 2013]): Oral:

Initial dose: 6.25 mg 3 times daily

Target dose: 50 mg 3 times daily

Hypertension: Oral:

Initial dose: 25 mg 2 to 3 times daily (a lower initial dose of 12.5 mg 3 times daily may also be considered [VA Cooperative Study Group, 1984]); may increase at 1- to 2-week intervals up to 50 mg 3 times daily; add thiazide diuretic, unless severe renal impairment coexists then consider loop diuretic, before further dosage increases or consider other treatment options; maximum dose: 150 mg 3 times daily

Target dose (JNC 8 [James, 2013]): 75 to 100 mg twice daily

Usual dose range (ASH/ISH [Weber, 2014]): 50 to 100 mg twice daily

LV dysfunction after MI: Oral: Initial: 6.25 mg; if tolerated, follow with 12.5 mg 3 times daily; then increase to 25 mg 3 times daily during next several days and then gradually increase over next several weeks to target dose of 50 mg 3 times daily (some dose schedules are more aggressive to achieve an increased goal dose within the first few days of initiation). Note: In those patients with STEMI in the anterior location, heart failure, or LV ejection fraction ≤ 0.4, an ACE inhibitor (eg, captopril) should be initiated within the first 24 hours after MI (ACCF/AHA [O'Gara, 2013]).

Diabetic nephropathy: Oral: Initial: 25 mg 3 times daily. May be taken with other antihypertensive therapy if required to further lower blood pressure.

Elderly: Hypertension: Consider lower initial doses and titrate to response (Aronow, 2011)

Dosage adjustment in renal impairment:

Manufacturers recommendations: Reduce initial daily dose and titrate slowly (1- to 2-week intervals) with smaller increments. Slowly back titrate to determine the minimum effective dose once the desired therapeutic effect has been reached.

Alternative recommendations (Aronoff, 2007):

Infants, Children, and Adolescents: Note: Renally adjusted dose recommendations are based on doses of 0.1 to 0.5 mg/kg/dose every 6 to 8 hours; maximum daily dose: 6 mg/kg/day.

GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of dose

GFR <10 mL/minute/1.73 m2: Administer 50% of dose

Intermittent hemodialysis: Administer 50% of dose

Peritoneal dialysis (PD): Administer 50% of dose

Adults:

CrCl 10 to 50 mL/minute: Administer at 75% of normal dose every 12-18 hours.

CrCl <10 mL/minute: Administer at 50% of normal dose every 24 hours.

Intermittent hemodialysis (IHD): Administer after hemodialysis on dialysis days

Peritoneal dialysis: Dose for CrCl 10-50 mL/minute; supplemental dose is not necessary

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Extemporaneously Prepared

A 1 mg/mL oral solution may be made by allowing two 50 mg tablets to dissolve in 50 mL of distilled water. Add the contents of one 500 mg sodium ascorbate injection ampul or one 500 mg ascorbic acid tablet and allow to dissolve. Add quantity of distilled water sufficient to make 100 mL. Label “shake well” and “refrigerate”. Stable for 56 days refrigerated.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer at least 1 hour before meals. Unstable in aqueous solutions; to prepare solution for oral administration, mix prior to administration and use within 10 minutes (Allen, 1996).

Dietary Considerations

Should be taken at least 1 hour before eating.

Storage

Store at 20°C to 25°C (68°F to 77°F); protect from moisture.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of ACE Inhibitors. Aliskiren may enhance the hypotensive effect of ACE Inhibitors. Aliskiren may enhance the nephrotoxic effect of ACE Inhibitors. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Allopurinol: ACE Inhibitors may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of ACE Inhibitors. Angiotensin II Receptor Blockers may increase the serum concentration of ACE Inhibitors. Management: In US labeling, use of telmisartan and ramipril is not recommended. It is not clear if any other combination of an ACE inhibitor and an ARB would be any safer. Consider alternatives to the combination when possible. Consider therapy modification

Antacids: May decrease the serum concentration of Captopril. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprotinin: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

AzaTHIOprine: ACE Inhibitors may enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of ACE Inhibitors. Canagliflozin may enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

Ciprofloxacin (Systemic): ACE Inhibitors may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of ACE Inhibitors. Monitor therapy

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DPP-IV Inhibitors: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Drospirenone: ACE Inhibitors may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Everolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Ferric Gluconate: ACE Inhibitors may enhance the adverse/toxic effect of Ferric Gluconate. Monitor therapy

Gold Sodium Thiomalate: ACE Inhibitors may enhance the adverse/toxic effect of Gold Sodium Thiomalate. An increased risk of nitritoid reactions has been appreciated. Monitor therapy

Grass Pollen Allergen Extract (5 Grass Extract): ACE Inhibitors may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). Specifically, ACE inhibitors may increase the risk of severe allergic reaction to Grass Pollen Allergen Extract (5 Grass Extract). Consider therapy modification

Heparin: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Icatibant: May diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

Iron Dextran Complex: ACE Inhibitors may enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Consider therapy modification

Lanthanum: May decrease the serum concentration of ACE Inhibitors. Management: Administer angiotensin-converting enzyme inhibitors at least two hours before or after lanthanum. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lithium: ACE Inhibitors may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Consider therapy modification

Loop Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Loop Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: ACE Inhibitors may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of ACE Inhibitors. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Pregabalin: ACE Inhibitors may enhance the adverse/toxic effect of Pregabalin. Specifically, the risk of angioedema may be increased. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sacubitril: ACE Inhibitors may enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Avoid combination

Salicylates: May enhance the nephrotoxic effect of ACE Inhibitors. Salicylates may diminish the therapeutic effect of ACE Inhibitors. Monitor therapy

Sirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

Sodium Phosphates: ACE Inhibitors may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ACEIs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Temsirolimus: May enhance the adverse/toxic effect of ACE Inhibitors. Monitor therapy

Thiazide Diuretics: May enhance the hypotensive effect of ACE Inhibitors. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

TiZANidine: May enhance the hypotensive effect of ACE Inhibitors. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of ACE Inhibitors. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Test Interactions

Positive Coombs' [direct]; may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent

Adverse Reactions

Frequency not defined:

Cardiovascular: Angina pectoris, cardiac arrest, cardiac arrhythmia, cardiac failure, flushing, myocardial infarction, orthostatic hypotension, Raynaud's phenomenon, syncope

Central nervous system: Ataxia, cerebrovascular insufficiency, confusion, depression, drowsiness, myasthenia, nervousness

Dermatologic: Bullous pemphigoid, erythema multiforme, exfoliative dermatitis, pallor, Stevens-Johnson syndrome

Endocrine & metabolic: Gynecomastia, hyponatremia (symptomatic)

Gastrointestinal: Cholestasis, dyspepsia, glossitis, pancreatitis

Genitourinary: Impotence, nephrotic syndrome, oliguria, urinary frequency

Hematologic & oncologic: Agranulocytosis, anemia, pancytopenia, thrombocytopenia

Hepatic: Hepatic necrosis (rare), hepatitis, increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases, jaundice

Hypersensitivity: Anaphylactoid reaction, angioedema

Neuromuscular & skeletal: Myalgia, weakness

Ophthalmic: Blurred vision

Renal: Polyuria, renal failure, renal insufficiency

Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis

1% to 10%:

Cardiovascular: Hypotension (1% to 3%), chest pain (1%), palpitations (1%), tachycardia (1%)

Dermatologic: Skin rash (maculopapular or urticarial [4% to 7%]; in patients with rash, a positive ANA and/or eosinophilia has been noted in 7% to 10%), pruritus (2%)

Endocrine & metabolic: Hyperkalemia (1% to 11%)

Gastrointestinal: Dysgeusia (2% to 4%; loss of taste or diminished perception)

Genitourinary: Proteinuria (1%)

Hematologic & oncologic: Neutropenia (≤4%; in patients with renal insufficiency or collagen-vascular disease)

Hypersensitivity: Hypersensitivity reaction (rash, pruritus, fever, arthralgia, and eosinophilia: 4% to 7%; depending on dose and renal function)

Renal: Increased serum creatinine, renal insufficiency (worsening; may occur in patients with bilateral renal artery stenosis or hypovolemia)

Respiratory: Cough (<1% to 2%)

Miscellaneous: Hypersensitivity reactions (rash, pruritus, fever, arthralgia, and eosinophilia) have occurred in 4% to 7% of patients (depending on dose and renal function); dysgeusia - loss of taste or diminished perception (2% to 4%)

<1% (Limited to important or life-threatening): Alopecia, angina pectoris, anorexia, aphthous stomatitis, aplastic anemia, cholestatic jaundice, eosinophilia, glomerulonephritis, Guillain-Barre syndrome, hemolytic anemia, Huntington's chorea (exacerbation), hyperthermia, increased erythrocyte sedimentation rate, insomnia, interstitial nephritis, Kaposi's sarcoma, peptic ulcer, pericarditis, psoriasis, seizure (in premature infants), systemic lupus erythematosus, vasculitis, visual hallucination (Doane, 2013)

ALERT: U.S. Boxed Warning

Fetal toxicity:

When pregnancy is detected, discontinue captopril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: At any time during treatment (especially following first dose) angioedema may occur rarely with ACE inhibitors; it may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). African-Americans and patients with idiopathic or hereditary angioedema may be at an increased risk. Risk may also be increased with concomitant use of mTOR inhibitor (eg, everolimus) therapy. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Use in patients with previous angioedema associated with ACE inhibitor therapy is contraindicated.

• Cholestatic jaundice: A rare toxicity associated with ACE inhibitors includes cholestatic jaundice, which may progress to fulminant hepatic necrosis (some fatal); discontinue if marked elevation of hepatic transaminases or jaundice occurs.

• Cough: An ACE inhibitor cough is a dry, hacking, nonproductive one that usually occurs within the first few months of treatment and should generally resolve within 1 to 4 weeks after discontinuation of the ACE inhibitor. Other causes of cough should be considered (eg, pulmonary congestion in patients with heart failure) and excluded prior to discontinuation.

• Hematologic effects: Captopril has been associated with neutropenia with myeloid hypoplasia and agranulocytosis; anemia and thrombocytopenia have also occurred. Patients with renal impairment are at high risk of developing neutropenia. Patients with both renal impairment and collagen vascular disease (eg, systemic lupus erythematosus) are at an even higher risk of developing neutropenia. Closely monitor CBC with differential for the first 3 months of therapy and periodically thereafter in these patients. Onset of neutropenia is usually within 3 months of captopril initiation. Neutrophil count generally returns to baseline within 2 weeks of discontinuation. If neutropenia develops (neutrophil count <1,000/mm3), discontinue therapy.

• Hyperkalemia: May occur with ACE inhibitors; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.

• Hypersensitivity reactions: Anaphylactic/anaphylactoid reactions can occur with ACE inhibitors. Severe anaphylactoid reactions may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of anaphylactoid reactions have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur with ACE inhibitors (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation.

• Proteinuria: Total urinary proteins greater than 1 g per day have been reported (<1%); nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months (whether or not captopril was continued).

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in BUN and serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small benign increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function (Bakris, 2000).

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.

• Collagen vascular disease: Use with caution in patients with collagen vascular disease especially with concomitant renal impairment; may be at increased risk for hematologic toxicity.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition (ACCF/AHA [Gersh, 2011]).

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution in preexisting renal insufficiency; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Black patients: ACE inhibitors effectiveness is less in black patients than in non-blacks. In addition, ACE inhibitors cause a higher rate of angioedema in black than in non-black patients.

• Pregnancy: [U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

Other warnings/precautions:

• Extemporaneous oral solutions: Extemporaneous preparations of liquid formulations may vary; this may affect the rate and extent of absorption causing intrapatient variability regarding dosing and safety profile for the patient; use with caution and monitor closely if dosage formulations are changed (Bhatt, 2011; Mulla, 2007).

• Surgery: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis, 2011).

Monitoring Parameters

BUN, electrolytes, serum creatinine; blood pressure. In patients with renal impairment and/or collagen vascular disease, closely monitor CBC with differential for the first 3 months of therapy and periodically thereafter.

2013 ACCF/AHA Heart Failure guideline recommendations: Within 1-2 weeks after initiation and periodically thereafter, reassess renal function and serum potassium especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, azotemia, or those taking potassium supplements (ACCF/AHA [Yancy, 2013]).

Pregnancy Risk Factor

D

Pregnancy Considerations

[U.S. Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Captopril crosses the placenta (Hurault de Lingy 1987). Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Their use in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Teratogenic effects may occur following maternal use of an ACE inhibitor during the first trimester, although this finding may be confounded by maternal disease. Because adverse fetal events are well documented with exposure later in pregnancy, ACE inhibitor use in pregnant women is not recommended (Seely 2014; Weber 2014). Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.

Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant and mother. ACE inhibitors are not recommended for the treatment of uncomplicated hypertension in pregnancy (ACOG 2013) and they are specifically contraindicated for the treatment of hypertension and chronic heart failure during pregnancy by some guidelines (Regitz-Zagrosek 2011). In addition, ACE inhibitors should generally be avoided in women of reproductive age (ACOG 2013). If treatment for hypertension or chronic heart failure in pregnancy is needed, other agents should be used (ACOG 2013; Regitz-Zagrosek 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weak, shortness of breath, numbness or tingling feeling), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), severe dizziness, passing out, cough that will not go away, severe abdominal pain, severe nausea, vomiting, angina, tachycardia, bruising, bleeding, or loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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