Capoten

Following oral administration of therapeutic doses of captopril, rapid absorption occurs with peak blood levels at about 1 hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40%. Based on C-14 labeling, average minimal absorption is approximately 70 to 75%. In a 24-hour period, over 95% of the absorbed dose is eliminated in the urine; 40 to 50% is unchanged drug although it appears this percentage may be smaller in patients with congestive heart failure; most of the remainder is the disulfide dimer of captopril and captopril-cysteine disulfide.

Approximately 25 to 30% of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is about 4 hours. The half-life of unchanged captopril is approximately 2 hours.

In patients with normal renal function, absorption and disposition of a labeled dose are not altered after 7 days of captopril administration. In patients with renal impairment, however, retention of captopril occurs (see Dosage).

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 (see Warnings).

When feasible the hypotensive effects may be minimized by either discontinuing the diuretic or increasing the salt intake approximately 1 week prior to initiation of treatment with captopril. Alternatively, provide medical supervision for at least 1 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.

In heart failure, special caution is necessary since sympathetic stimulation is a vital component supporting circulatory function and inhibition with beta-blockade always carries a potential hazard of further depressing myocardial contractility.

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 which contain potassium should also be used with caution.

Inhibitors of Endogenous Prostaglandin Synthesis: It has been reported that indomethacin may reduce the antihypertensive effect of captopril, especially in cases of low renin hypertension. Other nonsteroidal anti-inflammatory agents (e.g., ASA) may also have this effect.

The blood pressure lowering effects of captopril and beta-blockers are less than additive.

In patients with renal failure, the use of allopurinol concomitantly with captopril has been associated with neutropenia.

In patients with heart failure, the use of procainamide concomitantly with captopril has been associated with neutropenia.

Safety and effectiveness in children have not been established although there is limited experience with the use of captopril in children from 2 months to 15 years of age with secondary hypertension and varying degrees of renal insufficiency. Dosage, on a weight basis, was comparable to that used in adults. Captopril should be used in children only if other measures for controlling blood pressure have not been effective.

Captopril may cause false-positive reactions for urinary acetone and for dipstick tests for urinary ketones.

Patients should be told that taking captopril during pregnancy can cause injury and even death to the developing fetus. Patients should be advised to stop taking the medication and to contact their physician as soon as possible if they become pregnant while taking captopril.

Patients should be advised that captopril may pass into breast milk and that they should not breast-feed while taking captopril.

Patients should be told to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign of neutropenia, or of progressive edema, which might be related to proteinuria and nephrotic syndrome.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.

Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include viral like symptoms in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Patients should be warned against interruption or discontinuation of antihypertensive medications without the physician's advice.

Patients treated for severe congestive heart failure should be cautioned to increase their physical activity slowly.

Each white, oval tablet, biconvex with a full bisecting score on one side and imprinted CAPOTEN  50 on the other, contains: captopril 50 mg. Nonmedicinal ingredients: cornstarch, lactose, microcrystalline cellulose and stearic acid. Bottles of 100. Store at room temperature (15 to 30°C). Protect from moisture. Keep bottles tightly closed.

Each white, square tablet, quadrisect scored on one side and imprinted CAPOTEN  25 on the other, contains: captopril 25 mg. Nonmedicinal ingredients: cornstarch, lactose, microcrystalline cellulose and stearic acid. Bottles of 100. Store at room temperature (15 to 30°C). Protect from moisture. Keep bottles tightly closed.

The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breat-feeding.

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, captopril should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, patent ductus arteriosus, and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function, however, limited experience with those procedures has not been associated with significant clinical benefit.

Captopril may be removed from the general circulation by hemodialysis.

Animal Data: Captopril was embryocidal in rabbits when given in doses 2 to 70 times (on a mg/kg basis) the maximum recommended human dose, and low incidences of craniofacial malformations were seen. These effects in rabbits were most probably due to the particularly marked decrease in blood pressure caused by the drug in this species. Captopril was also embryocidal in sheep when given in doses similar to those given in humans. Captopril given to pregnant rats at 400 times the recommended human dose continuously during gestation and lactation caused a reduction in neonatal survival.

No teratogenic effects have been observed after large doses of captopril were administered to hamsters and rats.

Approximately 1 of every 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, polyuria, oliguria and urinary frequency.

pancreatitis, glossitis.

anemia, including aplastic and hemolytic.

myalgia, myasthenia.

asthenia, gynecomastia.

ataxia, confusion, depression, nervousness, somnolence.

Angioedema of the face, mucous membranes of the mouth, or of the extremities has been observed in approximately 1 of 1000 patients and is reversible on discontinuance of captopril therapy. Serum sickness and bronchospasm have been reported. One case of laryngeal edema has been reported.

blurred vision.

As with other ACE inhibitors, a syndrome has been reported which includes: fever, myalgia, arthralgia, rash or other dermatologic manifestations, eosinophilia and an elevated ESR. Findings have usually resolved with discontinuation of treatment.

Altered Laboratory Findings: Elevations of liver enzymes and/or serum bilirubin have occurred (see Precautions).

Rare cases of cholestatic jaundice and hepatocellular injury with or without secondary cholestasis, have been reported in association with captopril administration.

Elevation of BUN and serum creatinine may occur, especially in patients who are volume-depleted or who have renovascular hypertension. In instances of rapid reduction of long-standing or severely elevated blood pressure, the glomerular filtration rate may decrease transiently, also resulting in transient rises in serum creatinine and BUN.

Small increases in the serum potassium concentration frequently occur, especially in patients with renal impairment (see Precautions).

Diabetic Nephropathy: In 400 patients treated with captopril, the overall adverse reactions profile appeared to be similar to the above. However, the following adverse reactions have occurred more frequently in women than in men: dizziness (31% vs 20%), cough (23% vs 17%) and pharyngitis (20% vs 14%). In 395 patients treated with placebo, the incidences were: dizziness (22%), cough (15%) and pharyngitis (11%) in women and men combined.

The incidence of hypotension or orthostatic hypotension was 5.3% and was a reason for discontinuation of the drug in 1.8% of the patients.

The incidence of hyperkalemia related or possibly related to therapy in the diabetic patients studied with nephropathy and proteinuria was 3.6% and was a reason of discontinuation of the drug in 1% of the patients. Hyperkalemia was defined as persistent elevation of serum potassium to 6.0 mg/dL or more in the absence of a remediable cause, such as other drugs, volume depletion, exogenous potassium supplements, etc.

In patients with serum creatinine ≥1.5 mg/dL, the incidence of a marked abnormality in hemoglobin (a drop >3 g/dL) was 6% in patients treated with captopril versus 0% in those on placebo.

dizziness, headache, malaise, fatigue, insomnia and paresthesia.

bronchospasm, eosinophilic pneumonitis, rhinitis.

dry mouth, dyspnea, cough, alopecia, impotence, loss of libido, disturbed vision, and itching and/or dry eyes.

Other clinical adverse effects reported since the drug was marketed are listed below by body system. In many cases, an incidence or causal relationship cannot be accurately determined.

bullous pemphigus, Stevens-Johnson syndrome.

symptomatic hyponatremia.

2% of patients receiving 150 mg or less per day of captopril developed a diminution or loss of taste perception. At doses in excess of 150 mg/day, 7% of patients experienced this effect. 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.

The following have been reported in about 0.5 to 2% of patients:

hepatitis, including rare cases of necrosis, cholestasis (see Precautions).

cardiac arrest, cerebrovascular accident, syncope.

In the event of overdosage, correction of hypotension would be of primary concern. Volume expansion with an i.v. infusion of normal saline is the treatment of choice for restoration of blood pressure.

Captopril may be removed from the general circulation by hemodialysis.