ADVERSE REACTIONS

Reported incidences are based on clinical trials involving approximately 7000 patients.

Renal: About one of 100 patients developed proteinuria (seeWARNINGS).

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 (seeWARNINGS). 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 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; seeWARNINGS andPRECAUTIONS: 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 andPRECAUTIONS: Information for Patients.)

Cough: Cough has been reported in 0.5 to 2% of patients treated with captopril in clinical trials (seePRECAUTIONS: 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 (seeWARNINGS: Anaphylactoid and Possible Related Reactions andPRECAUTIONS: 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.

Fetal/Neonatal Morbidity and Mortality

SeeWARNINGS: Fetal/Neonatal Morbidity and Mortality.

Altered Laboratory Findings

Serum Electrolytes: Hyperkalemia: Small increases in serum potassium, especially in patients with renal impairment (seePRECAUTIONS).

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 long-standing 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 Funtion Tests: Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of captopril has not yet been fully elucidated. Its beneficial effects in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.

Captopril prevents the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. This inhibition has been demonstrated in both healthy human subjects and in animals by showing that the elevation of blood pressure caused by exogenously administered angiotensin I was attenuated or abolished by captopril. In animal studies, captopril did not alter the pressor responses to a number of other agents, including angiotensin II and norepinephrine, indicating specificity of action.

ACE is identical to “bradykininase,” and captopril may also interfere with the degradation of the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril.

Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss.

The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood.

Pharmacokinetics

After oral administration of therapeutic doses of captopril, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40 percent; captopril therefore should be given one hour before meals. Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24-hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is unchanged drug; most of the remainder is the disulfide dimer of captopril and captopril-cysteine disulfide.

Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate determination of half-life of unchanged captopril is not, at present, possible, but it is probably less than 2 hours. In patients with renal impairment, however, retention of captopril occurs (seeDOSAGE AND ADMINISTRATION).

Pharmacodynamics

Administration of captopril results in a reduction of peripheral arterial resistance in hypertensive patients with either no change, or an increase in cardiac output. There is an increase in renal blood flow following administration of captopril and glomerular filtration rate is usually unchanged.

Reductions of blood pressure are usually maximal 60 to 90 minutes after oral administration of an individual dose of captopril. The duration of effect is dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of captopril and thiazide-type diuretics are additive. In contrast, captopril and beta-blockers have a less than additive effect.

Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients. Abrupt withdrawal of captopril has not been associated with a rapid increase in blood pressure.

In patients with heart failure, significantly decreased peripheral (systemic vascular) resistance and blood pressure (afterload), reduced pulmonary capillary wedge pressure (preload) and pulmonary vascular resistance, increased cardiac output, and increased exercise tolerance time (ETT) have been demonstrated. These hemodynamic and clinical effects occur after the first dose and appear to persist for the duration of therapy. Placebo controlled studies of 12 week duration in patients who did not respond adequately to diuretics and digitalis show no tolerance to beneficial effects on ETT; open studies, with exposure up to 18 months in some cases, also indicate that ETT benefit is maintained. Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal.

The Survival and Ventricular Enlargement (SAVE) study was a multicenter, randomized, double-blind, placebo-controlled trial conducted in 2,231 patients (age 21-79 years) who survived the acute phase of myocardial infarction and did not have active ischemia. Patients had left ventricular dysfunction (LVD), defined as a resting left ventricular ejection fraction ≤40%, but at the time of randomization were not sufficiently symptomatic to require ACE inhibitor therapy for heart failure. About half of the patients had had symptoms of heart failure in the past. Patients were given a test dose of 6.25 mg oral captopril and were randomized within 3-16 days post-infarction to receive either captopril or placebo in addition to conventional therapy. Captopril was initiated at 6.25 mg or 12.5 mg t.i.d. and after two weeks titrated to a target maintenance dose of 50 mg tid. About 80% of patients were receiving the target dose at the end of the study. Patients were followed for a minimum of two years and for up to five years, with an average follow-up of 3.5 years.

Baseline blood pressure was 113/70 mmHg and 112/70 mmHg for the placebo and captopril groups, respectively. Blood pressure increased slightly in both treatment groups during the study and was somewhat lower in the captopril group (119/74 vs. 125/77 mmHg at 1 yr).

Therapy with captopril improved long-term survival and clinical outcomes compared to placebo. The risk reduction for all cause mortality was 19% (P=0.02) and for cardiovascular death was 21% (P=0.014). Captopril treated subjects had 22% (P=0.034) fewer first hospitalizations for heart failure. Compared to placebo, 22% fewer patients receiving captopril developed symptoms of overt heart failure. There was no significant difference between groups in total hospitalizations for all cause (2056 placebo; 2036 captopril).

Captopril was well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calcium antagonists and diuretics.

In a multicenter, double-blind, placebo controlled trial, 409 patients, age 18-49 of either gender, with or without hypertension, with type I (juvenile type, onset before age 30) insulin-dependent diabetes mellitus, retinopathy, proteinuria ≥500 mg per day and serum creatinine ≤2.5 mg/dL, were randomized to placebo or captopril (25 mg t.i.d.) and followed for up to 4.8 years (median 3 years). To achieve blood pressure control, additional antihypertensive agents (diuretics, beta blockers, centrally acting agents or vasodilators) were added as needed for patients in both groups.

The captopril group had a 51% reduction in risk of doubling of serum creatinine (P<0.01) and a 51% reduction in risk for the combined endpoint of end-stage renal disease (dialysis or transplantation) or death (P<0.01). Captopril treatment resulted in a 30% reduction in urine protein excretion within the first 3 months (P<0.05), which was maintained throughout the trial. The captopril group had somewhat better blood pressure control than the placebo group, but the effect of captopril on renal function were greater than would be expected from the group differences in blood pressure reduction alone. Captopril was well tolerated in this patient population.

In two multicenter, double-blind, placebo controlled studies, a total of 235 normotensive patients with insulin-dependent diabetes mellitus, retinopathy and microalbuminuria (20-200 mcg/min) were randomized to placebo or captopril (50 mg b.i.d.) and followed for up to 2 years. Captopril delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both studies (risk reduction 67% to 76%; P<0.05). Captopril also reduced the albumin excretion rate. However, the long term clinical benefit of reducing the progression from microalbuminuria to proteinuria has not been established.

Studies in rats and cats indicate that captopril does not cross the blood- brain barrier to any significant extent.