NOVO-CAPTORIL (captopril) is an angiotensin converting enzyme inhibitor which is used in the treatment of hypertension and heart failure. The mechanism of action of captopril has not yet been fully elucidated. It appears to lower blood pressure and be an adjunct in the therapy of congestive heart failure primarily through 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 carboxyhydrolase. ACE is identical to "bradykininase" and captopril may also interfere with the degradation of the vasopressor peptide, bradykinin. However, the effectiveness of captopril in therapeutic doses appears to be unrelated to potentiation of the actions of bradykinin. Increased concentrations of bradykinin or prostaglandin E2 may also have a role in the therapeutic effect of captopril, especially in low-renin hypertension. 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. 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. In instances of rapid reduction of long-standing or severely elevated blood pressure, the glomerular filtration rate may decrease transiently. Peak reductions of blood pressure usually occur within 60 to 90 minutes after oral administration of a single dose of captopril. The duration of effect appears to be 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 appear to be 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. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black patients than in non-blacks. In patients with heart failure captopril significantly decreased systemic vascular resistance (afterload), reduced pulmonary capillary wedge pressure (preload) and pulmonary vascular resistance, increased cardiac output (stroke index), and increased exercise tolerance time (ETT). Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal. Studies in rats and cats indicate that captopril does not cross the blood-brain barrier to any significant extent.

Following 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. Based on carbon-14 labeling, average minimal absorption is approximately 70-75 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 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 percent 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 seven days of captopril administration. In patients with renal impairment, however, retention of captopril occurs (see DOSAGE AND ADMINISTRATION).

A single dose two-way, crossover study was performed to compare the rate and extent of absorption and bioequivalence of NOVO-CAPTORIL 100 mg tablets with Capoten(r) 100 mg tablets. The pharmacokinetic plasma data (mean +- standard deviation) calculated for the two products are tabulated below: NOVO-CAPTORIL CAPOTEN(r) PERCENTAGE

Cmax * (ng/mL) 2807 (19) 2981 (23) 94 Tmax+ 0.84 (0.23) 0.98 (0.31) - (h) T1/2+ 4.16 (0.66) 4.00 (1.16) - (h)

NOVO-CAPTORIL (captopril) is indicated for the treatment of essential or renovascular hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive. In using NOVO-CAPTORIL, consideration should be given to the risk of neutropenia/ agranulocytosis (see WARNINGS).

NOVO-CAPTORIL should normally be used in those patients in whom treatment with diuretic or beta-blockers was found ineffective or has been associated with unacceptable adverse effects. NOVO-CAPTORIL can be tried as an initial agent in those patients with severe hypertension or in those in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which those drugs frequently cause serious adverse effects. In patients with impaired renal function: In these patients, 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 (see PRECAUTIONS).

NOVO-CAPTORIL is indicated in the treatment of congestive heart failure as concomitant therapy with a diuretic in patients who have not responded adequately to digitalis and diuretics or in whom the administration of digitalis is contraindicated or has been associated with unacceptable side effects. NOVO-CAPTORIL therapy must be initiated under close medical supervision.

CONTRAINDICATIONS

NOVO-CAPTORIL (captopril) is contraindicated in patients with a history of hypersensitivity to the drug and in patients with a history of angioedema related to previous treatment with an Angiotensin Converting Enzyme inhibitor.

WARNINGS

When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, NOVO-CAPTORIL should be discontinued as soon as possible.

Angioedema has been reported in patients treated with ACE inhibitors, including captopril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, captopril should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS). The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see CONTRAINDICATIONS).

Total urinary proteins greater than 1 g per day were seen in less than one percent of patients receiving captopril. These have been predominantly in those who had prior renal disease, or in those receiving relatively high doses (in excess of 150 mg per day), or both. In patients without prior evidence of renal disease, the incidence of proteinuria was 0.5 percent. In those patients without prior evidence of renal disease receiving 150 mg of captopril or less per day, the incidence was 0.2 percent. Parameters of renal function, such as BUN and serum creatinine, were seldom altered in the patients with proteinuria. In most cases, proteinuria subsided or cleared within 6 months whether or not captopril was continued, but some patients had persistent proteinuria. Nephrotic syndrome occurred in about one-fifth of the proteinuric patients. Membranous glomerulopathy was found in biopsies taken from proteinuric patients. A causal relationship to captopril has not been established since pre-treatment biopsies were not taken and membraneous glomerulopathy has been shown to occur in hypertensive patients not receiving captopril. Since most cases of proteinuria occurred by the eighth month of therapy, patients with prior renal disease or those receiving captopril at doses greater than 150 mg per day should have urinary protein estimations (dipstick on first morning urine or quantitative 24-hour urine) prior to therapy, at approximately monthly intervals for the first nine months of treatment, and periodically thereafter. When proteinuria is persistent, 24-hour quantitative determinations provide greater precision. For patients who develop proteinuria exceeding 1 g/day, or proteinuria that is increasing, the benefits and risks of continuing captopril should be evaluated.

Neutropenia (< 1000/mm3) with myeloid hypoplasia has resulted from use of captopril. About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. The risk of neutropenia is dependent on the clinical status of the patient: In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen disease), neutropenia has been seen in one patient out of over 8,600 exposed. In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of captopril were relatively high in these patients, particularly in view of their diminished renal function. In patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia. In patients with collagen vascular disease (e.g., systemic lupus, erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients in clinical trials. While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. About half of the reported cases had serum creatinine > 1.6 mg/dL and more than 75 percent were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present. The neutropenia has been detected within three months after captopril was started. Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes (e.g. hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen. In general, neutrophils returned to normal in about two weeks after captopril was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors. Evaluation of the hypertensive or heart failure patient should always include assessment of renal function. If captopril is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically. In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then with caution. All patients treated with captopril should be told to report any signs of infection (e.g. sore throat, fever). If infection is suspected, white cell counts should be performed without delay. Since discontinuation of captopril and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count < 1000/mm3) the physician should withdraw captopril and closely follow the patient's course. Since captopril decreases aldosterone production, elevation of serum potassium may occur rarely, especially in patients with renal failure (See PRECAUTIONS - Drug Interactions).

Excessive hypotension was seen in hypertensive patients but is a possible consequence of captopril use in severely salt/volume depleted persons such as those treated vigorously with diuretics, for example patients with severe congestive heart failure (see Precautions [Drug Interactions]). In heart failure, where the blood pressure was either normal or low, decreases in mean blood pressure greater than 20 percent were recorded in about half of the patients. This transient hypotension may occur after any of the first several doses and produces either no symptoms or brief mild lightheadedness, although in rare instances, it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6% of patients with heart failure. BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS, THERAPY SHOULD BE STARTED UNDER CLOSE MEDICAL SUPERVISION. A low starting dose may minimize the hypotensive effect (see DOSAGE AND ADMINISTRATION). Patients should be followed closely for the first two weeks of treatment and whenever the dose of NOVO-CAPTORIL, or diuretic, is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. Hypotension in itself is not a reason to discontinue NOVO-CAPTORIL. If associated symptoms are troublesome or persist, they are usually relieved by a reduction in the dose of either captopril or diuretic.

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, NOVO-CAPTORIL 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.

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.

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

PRECAUTIONS

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk. Use of NOVO-CAPTORIL (captopril) should include appropriate assessment of renal function.

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including captopril. When treated with ACE inhibitors, patients at risk for the development of hyperkalemia include those with: renal insufficiency; diabetes mellitus; and those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or other drugs associated with increases in serum potassium (e.g., heparin). 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 for 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.

Elevations of liver enzymes and/or serum bilirubin, cases of cholestatic jaundice, and of hepatocellular injury with or without secondary cholestasis, have occurred during therapy with captopril in patients without pre-existing liver abnormalities. In most cases the changes were reversible on discontinuation of the drug. Should the patient receiving NOVO-CAPTORIL experience any unexplained symptoms (see Information for Patients), particularly during first weeks or months of treatment, it is recommended that a full set of liver enzyme tests and other necessary investigations be carried out. Discontinuation of NOVO-CAPTORIL should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. NOVO- CAPTORIL should be used with particular caution in patients with pre-existent liver abnormalities. Such patients should have their baseline liver function test obtained before administration of the drug. Close monitoring of response and metabolic effects should apply to these patients.

Cough has been reported with the use of captopril. Characteristically, ACE-inhibitor induced cough is nonproductive, persistent and resolves after discontinuation of therapy or lowering of the dose. captopril induced cough should be considered as part of the differential diagnosis of the cough.

There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, captopril will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension, which can be corrected by volume expansion.

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g. polyacrylonitrile (PAN)) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

There have been isolated reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.

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. NOVO-CAPTORIL should be used in children only if other measures for controlling blood pressure have not been effective.

Patients should be told that taking NOVO-CAPTORIL 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 NOVO-CAPTORIL.

Patients should be advised that NOVO-CAPTORIL may pass into breast milk and that they should not breast-feed while taking NOVO-CAPTORIL. 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. Patients should be told that for the management of a suspected drug overdose, they should contact their regional Poison Control Centre.

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 one week prior to initiation of treatment with NOVO-CAPTORIL. 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.

Data on the effect of concomitant use of other vasodilators in patients receiving captopril for heart failure are not available; therefore, nitroglycerine or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting NOVO-CAPTORIL. If resumed during NOVO-CAPTORIL therapy, such agents should be administered cautiously, and perhaps at lower dosage.

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.

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.

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.

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. acetylsalicylic acid) 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.

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

ADVERSE REACTIONS

Hypertension and Congestive Heart Failure

Reported incidences are based on clinical trials involving approximately 7,000 patients treated with captopril.

Renal:

Approximately one 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.

Hematologic:

Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopenia have been reported.

Dermatologic:

A rash occurred in 8.5 percent of patients with normal renal function and 13 percent of patients with evidence of prior renal functional impairment. It was dose related, having occurred in 7 percent of patients at doses of 150 mg or less per day. The rash is usually maculopapular, but rarely urticarial, and generally occurs during the first four weeks of therapy. 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.

Allergic:

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.

Cardiovascular:

Hypotension may occur; see WARNINGS and PRECAUTIONS [Drug Interactions] for discussion of hypotension on initiation of 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. Flushing or pallor has been reported in 2 to 5 of 1000 patients.

Alterations in Taste:

Two percent 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 per day, 7 percent 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 percent of patients:

Gastro-Intestinal:

gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers and peptic ulcer.

Central Nervous System: dizziness, headache, malaise, fatigue, insomnia and paresthesia. Others: 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.

General:

asthenia, gynecomastia

Cardiovascular: cardiac arrest, cerebrovascular accident, syncope Dermatologic: bullous pemphigus, Stevens-Johnson syndrome Gastrointestinal: pancreatitis, glossitis

Hematologic:

anemia, including aplastic and hemolytic

Hepatobiliary:

hepatitis, including rare cases of necrosis, cholestasis (see PRECAUTIONS)

Metabolic: symptomatic hyponatremia Musculoskeletal: myalgia, myasthenia

Nervous/psychiatric: ataxia, confusion, depression, nervousness, somnolence Respiratory: bronchospasm, eosinophilic pneumonitis, rhinitis Special senses: 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 of 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 longstanding 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).

SYMPTOMS AND TREATMENT OF OVERDOSAGE

In the event of overdosage, correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure. Captopril may be removed from the general circulation by hemodialysis. For management of a suspected drug overdose, contact your regional Poison Control Centre.

DOSAGE AND ADMINISTRATION

NOVO-CAPTORIL (captopril) tablets should be taken one hour before meals. DOSAGE MUST BE INDIVIDUALIZED.

ADULTS

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 NOVO-CAPTORIL (captopril). If this is impossible, especially in severe hypertension, the diuretic should be continued. The initial dose of NOVO-CAPTORIL is 25 mg b.i.d. or t.i.d. If a 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. The dose of NOVO-CAPTORIL in hypertension usually does not exceed 150 mg daily. 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 NOVO-CAPTORIL is being started in a patient already receiving a diuretic, NOVO- CAPTORIL therapy should be initiated under close medical supervision (see WARNINGS AND PRECAUTIONS [Drug Interactions] regarding hypotension), with dosage and titration of NOVO-CAPTORIL as noted above. In severe hypertension, if further blood pressure reduction is required, the dose of NOVO-CAPTORIL 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 given in three equally divided doses should not be exceeded. For patients with 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 concurrent antihypertensive medication stopped and NOVO-CAPTORIL dosage promptly initiated at 25 mg t.i.d., under close medical supervision. When necessitated by the patient's clinical condition, the daily dose of NOVO-CAPTORIL may be increased every 24 hours under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of NOVO-CAPTORIL 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 NOVO-CAPTORIL 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 NOVO-CAPTORIL should not be exceeded. NOVO-CAPTORIL is to be used in conjunction with a diuretic. NOVO-CAPTORIL therapy must be initiated under very close medical supervision.

DOSAGE ADJUSTMENT IN RENAL IMPAIRMENT

Because NOVO-CAPTORIL 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. Captopril is removed by hemodialysis.

Renal Impairment Not Due to Diabetic Nephropathy

For patients with significant renal impairment not due to diabetic nephropathy, initial daily dosage of NOVO-CAPTORIL 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 these patients with impaired renal function. (See PRECAUTIONS, Anaphylactoid reactions during membrane exposure) The following table which is based on theoretical considerations may be useful as a guide to minimize drug accumulation.

DOSAGE FORMS AND AVAILABILITY

NOVO-CAPTORIL (captopril) is available as tablets containing: 6.25 mg - white to off-white, round, flat face, bevel edge compressed tablets, engraved

on one side and plain on the other side.

12.5 mg - white, biconvex, capsule-shaped, compressed tablets, engraved 'no/vo' on one side, '12.5' on the reverse. 25 mg - white, square-shaped, compressed tablets, quadrisect scored on one side, engraved 'novo'and '25' on the other side. 50 mg - white, oval-shaped, bi-convex, single scored, compressed tablets, engraved 'no/vo' on one side, '50' on the other. 100 mg - white, oval-shaped, bi-convex, single scored, compressed tablets, engraved 'no/vo' on one side, '100' on the other side. Supplied in bottles of 100, 500 and 1000 and in boxes of 100 as unit dose strips for 12.5 mg, 25 mg, 50 mg and 100 mg strengths. Supplied in bottles of 100, 500 and 1000 for mg strength.

PHARMACEUTICAL INFORMATION
I.	Drug Substance
	Proper Name:	Captopril
	Trade Name:	NOVO-CAPTORIL
	Chemical Name:	1-[(2S)-3-mercapto-2-methylpropionyl]-P-L-proline
	Empirical Formula: Molecular Weight:	C 9 H 15 NO 3 S 217.2
	Structural Formula:

Description: Captopril is a white to off-white crystalline powder which may have a characteristic sulfide-like odour. It is freely soluble in water, methanol, alcohol and chloroform. The melting point is in the range of 104deg-110degC.
II.	Composition	In addition to the active ingredient, captopril, each tablet contains sodium starch glycolate, sodium lauryl sulfate, pregelatinized starch, colloidal silicone dioxide, microcrystalline cellulose and magnesium stearate.
III.	Storage	Store between 15-30degC in tightly closed bottles. Protect product from moisture. Store unit dose packages between 15-25degC and protect from high humidity.

PHARMACOLOGY

Captopril, administered orally, decreased mean blood pressure in intact spontaneously hypertensive rats, renal hypertensive rats, and renal hypertensive dogs. Captopril did not lower blood pressure in spontaneously and renal hypertensive rats that were bilaterally nephrectomized. In anesthetized intact dogs, intravenously administered captopril caused a decrease in blood pressure, coronary and peripheral vascular resistance, renal vascular resistance, and an increase in renal blood flow. Renal blood flow was found to increase following administration of single oral doses of 5 to 25 mg of captopril to normotensive sodium-depleted or sodium- loaded subjects and to sodium-depleted hypertensive patients. The greatest increase occurred in the hypertensive patients (average 45%, range 0-73%) while the least increase occurred in the sodium- loaded normotensive subjects (average 9%, range 8-54%). In a renal function study in monkeys with hyperplasia of the renal juxtoglomerular apparatus induced by chronic captopril therapy, the various indices of renal function were not compromised in comparison with control animals, despite the lower systemic blood pressure and the presence of the hyperplasia. Single 100 mg doses of captopril-14C were administered to 15 patients with various degrees of renal impairment (creatinine clearances ranging from 0 to 56 mL/minute). The blood half-life for the radioactivity was found to be inversely related to endogenous creatinine clearance with a linear relationship between creatinine clearance and the overall elimination rate constant for total radioactivity. In tissue-distribution studies in rats, the highest concentrations of orally- administered captopril were found in the kidney, liver, blood and lung. An increase in cerebral blood flow after captopril administration has been found in spontaneously hypertensive rats. In human studies, single oral doses of 2.5 to 20 mg of captopril produced 90 to 100% inhibition of pressor responses induced by intravenous administration of angiotensin I. Blockade was noted within 15 minutes. Captopril had no significant effect on the pressor response to angiotensin II. In clinical studies, during long-term therapy, approximately 80 to 85% of patients with chronic congestive heart failure exhibited sustained improvement in their functional status and progressive improvement in their ability to perform treadmill exercise.

TOXICOLOGY

Signs of toxicity in mice were respiratory depression, ataxia, convulsions, loss of grip strength, transient weight loss, edema of tail, collapse, and irritation at the site of intravenous injection. Signs of toxicity in rats were diarrhea, transient weight loss, cyanosis, ataxia and convulsions. Most deaths occurred within 1 day.

Chronic oral toxicity studies were conducted in rats (2 years), dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). Significant drug-related toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood vessels. Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at doses of 500 to 1500 mg/kg/day. Anemia, leukopenia, thrombocytopenia, and bone marrow depression occurred in dogs at doses of 80 to 300 mg/kg/day. The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (80 to 300 mg/kg/day) in dogs, whereas moderate to marked leukopenia was noted only at 150 to 300 mg/kg and thrombocytopenia at 300 mg/kg. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47-week study at a dose of 300 mg/kg/day, bone marrow suppression was found to be reversible upon continued drug administration. Captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys at doses 70 to 2000 mg/kg in rats and mice, at 200 to 600 mg/kg in monkeys and at 200 mg/kg/day in dogs. Gastric erosions ulcerations were increased in incidence at 200 and 2000 mg/kg doses in male rats and at 300 and 650 mg/kg doses in dogs and monkeys respectively. Rabbits developed gastric and intestinal ulcers when given oral doses of approximately 300 mg/kg for only 5 to 7 days. In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (70 to 2000 mg/kg/day) in a dose-related fashion. The effect was first observed in the 88th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing.

Comparison of captopril (SQ 14,225) with hydrochlorothiazide in the treatment of essential hypertension. Int. J. Clin. Pharmacol. Ther. Toxicol. 19:368-371, 1981. Ader R., Chatterjee K., Ports T., Brundage B., Hiramatsu B., Parmley B. Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulation 61:931- 937, 1980. Atkinson A.B., Brown J.J., Lever A.F., Robertson J.I.S. Combined treatment of severe intractable hypertension with captopril and diuretic. Lancet 2:105-108, 1980. Atkinson A.B., Robertson J.I.S. Benefits versus risks of captopril therapy. In: Recent Advances in Hypertension Therapy: Captopril H.R. Brunner & F. Gross eds. Amsterdam: Exerpta Medica 1981, pp. 50-69. Awan N.A., Amsterdam E.A., Hermanovich J., Bommer W.J., Needham K.E., Mason D.T. Long-term hemodynamic and clinical efficacy of captopril therapy in ambulatory management of severe chronic congestive heart failure. Amer. Heart J. 103(4):474-479, 1982. Bravo E.L., Tarazi R.C., Fouad F.M. Hemodynamic effects of long-term captopril therapy in hypertensive man. In: Angiotensin Converting Enzyme Inhibitors - Mechanisms of Action and Clinical Implications. Z.P. Horovitz, ed. Baltimore: Urban and Schwarzenberg, 1981, pp. 263-272. Captopril Collaborative Study Group. Does captopril cause renal damage in hypertensive patients? Lancet 1:988-990, 1982. Case D.B., Atlas S.A., Marion R.M., Laragh J.H. Long-term efficacy of captopril in renovascular and essential hypertension. Am. J. Cardiol. 49:1440-1446, 1982. Cowley A.J., Stainer K.L., Rowley J.M., Hampton J.R. Captopril therapy for heart failure. A placebo controlled study. Lancet 2: 730-732, 1982. Drayer J.I.M., Weber M.A. Monotherapy of essential hypertension with a converting-enzyme inhibitor. Supp III Hypertension 5(5): III-108 - III-113, 1983. Ferguson R.K., Rotmensch H.H., Vlasses P.H. Clinical use of captopril. J.A.M.A. 247(6):2117-2119, 1982. Ferguson R.K.,Vlasses P.H.,Koplin J.R.,Shirinian A., Burke J.F. Jr., Alexander J.C. Captopril in severe treatment-resistant hypertension. Am. Heart J. 99:579-585, 1980. Gronda E., Brusoni B., Mangiovacchi M., Oppizzi M., Inglese E., Caroli A. and Rovelli F. Haemodynamic, Radionuclide Ventriculography and Ergometric Evaluation of Captopril Treatment in Congestive Heart Failure. Postgrad. Med. J. 62(Suppl. 1): 167-169, 1986. Jenkins A.C. Captopril in Hypertension: Seven Years Later. J.Cardiovasc. Pharmacol. 7:S96- S101, 1985. MacGregor G.A., Markandu N.D., Banks R.A., Bayliss J., Roulston J.E., Jones J.C. Captopril in essential hypertension: contrasting effects of adding hydrochlorothiazide or propranolol. Br. Med. J. 284:693-696, 1982. Magnani B., Magelli C. Captopril in Mild Heart Failure: Preliminary Observations of a Long-Term, Double-Blind, Placebo-Controlled Multicentre Trial. Postgrad. Med. J. 62(Suppl. 1), 153-158, 1986. Maskill M.R., Orme M.L.E., MacIver M., Serlin M.J., Breckenridge A.M. Efficacy and adverse effects of captopril in severe refractory hypertension. J. Cardiovasc. Pharmacol. 3:1287-1295, 1981. Mason D.T. New strategies in the management of severe chronic heart failure: captopril. American Heart Journal 104(5) (Part 2):1125-1228, Nov. 1982. Massie B.M., Conway M. Survival of patients with Congestive Heart Failure: Past, Present and Future Prospects. Circulation 75(suppl. IV): IV II-IV19, 1987. Massie B., Kramer B.L., Topic N., Henderson S.G. Hemodynamic and radionuclide effects of acute captopril therapy for heart failure: changes in left and right ventricular volumes and function at rest and during exercise. Circulation 65:1374-1381, 1982. Millar J.A., McGrath B.P., Matthews P.G., Johnston C.I. Acute effects of captopril on blood pressure and circulating hormone levels in salt-replete and depleted normal subjects and essential hypertensive patients. Clin. Sci. 61:75-83, 1981. Rouleau J.L., Chatterjee K., Benge W., Parmley W.W., Hirainatsu B. Alterations in left ventricular function and coronary hemodynamics with captopril, hydralazine and prazosin in chronic ischemic heart failure: a comparative study. Circulation 65:671-680, 1982. Sharpe D.N., Coxon R.J., Douglas J.E., Long B. Low-dose captopril in chronic heart failure: acute haemodynamic effects and long-term treatment. Lancet 2:1154-1157, 1980.

AUC T : (ng h/mL)	1224 (29)	1313 (26)	93
AUC I : (ng h/mL)	1287 (34)	1366 (28)	94
C max * (ng/mL)	1022 (32)	1064 (26)	96
T max + (h)	0.66 (0.16)	0.73 (0.28)	-
T 1/2 + (h)	1.66 (1.75)	1.23 (1.30)	-
*Geometric means (CV)
+Arithmetic means (SD)
	NOVO-CAPTORIL	CAPOTEN(r)	PERCENTAGE
TOTAL DRUG	(1 x 100 mg)	(1 x 100 mg)	OF CAPOTEN
AUC T : (ng h/mL)	9321 (16)	9799 (17)	95
AUC I : (ng h/mL)	10,405 (16)	10,938 (18)	95

Species	Sex	Route of Administration	LD 50 (mg/kg)
Mouse	M F	oral oral	5650-7900 600-7300
Mouse	M F	i.v. i.v.	970-1130 810-1290
Mouse	M F	i.p. i.p.	270-415 340-490
Rat	M F	oral oral	6000 5500
Rat	M F	i.p. i.p.	410 380