SAIPRIL

Captopril is a potent, competitive inhibitor of angiotensin-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII).

ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS).

Captopril may be used in the treatment of hypertension.

For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics).

May be used to treat congestive heart failure in combination with other drugs (e.g. cardiac glycosides, diuretics, β-adrenergic blockers).

May improve survival in patients with left ventricular dysfunction following myocardial infarction.

May be used to treat nephropathy, including diabetic nephropathy.

Captopril, an ACE inhibitor, antagonizes the effect of the RAAS.

RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance.

During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys.

In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE.

ATII increases blood pressure using a number of mechanisms.

First, it stimulates the secretion of aldosterone from the adrenal cortex.

Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes.

Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland.

ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules.

Third, ATII increases blood pressure through direct arterial vasoconstriction.

Stimulation of the

Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction.

In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons.

ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure.

ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator.

Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure.

60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant).

Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril.

Metabolites may undergo reversible interconversion.

Hover over products below to view reaction partners Captopril captopril-cysteine disulfide.

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Symptoms of overdose include emesis and decreased blood pressure.

Side effects include dose-dependent rash (usually maculopapular), taste alterations, hypotension, gastric irritation, cough, and angioedema.

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including captopril) may be subject to a variety of adverse reactions, some of them serious.

Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including captopril.

If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.

Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted.

Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of treatment; some cases required medical therapy.

Intestinal angioedema has been reported in patients treated with ACE inhibitors.

These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.

The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Neutropenia/Agranulocytosis: Neutropenia (< 1000/mm 3 ) 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 vascular 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 foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with captopril has been associated with neutropenia but this association has not appeared in U.S. reports.

In patients with collagen vascular diseases (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 usually 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/mm 3 ) the physician should withdraw captopril and closely follow the patient’s course.

Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients receiving captopril.

About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of captopril (in excess of 150 mg/day), or both.

The 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.

Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.

Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of captopril use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis.

Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women.

Several dozen cases have been reported in the world literature.

When pregnancy is detected, ACE inhibitors 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; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed.

Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of captopril as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found.

In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, captopril should be discontinued unless it is considered life-saving for the mother.

Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories 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 disordered renal function.

While captopril may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children.

Peritoneal dialysis is not effective for removing captopril; there is no information concerning exchange transfusion for removing captopril from the general circulation.

When captopril was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen.

No teratogenic effects of captopril were seen in studies of pregnant rats and hamsters.

On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose.

Rarely, ACE Inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.

The mechanism of this syndrome is not understood.

Patients receiving

ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Thiazides should be used with caution in severe renal disease.

In patients with renal disease, thiazides may precipitate azotemia.

Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

In general, lithium should not be given with diuretics.

This product is contraindicated in patients who are hypersensitive to captopril or any other angiotensin-converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

Hydrochlorothiazide is contraindicated in anuria.

It is also contraindicated in patients who have previously demonstrated hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs.

& ADMINISTRATION DOSAGE MUST BE INDIVIDUALIZED ACCORDING TO PATIENT'S RESPONSE.

Captopril and hydrochlorothiazide tablets may be substituted for the previously titrated individual components.

Alternatively, therapy may be instituted with a single tablet of captopril and hydrochlorothiazide 25 mg/15 mg taken once daily.

For patients insufficiently responsive to the initial dose, additional captopril or hydrochlorothiazide may be added as individual components or by using captopril and hydrochlorothiazide tablets 50 mg/15 mg, 25 mg/25 mg or 50 mg/25 mg, or divided doses may be used.

Because the full effect of a given dose may not be attained for to 8 weeks, dosage adjustments should generally be made at 6 week intervals, unless the clinical situation demands more rapid adjustment.

In general, daily doses of captopril should not exceed 150 mg and of hydrochlorothiazide should not exceed 50 mg. Captopril and hydrochlorothiazide tablets should be taken one hour before meals.

Because captopril and hydrochlorothiazide are 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 of captopril and hydrochlorothiazide.

After the desired therapeutic effect has been achieved, the dose intervals should be increased or the total daily dose reduced until the minimal effective dose is achieved.

When concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic is preferred for use with captopril; therefore, for patients with severe renal dysfunction the captopril-hydrochlorothiazide combination tablet is not usually recommended. See WARNINGS: Captopril: Anaphylactoid Reactions During Membrane Exposure and PRECAUTIONS: Hemodialysis.

Tablets, USP are available containing 25 mg or 50 mg of captopril, USP with 15 mg or 25 mg of hydrochlorothiazide, USP providing the following available combinations: 25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg or 50 mg/25 mg. The 25 mg/15 mg tablets are supplied as a white, round, biconvex tablet debossed with ‘R over 27’ on one side of the tablet and quadrisect scored on the other side.

They are available as follows

Bottles of 90 tablets.

• NDC 16571-827-09 The 25 mg/25 mg tablets are supplied as a peach, round, biconvex tablet debossed with ‘R over 28’ on one side of the tablet and quadrisect scored on the other side.

• NDC 16571-828-09 The 50 mg/15 mg tablets are supplied as a white, capsule-shaped, biconvex tablet debossed with ‘ R ’ to the left of the partial score and ‘ 29 ’ to the right of the partial score on one side of the tablet and partially scored on the other side.

• NDC 16571-829-09 The 50 mg/25 mg tablets are supplied as a peach, capsule-shaped, biconvex tablet debossed with R to the left of the partial score and to the right of the partial score on one side of the tablet and partially scored on the other side.

• NDC 16571-830-09 Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Keep container tightly closed.

Store at 20° to 25°C (68° to 77°F).

Protect from moisture.

Manufactured for

Brunswick, NJ 08816 Issued: 12/2022 200640 PIR83001-00.

Female patients of childbearing age should be told about the consequences of second.

• and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester.

These patients should be asked to report pregnancies to their physicians as soon as possible.

Both captopril and hydrochlorothiazide are excreted in human milk.

Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of captopril and hydrochlorothiazide to the mother.

Safety and effectiveness in pediatric patients have not been established.

There is limited experience reported in the literature with the use of captopril in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults.

Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of captopril.

Excessive, prolonged and un-predictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported.

Captopril and hydrochlorothiazide should be used in pediatric patients only if other measures for controlling blood pressure have not been effective.