Captopril/Hydrochlorothiazide

Description

Captopril and hydrochlorothiazide tablets, USP, are formulated for oral administration and combine two antihypertensive agents: captopril and hydrochlorothiazide. Captopril is a specific competitive inhibitor of angiotensin I-converting enzyme (ACE), which plays a crucial role in the conversion of angiotensin I to angiotensin II. Hydrochlorothiazide is classified as a benzothiadiazide (thiazide) diuretic-antihypertensive.

Captopril, USP, is characterized as a white to off-white crystalline powder with a distinctive sulfide-like odor. It exhibits high solubility in water, ethanol, methanol, chloroform, isopropyl alcohol, and methylene chloride, and is also soluble in ethyl acetate. It can dissolve in dilute solutions of alkali hydroxide. Chemically, captopril is designated as 1-(2S)-3-Mercapto-2-methylpropionyl-L-proline.

Hydrochlorothiazide, USP, appears as a white or almost white, nearly odorless crystalline powder. It is very slightly soluble in water, sparingly soluble in ethanol and methanol, and soluble in acetone. Hydrochlorothiazide is freely soluble in N,N-Dimethylformamide, n-butylamine, and diluted solutions of alkali hydroxides, while it is practically insoluble in ether, chloroform, and diluted mineral acids. Its chemical designation is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

Captopril and hydrochlorothiazide tablets are available in four combinations: 25 mg captopril with 15 mg hydrochlorothiazide, 25 mg captopril with 25 mg hydrochlorothiazide, 50 mg captopril with 15 mg hydrochlorothiazide, and 50 mg captopril with 25 mg hydrochlorothiazide. Each tablet contains inactive ingredients including anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), and sodium lauryl sulfate. The 25 mg/25 mg and 50 mg/25 mg formulations also include FD&C Yellow No. 6 Aluminum Lake.

Uses and Indications

Captopril and hydrochlorothiazide tablets are indicated for the treatment of hypertension. The blood pressure-lowering effects of captopril and thiazides are approximately additive, allowing for effective management of blood pressure.

This fixed combination may be utilized as initial therapy or as a substitution for previously titrated doses of the individual components. When administered together, it may not be necessary to give captopril in divided doses to achieve adequate blood pressure control at trough levels (before the next dose). A daily dose of 15 mg of hydrochlorothiazide may be sufficient when used in conjunction with captopril.

Treatment initiation may commence with captopril and hydrochlorothiazide tablets 25 mg/15 mg once daily. Subsequent titration can be achieved with additional doses of the individual components (captopril, hydrochlorothiazide) or through the fixed combination in strengths of 50 mg/15 mg, 25 mg/25 mg, or 50 mg/25 mg.

Captopril and hydrochlorothiazide are suitable for patients with normal renal function, where the risk of adverse effects is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, this combination should be reserved for hypertensive patients who have either experienced unacceptable side effects from other antihypertensive medications or have not responded satisfactorily to alternative drug combinations.

Dosage and Administration

Dosage must be individualized according to the patient's response. Captopril and hydrochlorothiazide tablets may be substituted for the previously titrated individual components. Alternatively, therapy may be initiated with a single tablet of captopril and hydrochlorothiazide 25 mg/15 mg taken once daily.

For patients who are insufficiently responsive to the initial dose, additional captopril or hydrochlorothiazide may be added as individual components or by using captopril and hydrochlorothiazide tablets in the following strengths: 50 mg/15 mg, 25 mg/25 mg, or 50 mg/25 mg. Divided doses may also be utilized as necessary.

It is important to note that the full effect of a given dose may not be attained for 6 to 8 weeks; therefore, dosage adjustments should generally be made at 6-week intervals, unless the clinical situation necessitates more rapid adjustment. In general, daily doses of captopril should not exceed 150 mg, and daily doses of hydrochlorothiazide should not exceed 50 mg.

Captopril and hydrochlorothiazide tablets should be taken one hour before meals to optimize absorption.

For patients with renal impairment, dosage adjustments may be required. These patients may respond to smaller or less frequent doses of captopril and hydrochlorothiazide. Once 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 established.

Contraindications

This product is contraindicated in patients with a known hypersensitivity to captopril or any other angiotensin-converting enzyme (ACE) inhibitor, particularly those who have experienced angioedema during therapy with any ACE inhibitor.

Hydrochlorothiazide is contraindicated in patients with anuria and in individuals who have previously shown hypersensitivity to hydrochlorothiazide or other sulfonamide-derived medications.

Warnings and Precautions

Patients receiving ACE inhibitors, including captopril, may experience serious adverse reactions, including anaphylactoid and related reactions. It is crucial for healthcare professionals to be vigilant for signs of these reactions, as they can be life-threatening.

Angioedema Angioedema involving the tongue, glottis, or larynx poses a significant risk of airway obstruction and can be fatal. In such cases, emergency therapy, including the subcutaneous administration of a 1:1000 solution of epinephrine, should be promptly instituted. Additionally, intestinal angioedema has been reported in patients treated with ACE inhibitors, typically presenting with abdominal pain; symptoms generally resolve upon discontinuation of the medication.

Desensitization Reactions Patients undergoing desensitization while on ACE inhibitors have experienced life-threatening anaphylactoid reactions. Therefore, caution is advised when considering desensitization protocols for these patients.

Neutropenia and Agranulocytosis Captopril use has been associated with neutropenia (defined as a white blood cell count of less than 1000/mm³) and myeloid hypoplasia, particularly in individuals with renal failure or collagen vascular diseases. Regular monitoring of white blood cell counts is recommended, and if neutropenia is confirmed, captopril should be withdrawn immediately.

Fetal and Neonatal Risks ACE inhibitors can cause significant fetal and neonatal morbidity and mortality when administered to pregnant women. It is imperative to discontinue the medication as soon as pregnancy is detected to mitigate these risks.

Hepatic Failure Rare cases of hepatic failure associated with cholestatic jaundice progressing to fulminant hepatic necrosis have been reported. If patients exhibit jaundice or marked elevations in hepatic enzymes, discontinuation of captopril is warranted.

General Precautions Patients with impaired renal function may experience increases in blood urea nitrogen (BUN) and serum creatinine levels, necessitating dosage adjustments or discontinuation of therapy. There is also a risk of hyperkalemia in patients with renal insufficiency, diabetes, or those using potassium-sparing diuretics or supplements. Healthcare providers should monitor serum electrolyte levels regularly.

A persistent nonproductive cough may occur in some patients, which typically resolves after discontinuation of therapy. Additionally, during major surgery or anesthesia, captopril may inhibit angiotensin II formation, potentially leading to hypotension.

Monitoring and Reporting Patients should be instructed to report any signs of infection, such as sore throat or fever. If infection is suspected, white blood cell counts should be performed without delay. In the event of confirmed neutropenia, captopril should be withdrawn.

Side Effects

Adverse reactions associated with captopril and hydrochlorothiazide have been observed in clinical trials and postmarketing experiences, with varying degrees of seriousness and frequency.

Serious Adverse Reactions:

Captopril has been associated with angioedema, which can involve the extremities, face, lips, mucous membranes, tongue, glottis, or larynx, occurring in approximately one in 1000 patients. Notably, angioedema involving the upper airways has led to fatal airway obstruction. Other serious cardiovascular events reported include cardiac arrest, cerebrovascular accident/insufficiency, and rhythm disturbances. Patients may also experience renal complications such as renal failure and nephrotic syndrome, with renal insufficiency reported in about 1 to 2 of 1000 patients.

Hydrochlorothiazide has been linked to serious hematologic reactions, including agranulocytosis, thrombocytopenia, and aplastic anemia. Additionally, hypersensitivity reactions such as anaphylactic reactions and necrotizing angiitis (vasculitis) have been documented.

Common Adverse Reactions:

In clinical trials, captopril has shown that approximately 4 to 7 of 100 patients may develop a rash, often accompanied by pruritus, fever, arthralgia, and eosinophilia, particularly during the first four weeks of therapy. Other dermatologic reactions include flushing or pallor in 2 to 5 of 1000 patients and pruritus without rash in about 2 of 100 patients. Dysgeusia, characterized by a diminution or loss of taste perception, has been reported in approximately 2 to 4 of 100 patients, typically reversible within 2 to 3 months.

Hydrochlorothiazide has been associated with gastrointestinal symptoms such as anorexia, nausea, vomiting, and diarrhea. Central nervous system effects, including dizziness and headache, have also been reported. Orthostatic hypotension is a common cardiovascular reaction.

Other Notable Adverse Reactions:

Captopril may cause renal adverse effects, with proteinuria occurring in about one of 100 patients. Hematologic reactions include neutropenia/agranulocytosis, with cases of anemia and thrombocytopenia reported. Gastrointestinal disturbances such as gastric irritation and abdominal pain have been noted in about 0.5 to 2 percent of patients.

Hydrochlorothiazide has been associated with metabolic changes, including hyperglycemia and hyperuricemia, as well as muscle spasms and weakness. Postmarketing data indicate an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma, in white patients receiving large cumulative doses.

Fetal/Neonatal Considerations:

Both captopril and hydrochlorothiazide carry warnings regarding fetal and neonatal morbidity and mortality when administered to pregnant women, necessitating careful consideration of their use in this population.

Overall, healthcare providers should monitor patients for these adverse reactions and weigh the benefits against the risks when prescribing these medications.

Drug Interactions

Captopril and hydrochlorothiazide exhibit several significant drug interactions that may necessitate careful monitoring and dosage adjustments.

Captopril Interactions

Pharmacodynamic Interactions:

• Diuretics: Patients on diuretics, particularly those recently initiated on therapy or those with severe dietary salt restrictions or undergoing dialysis, may experience significant hypotension after the first dose of captopril. Close monitoring of blood pressure is advised.

• Vasodilators: The concomitant use of other vasodilators (e.g., nitroglycerin) with captopril is not well-studied. If these agents are used, they should be administered cautiously and potentially at reduced dosages.

• Renin-Releasing Agents: Antihypertensive agents that stimulate renin release, such as thiazide diuretics, may enhance the effects of captopril. Monitoring of blood pressure is recommended.

• Sympathetic Activity Modulators: Caution is advised when using agents that affect sympathetic activity (e.g., ganglionic blockers) alongside captopril, as they may further lower blood pressure. Beta-adrenergic blockers may provide additional antihypertensive effects, but the overall response may be less than additive.

• Potassium-Increasing Agents: Captopril can elevate serum potassium levels due to decreased aldosterone production. Potassium-sparing diuretics and potassium supplements should only be used for documented hypokalemia and with caution.

Pharmacokinetic Interactions:

• Lithium: The combination of captopril and lithium may lead to increased serum lithium levels and toxicity. Frequent monitoring of serum lithium levels is recommended.

• Prostaglandin Synthesis Inhibitors: Non-steroidal anti-inflammatory drugs (NSAIDs) like indomethacin may reduce the antihypertensive effect of captopril, particularly in low renin hypertension.

Other Interactions:

• Gold: Rare nitritoid reactions have been reported in patients receiving injectable gold alongside captopril.

• Diagnostic Tests: Captopril may cause a false-positive urine test for acetone.

Hydrochlorothiazide Interactions

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, Narcotics: These substances may potentiate orthostatic hypotension when used with hydrochlorothiazide.

• Electrolyte Imbalance Agents: Amphotericin B, corticosteroids, and ACTH may exacerbate electrolyte imbalances, particularly hypokalemia. Potassium levels should be monitored, and replacements used as necessary.

• Anticoagulants: Hydrochlorothiazide may diminish the effects of oral anticoagulants, necessitating dosage adjustments.

• Antigout Medications: Dosage adjustments may be required for antigout medications due to potential increases in blood uric acid levels.

• Other Antihypertensives: Hydrochlorothiazide may enhance the effects of other antihypertensive agents, requiring dosage adjustments.

• Antidiabetic Agents: Thiazides can elevate blood glucose levels, which may necessitate adjustments in antidiabetic medication dosages.

• Calcium Salts: Increased serum calcium levels may occur; monitoring and dosage adjustments of calcium supplements are advised.

• Cardiac Glycosides: There is an increased risk of digitalis toxicity associated with hypokalemia; potassium levels should be monitored.

• Non-steroidal Anti-inflammatory Agents: The effectiveness of hydrochlorothiazide may be reduced by NSAIDs, requiring close observation of diuretic efficacy.

Pharmacokinetic Interactions:

• Lithium: Hydrochlorothiazide may reduce renal clearance of lithium, increasing the risk of toxicity. Frequent monitoring of serum lithium levels is recommended.

• Cholestyramine and Colestipol Resins: These agents can significantly impair the absorption of hydrochlorothiazide, reducing its effectiveness.

• Pressor Amines: Hydrochlorothiazide may decrease the responsiveness to pressor amines, although this does not preclude their therapeutic use. Caution is advised during surgical procedures.

• Methenamine: The effectiveness of methenamine may be decreased due to urine alkalinization.

Diagnostic Test Interactions:

• Hydrochlorothiazide may interfere with the bentiromide test, leading to diagnostic inaccuracies.

In summary, careful consideration of these interactions is essential for optimizing therapeutic outcomes and minimizing adverse effects when prescribing captopril and hydrochlorothiazide. Regular monitoring and appropriate dosage adjustments are recommended based on the specific interactions noted.

Packaging & NDC

The table below lists all NDC Code configurations of Captopril and Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of captopril in pediatric patients have not been established. Limited experience with captopril in the pediatric population indicates that dosages, based on weight, are generally comparable to or less than those used in adults.

Particular caution is warranted in infants, especially newborns, who may be more susceptible to the adverse hemodynamic effects of captopril. Reports have indicated that excessive, prolonged, and unpredictable decreases in blood pressure can occur, leading to complications such as oliguria and seizures.

Captopril, in combination with hydrochlorothiazide, should be considered for use in pediatric patients only when other measures for controlling blood pressure have proven ineffective.

Geriatric Use

Elderly patients may exhibit increased sensitivity to the side effects of captopril and hydrochlorothiazide, necessitating cautious use of these medications in this population. It is important to consider that geriatric patients often have reduced kidney function, which can significantly impact the pharmacokinetics of both captopril and hydrochlorothiazide.

Due to the potential for renal impairment, dosage adjustments may be required for elderly patients, particularly those with compromised renal function. Regular monitoring of renal function is strongly recommended for geriatric patients receiving these medications to ensure safety and efficacy.

Additionally, the risk of hypotension may be heightened in elderly patients, especially in those who are volume-depleted or concurrently using diuretics. Careful monitoring for signs of hypotension is advised.

Furthermore, elderly patients should be closely observed for signs of infection, as neutropenia has been associated with captopril use, and this risk may be elevated in the geriatric population.

Pregnancy

Female patients of childbearing age should be informed about the potential consequences of exposure to ACE inhibitors during the second and third trimesters of pregnancy. It is important to note that these consequences do not appear to arise from intrauterine exposure to ACE inhibitors that is limited to the first trimester.

Patients are encouraged to report any pregnancies to their healthcare providers as soon as possible to ensure appropriate management and monitoring.

Lactation

Both captopril and hydrochlorothiazide are excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants from both medications, lactating mothers should carefully consider whether to discontinue nursing or to discontinue therapy. This decision should take into account the importance of captopril and hydrochlorothiazide to the mother’s health.

Renal Impairment

Evaluation of the hypertensive or heart failure patient should always include assessment of renal function. In patients with impaired renal function, if captopril is utilized, it is essential to evaluate white blood cell and differential counts prior to initiating treatment and at approximately two-week intervals for about three months, followed by periodic assessments.

Captopril should be administered with caution in patients with collagen vascular disease or those exposed to other drugs known to affect white cells or the immune response, particularly when renal function is compromised. All patients receiving captopril must be instructed to report any signs of infection, such as sore throat or fever. In cases where infection is suspected, white cell counts should be performed without delay.

Upon confirmation of neutropenia (neutrophil count < 1000/mm³), captopril should be discontinued, as the withdrawal of captopril and other drugs has generally led to a prompt return of the white count to normal.

Total urinary proteins greater than 1 g per day were observed in approximately 0.7 percent of patients treated with captopril, with about 90 percent of these patients having evidence of prior renal disease or receiving relatively high doses of captopril (exceeding 150 mg/day), or both. Nephrotic syndrome occurred in about one-fifth of proteinuric patients, although in most cases, proteinuria subsided or cleared within six months, regardless of whether captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in patients with proteinuria.

Excessive hypotension, while rarely seen in hypertensive patients, remains a potential consequence of captopril use in salt/volume depleted individuals (such as those vigorously treated with diuretics), patients with heart failure, or those undergoing renal dialysis. Additionally, thiazides should be used with caution in severe renal disease, as they may precipitate azotemia and cumulative effects of the drug may develop in patients with impaired renal function.

Hepatic Impairment

Patients with hepatic impairment should be closely monitored when receiving treatment with ACE inhibitors. Rarely, these medications have been associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, which may result in death. The underlying mechanism of this syndrome remains unclear. Therefore, if patients receiving ACE inhibitors develop jaundice or exhibit marked elevations in hepatic enzymes, the ACE inhibitor should be discontinued immediately, and appropriate medical follow-up should be initiated.

In addition, thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful monitoring and potential dosage adjustments.

Overdosage

In cases of overdosage with captopril, the primary concern is the correction of hypotension. The recommended treatment involves volume expansion through an intravenous infusion of normal saline to restore blood pressure effectively.

Captopril can be removed from the adult circulation via hemodialysis; however, there is insufficient data regarding its efficacy in neonates or children. It is important to note that peritoneal dialysis is ineffective for the removal of captopril, and there is no available information on the use of exchange transfusion for this purpose.

Hydrochlorothiazide overdosage may lead to significant diuresis and varying degrees of lethargy, which can progress to coma within a few hours. This condition typically presents with minimal depression of respiration and cardiovascular function, and there is often no evidence of serum electrolyte changes or dehydration. The mechanism behind thiazide-induced central nervous system (CNS) depression remains unclear. Additionally, gastrointestinal irritation and hypermotility may occur, along with a transitory increase in blood urea nitrogen (BUN). Serum electrolyte changes may be observed, particularly in patients with impaired renal function.

Management of hydrochlorothiazide overdosage should include gastric lavage and supportive therapy for stupor or coma. Symptomatic treatment for gastrointestinal effects may also be necessary. The extent to which hemodialysis can remove hydrochlorothiazide has not been clearly established. Therefore, it is crucial to implement measures to maintain hydration, electrolyte balance, and ensure proper respiratory, cardiovascular, and renal function as required.

Nonclinical Toxicology

No teratogenic effects have been identified in the studies conducted.

Captopril has been evaluated in studies involving rats, which demonstrated no impairment of fertility. Similarly, hydrochlorothiazide did not exhibit adverse effects on the fertility of both male and female mice and rats when administered via diet at doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Carcinogenicity and fertility studies specifically involving captopril and hydrochlorothiazide tablets have not been performed; however, individual components have undergone such evaluations in animal studies. Captopril, when tested in a 2:1 combination with hydrochlorothiazide, was found to be non-mutagenic and non-clastogenic in various in vitro assays, both with and without metabolic activation. A cytogenetics study utilizing human lymphocytes revealed no significant increases in chromosomal abnormalities, regardless of metabolic activation at 28 hours post-treatment. Although a statistically significant increase in chromosomal abnormalities was observed at 22 hours with metabolic activation at three tested concentrations, the absence of a dose-response relationship suggests that this finding may be attributed to an unusual lack of abnormalities in the negative-control cultures.

In an oral micronucleus study conducted in mice, the captopril/hydrochlorothiazide combination (2:1 mixture at a total weight of 2500 mg/kg) did not demonstrate genotoxicity.

Animal studies assessing the carcinogenic potential of captopril involved two-year evaluations with doses ranging from 50 to 1350 mg/kg/day in mice and rats, which did not reveal any evidence of carcinogenicity. Similarly, two-year feeding studies with hydrochlorothiazide in mice and rats showed no evidence of carcinogenic potential in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to approximately 100 mg/kg/day. However, the National Toxicology Program (NTP) reported equivocal evidence for hepatocarcinogenicity in male mice. Hydrochlorothiazide was not found to be genotoxic in in vitro assays, with positive results occurring only in specific assays at certain concentrations.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, as reported in postmarketing surveillance. Data from a study conducted within the Sentinel System indicate that the elevated risk is primarily linked to squamous cell carcinoma (SCC), particularly among white patients receiving large cumulative doses. The overall population exhibits an approximate risk increase of 1 additional case of SCC per 16,000 patients per year. Notably, for white patients who have taken a cumulative dose of 50,000 mg or more, the risk escalates to approximately 1 additional case of SCC for every 6,700 patients per year.

Patient Counseling

Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema, which may include swelling of the face, eyes, lips, tongue, larynx, and extremities, as well as difficulty in swallowing or breathing and hoarseness. They should be instructed to discontinue therapy if such symptoms occur.

Patients must be informed to promptly report any indications of infection, such as a sore throat or fever, as these may be signs of neutropenia. Additionally, they should be vigilant for signs of progressive edema, which might be related to proteinuria and nephrotic syndrome.

All patients should be cautioned that excessive perspiration and dehydration can lead to a significant drop in blood pressure due to reduced fluid volume. They should also be aware that other causes of volume depletion, such as vomiting or diarrhea, may similarly result in a fall in blood pressure, and should consult with their physician if these situations arise.

Patients should be advised against using potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes without prior consultation with their physician. Furthermore, they should be warned against interrupting or discontinuing their medication unless specifically instructed by their physician.

Heart failure patients on captopril therapy should be cautioned against making rapid increases in physical activity. It is important for patients to understand that captopril and hydrochlorothiazide tablets should be taken one hour before meals to ensure optimal absorption.

Female patients of childbearing age should be informed about the potential consequences of exposure to ACE inhibitors during the second and third trimesters of pregnancy. They should be reassured that such consequences do not appear to arise from intrauterine exposure limited to the first trimester. These patients should be encouraged to report any pregnancies to their physicians as soon as possible.

Lastly, it is essential that serum electrolyte levels be regularly monitored to ensure patient safety and medication efficacy.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. The container must be kept tightly closed to protect the contents from moisture and maintain product integrity.

Additional Clinical Information

Serum electrolyte levels in patients should be regularly monitored during treatment. Clinicians are advised to refer to the WARNINGS section regarding Captopril and Hydrochlorothiazide, as well as the PRECAUTIONS section under General for Hydrochlorothiazide, for further guidance on monitoring protocols.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Captopril and Hydrochlorothiazide as submitted by Rising Pharma Holdings, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)