Captopril/Hydrochlorothiazide

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, making this fixed combination drug suitable for use 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 blood pressure control at trough (before the next dose). A daily dose of 15 mg of hydrochlorothiazide may be adequate when used in combination with captopril. Treatment may be initiated with captopril and hydrochlorothiazide tablets at a dosage of 25 mg/15 mg once daily. Subsequent titration can be achieved with additional doses of the components as single agents or as captopril and hydrochlorothiazide tablets at dosages of 50 mg/15 mg, 25 mg/25 mg, or 50 mg/25 mg.

Captopril and hydrochlorothiazide may be used in patients with normal renal function, where the risk is relatively low. However, in patients with impaired renal function, particularly those with collagen vascular disease, this combination should be reserved for hypertensive patients who have either developed unacceptable side effects on other medications or have failed to respond satisfactorily to other 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. 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 strengths of 50 mg/15 mg, 25 mg/25 mg, or 50 mg/25 mg. Divided doses may also be utilized. 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 adjustments.

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.

For patients with impaired renal function, smaller or less frequent doses of captopril and hydrochlorothiazide may be required. After achieving the desired therapeutic effect, 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 who are hypersensitive to captopril or any other angiotensin-converting enzyme inhibitor, particularly in those who have experienced angioedema during therapy with any ACE inhibitor. Additionally, hydrochlorothiazide is contraindicated in patients with anuria and in those who have previously demonstrated hypersensitivity to hydrochlorothiazide or other sulfonamide-derived drugs.

Warnings and Precautions

Patients receiving ACE inhibitors, including captopril, may experience serious adverse reactions, including anaphylactoid and related reactions. Notably, head and neck angioedema can occur, which may involve the tongue, glottis, or larynx, leading to airway obstruction and potentially fatal outcomes. In such cases, emergency therapy, including the subcutaneous administration of a 1:1000 solution of epinephrine, should be promptly instituted. Intestinal angioedema has also been reported in patients treated with ACE inhibitors, presenting with abdominal pain; symptoms typically resolve upon discontinuation of the medication.

Life-threatening anaphylactoid reactions may occur in patients undergoing desensitization while on ACE inhibitors. Additionally, neutropenia or agranulocytosis, characterized by neutrophil counts below 1000/mm³ and myeloid hypoplasia, has been associated with captopril use, particularly in patients with renal failure or collagen vascular diseases.

Captopril poses risks of fetal and neonatal morbidity and mortality when administered to pregnant women; therefore, it should be discontinued as soon as pregnancy is detected. Rarely, hepatic failure has been linked to captopril, manifesting as cholestatic jaundice that can progress to fulminant hepatic necrosis; discontinuation is advised if jaundice or significant elevations in hepatic enzymes occur.

General Precautions

Patients with impaired renal function may experience increases in blood urea nitrogen (BUN) and serum creatinine levels, necessitating dosage reduction 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. A persistent nonproductive cough may develop during treatment but typically resolves after discontinuation. Captopril may interfere with angiotensin II formation during major surgery or anesthesia, potentially leading to hypotension.

Laboratory Tests

Regular monitoring of serum electrolyte levels is recommended to ensure patient safety.

Emergency Medical Help

Patients should seek emergency medical assistance if they experience angioedema involving the tongue, glottis, or larynx.

Reporting Symptoms

Patients are advised to report any signs of infection, such as sore throat or fever. If an infection is suspected, white blood cell counts should be performed without delay. In cases of confirmed neutropenia, captopril should be withdrawn immediately.

Side Effects

Patients receiving Captopril and Hydrochlorothiazide may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious Adverse Reactions

• Angioedema: Occurring in approximately 1 in 1000 patients, angioedema can involve the extremities, face, lips, mucous membranes, tongue, glottis, or larynx, with potential for fatal airway obstruction.

• Renal Complications: Serious renal effects such as renal failure, nephrotic syndrome, and renal insufficiency have been reported in 1 to 2 of 1000 patients.

• Hematologic Disorders: Neutropenia/agranulocytosis, along with cases of anemia, thrombocytopenia, and pancytopenia, have been documented.

• Fetal/Neonatal Risks: ACE inhibitors, including Captopril, can lead to fetal and neonatal morbidity and mortality when administered to pregnant women.

Common Adverse Reactions

• Dermatologic Reactions: Rash, often maculopapular, occurs in about 4 to 7 of 100 patients, typically within the first four weeks of therapy. Pruritus without rash is reported in about 2 of 100 patients. Eosinophilia and positive ANA titers have been observed in 7 to 10 percent of patients with skin rash.

• Gastrointestinal Symptoms: Reported in approximately 0.5 to 2 percent of patients, these include gastric irritation, abdominal pain, nausea, vomiting, diarrhea, and constipation.

• Cough: Cough has been reported in 0.5 to 2% of patients treated with Captopril in clinical trials.

• Dysgeusia: Approximately 2 to 4 of 100 patients may experience a reduction or loss of taste perception, which is usually reversible.

Less Common Adverse Reactions

• Cardiovascular Effects: Hypotension may occur, with tachycardia, chest pain, and palpitations observed in about 1 of 100 patients. Angina pectoris, myocardial infarction, and congestive heart failure have been reported in 2 to 3 of 1000 patients.

• Respiratory Issues: Bronchospasm and eosinophilic pneumonitis have been noted, along with cough and rhinitis.

• Central Nervous System Effects: Dizziness, headache, and somnolence have been reported, along with confusion and ataxia.

• Hematologic Effects: Hydrochlorothiazide may cause leukopenia, agranulocytosis, and aplastic anemia.

• Hypersensitivity Reactions: These include purpura, photosensitivity, rash, urticaria, and anaphylactic reactions.

Rare Adverse Reactions

• Dermatologic: Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), and exfoliative dermatitis have been reported.

• Hepatobiliary Disorders: Rare cases of jaundice, hepatitis, and cholestasis have been documented.

• Metabolic Effects: Symptomatic hyponatremia and hyperglycemia have been observed.

• Musculoskeletal Symptoms: Myalgia and muscle weakness have been reported.

• Urogenital Effects: Impotence has been noted in some patients.

Postmarketing Experience

Hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses.

Patients should be monitored for these adverse reactions, and any serious or concerning symptoms should be reported to a healthcare provider promptly.

Drug Interactions

Patients receiving captopril and hydrochlorothiazide should be aware of several potential drug interactions that may affect their treatment outcomes.

Captopril Interactions

Pharmacodynamic Interactions:

• Hypotension: Patients on diuretics, particularly those recently initiated on therapy or those with severe dietary salt restrictions or dialysis, may experience significant hypotension after the first dose of captopril.

• Vasodilators: The concomitant use of other vasodilators (e.g., nitroglycerin) may require caution, as data on their combined effects with captopril are limited. If these agents are resumed during captopril therapy, they should be administered at lower dosages.

• Renin-Release Agents: Antihypertensive agents that stimulate renin release, such as diuretics, may enhance the effects of captopril.

• Sympathetic Activity Modulators: Agents affecting sympathetic activity (e.g., ganglionic blockers) should be used cautiously, as they may further influence blood pressure control.

Electrolyte and Renal Interactions:

• Potassium Levels: Captopril can increase serum potassium levels due to decreased aldosterone production. Caution is advised when using potassium-sparing diuretics or potassium supplements.

• Lithium: Increased serum lithium levels and toxicity have been reported with concurrent use of lithium and captopril. Monitoring of serum lithium levels is recommended.

Other Interactions:

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

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

Hydrochlorothiazide Interactions

Pharmacodynamic Interactions:

• Orthostatic Hypotension: The use of alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension.

• Electrolyte Imbalance: Concomitant use of amphotericin B, corticosteroids, or ACTH may exacerbate electrolyte imbalances, particularly hypokalemia.

• Anticoagulants: Hydrochlorothiazide may decrease the effectiveness of oral anticoagulants, necessitating dosage adjustments.

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

Diabetes and Calcium Interactions:

• Antidiabetic Agents: Hydrochlorothiazide may elevate blood glucose levels, requiring adjustments in the dosages of antidiabetic medications.

• Calcium Salts: Increased serum calcium levels may occur; monitoring and dosage adjustments are advised if calcium supplementation is necessary.

Other Interactions:

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

• Non-steroidal Anti-inflammatory Agents: The effectiveness of hydrochlorothiazide may be reduced when used with NSAIDs, necessitating close observation of diuretic efficacy.

• Lithium: Similar to captopril, hydrochlorothiazide may reduce renal clearance of lithium, increasing the risk of toxicity.

• Pressor Amines: Caution is advised when using pressor amines, as hydrochlorothiazide may decrease arterial responsiveness.

Laboratory Test Interactions

• Captopril: May cause false-positive urine tests for acetone.

• Hydrochlorothiazide: Can interfere with the bentiromide test, affecting diagnostic accuracy.

Patients should be monitored closely for these interactions, and healthcare providers should consider necessary adjustments to therapy based on individual patient circumstances.

Pediatric Use

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

Infants, particularly newborns, may be more susceptible to the adverse hemodynamic effects of captopril. Reports indicate that excessive, prolonged, and unpredictable decreases in blood pressure can occur, leading to complications such as oliguria and seizures. Therefore, captopril and hydrochlorothiazide should be considered for use in pediatric patients only when other measures for controlling blood pressure have proven ineffective.

Geriatric Use

Captopril and hydrochlorothiazide should be used with caution in elderly patients due to the potential for increased sensitivity to side effects. Geriatric patients may exhibit reduced kidney function, which can significantly affect the pharmacokinetics of these medications. Therefore, dosage adjustments may be necessary, particularly for those with renal impairment.

Regular monitoring of renal function is recommended for elderly patients receiving this combination therapy. Additionally, the risk of hypotension may be heightened in this population, especially among those who are volume-depleted or concurrently using diuretics. It is also important to monitor elderly patients for signs of infection, as neutropenia has been associated with captopril use, and this risk may be elevated in geriatric patients.

Pregnancy

Female patients of childbearing age should be informed about the potential consequences of second- and third-trimester exposure to ACE inhibitors, including Captopril and Hydrochlorothiazide. Evidence suggests that exposure during these later trimesters may lead to adverse fetal outcomes. However, intrauterine exposure to ACE inhibitors limited to the first trimester does not appear to result in similar consequences.

It is recommended that these patients report any pregnancies to their healthcare providers as soon as possible to ensure appropriate management and monitoring throughout their pregnancy.

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 breastfeeding 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 renal function is essential in patients with renal impairment who are being considered for treatment with captopril and hydrochlorothiazide. Prior to initiating therapy, a thorough assessment of renal status should be conducted, and ongoing monitoring is crucial throughout the treatment period.

For patients with impaired renal function, it is recommended that white blood cell and differential counts be evaluated before starting captopril and at approximately two-week intervals for the first three months, followed by periodic assessments. In cases where patients have collagen vascular disease or are taking other medications that may affect white blood cells or immune response, captopril should be prescribed with caution after a careful evaluation of the potential benefits and risks.

Patients should be instructed to report any signs of infection, such as sore throat or fever, immediately. If an infection is suspected, white cell counts should be obtained without delay. In the event of confirmed neutropenia (neutrophil count < 1000/mm³), captopril should be discontinued, and the patient's condition should be closely monitored.

It is important to note that total urinary protein levels exceeding 1 g per day have been observed in approximately 0.7% of patients receiving captopril, particularly among those with pre-existing renal disease or those on higher doses (greater than 150 mg/day). While nephrotic syndrome occurred in about one-fifth of these proteinuric patients, most experienced a resolution of proteinuria within six months, regardless of whether captopril was continued. Parameters of renal function, such as blood urea nitrogen (BUN) and creatinine levels, were rarely affected in these cases.

Caution is advised when using thiazides in patients with severe renal disease, as they may precipitate azotemia and lead to cumulative effects. Additionally, captopril may cause excessive hypotension in patients who are salt/volume depleted, such as those receiving aggressive diuretic therapy, those with heart failure, or patients undergoing renal dialysis. Regular monitoring and appropriate dose adjustments are essential to ensure patient safety and therapeutic efficacy.

Hepatic Impairment

Patients with hepatic impairment may experience significant risks when treated with Captopril and Hydrochlorothiazide. ACE inhibitors, including Captopril, have been rarely associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, potentially resulting in death. The underlying mechanism of this syndrome remains unclear. Therefore, it is crucial for patients receiving ACE inhibitors to be monitored for the development of jaundice or marked elevations in hepatic enzymes. If such symptoms occur, the ACE inhibitor should be discontinued immediately, and appropriate medical follow-up should be initiated.

Thiazide diuretics, such as Hydrochlorothiazide, should also 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. Regular monitoring of liver function tests and electrolyte levels is recommended to ensure patient safety and to adjust treatment as necessary.

Overdosage

In cases of overdose with Captopril and Hydrochlorothiazide, the primary concern is the correction of hypotension. Volume expansion with an intravenous infusion of normal saline is recommended as the treatment of choice for restoring blood pressure.

Captopril may be removed from the adult circulation through hemodialysis; however, there is insufficient data regarding its effectiveness in neonates or children. Peritoneal dialysis is not effective for the removal of captopril, and there is no information available on the efficacy of exchange transfusion for this purpose.

Hydrochlorothiazide overdose may lead to varying degrees of lethargy, potentially progressing to coma within a few hours. This condition is typically accompanied by minimal depression of respiration and cardiovascular function, and there may be no evidence of serum electrolyte changes or dehydration. The mechanism behind thiazide-induced central nervous system depression remains unknown. Gastrointestinal irritation and hypermotility may also 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 overdose should include gastric lavage and supportive therapy for stupor or coma, along with symptomatic treatment for gastrointestinal effects. The extent to which hydrochlorothiazide is removed by hemodialysis has not been clearly established. It is essential to implement measures to maintain hydration, electrolyte balance, and support respiratory, cardiovascular, and renal function as required.

Nonclinical Toxicology

Teratogenicity

No teratogenic effects have been reported for captopril and hydrochlorothiazide.

Impairment of Fertility

Captopril has been shown to have no impairment of fertility in studies conducted with rats. Similarly, hydrochlorothiazide did not exhibit adverse effects on the fertility of mice and rats of either sex when administered doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Carcinogenesis

Carcinogenicity studies have not been conducted with captopril and hydrochlorothiazide tablets; however, individual components have been evaluated in animal studies. Two-year studies involving captopril at doses ranging from 50 to 1350 mg/kg/day in mice and rats did not reveal any evidence of carcinogenic potential. Hydrochlorothiazide also demonstrated no carcinogenic potential in two-year feeding studies in female mice (up to approximately 600 mg/kg/day) and in male and female rats (up to approximately 100 mg/kg/day). Notably, the National Toxicology Program (NTP) found equivocal evidence for hepatocarcinogenicity in male mice.

Mutagenesis

Mutagenicity studies indicate that a 2:1 combination of captopril and hydrochlorothiazide was not mutagenic or clastogenic in various in vitro assays, both with and without metabolic activation. In a cytogenetics study using human lymphocytes, no increases in chromosomal abnormalities were observed, regardless of metabolic activation at 28 hours post-treatment. A statistically significant increase in chromosomal abnormalities was noted at 22 hours with metabolic activation at three tested concentrations; however, the absence of a dose-response relationship suggests that this finding may be attributable to an unusual lack of abnormalities in the negative-control cultures. Furthermore, an oral micronucleus study in mice demonstrated that the captopril/hydrochlorothiazide combination (2:1 mixture at 2500 mg/kg total weight) was not genotoxic.

Summary

Overall, the available nonclinical data indicate that captopril and hydrochlorothiazide do not exhibit teratogenic effects, impair fertility, or demonstrate significant carcinogenic or mutagenic potential in animal studies.

Storage and Handling

Captopril and Hydrochlorothiazide is supplied in tablet form.

Tablets should be stored at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the tablets from moisture.

The product must be dispensed in a tight, light-resistant container as defined by the USP, utilizing a child-resistant closure. Additionally, the container should be kept tightly closed to maintain the integrity of the tablets.