Quinapril hydrochloride/Hydrochlorothiazide

Uses and Indications

Quinapril and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. Lowering blood pressure is associated with a reduction in the risk of both fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

Control of high blood pressure should be part of a comprehensive cardiovascular risk management strategy, which includes lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients may require more than one antihypertensive medication to achieve their blood pressure goals.

Numerous antihypertensive drugs have been demonstrated in randomized controlled trials to reduce cardiovascular morbidity and mortality, with blood pressure reduction being a significant contributor to these benefits. The most substantial and consistent cardiovascular outcome benefit observed is a reduction in the risk of stroke, along with reductions in myocardial infarction and cardiovascular mortality.

Elevated systolic or diastolic blood pressure increases cardiovascular risk, and even modest reductions in severe hypertension can provide substantial benefits. The relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, with greater absolute benefits seen in patients at higher risk, including those with diabetes or hyperlipidemia.

It is important to note that some antihypertensive drugs may have smaller blood pressure effects when used as monotherapy in black patients, and many of these drugs have additional approved indications and effects, such as those related to angina, heart failure, or diabetic kidney disease. This fixed combination of quinapril and hydrochlorothiazide is not indicated for the initial therapy of hypertension.

Dosage and Administration

Quinapril is indicated for once-daily administration in doses ranging from 10 mg to 80 mg. Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg. In combination therapy, quinapril doses of 2.5 mg to 40 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg may be utilized, with increased antihypertensive effects observed at higher doses.

For patients whose blood pressure is not adequately controlled with quinapril monotherapy, quinapril and hydrochlorothiazide tablets in strengths of 10/12.5 mg or 20/12.5 mg may be prescribed. Further increases in either or both components should be based on clinical response. It is recommended that the hydrochlorothiazide dose not be increased until 2 to 3 weeks have elapsed.

Patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide without significant electrolyte disturbances may switch to quinapril and hydrochlorothiazide tablets 20/25 mg. Regimens of therapy with quinapril and hydrochlorothiazide tablets do not require adjustments based on renal function as long as the patient's creatinine clearance is greater than 30 mL/min/1.73 m².

The medication should be administered orally, once daily.

Contraindications

Quinapril and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to quinapril or hydrochlorothiazide, as well as in those with a history of angioedema related to previous treatment with an ACE inhibitor. The use of these tablets is also contraindicated in combination with a neprilysin inhibitor, such as sacubitril; administration should not occur within 36 hours of switching to or from sacubitril/valsartan. Additionally, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs due to the hydrochlorothiazide component. Co-administration with aliskiren is contraindicated in patients with diabetes.

Warnings and Precautions

Anaphylactoid and Possibly Related Reactions Patients receiving ACE inhibitors, including quinapril, may experience a variety of adverse reactions, some of which can be serious.

Head and Neck Angioedema Angioedema affecting the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with quinapril and hydrochlorothiazide should be discontinued immediately, and the patient should be treated according to accepted medical care. Emergency therapy, including subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), should be promptly administered if airway obstruction is likely.

Intestinal Angioedema Intestinal angioedema has been reported in patients treated with ACE inhibitors, with symptoms resolving after discontinuation of the medication.

Patients With a History of Angioedema Individuals with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.

Anaphylactoid Reactions During Desensitization Life-threatening anaphylactoid reactions have occurred in patients undergoing desensitization treatment while receiving ACE inhibitors.

Hepatic Failure Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the medication and receive appropriate medical follow-up. Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis and death.

Hypotension Quinapril and hydrochlorothiazide can cause symptomatic hypotension. If excessive hypotension occurs, the patient should be placed in a supine position and treated with intravenous infusion of normal saline. A dose reduction or discontinuation of therapy may be necessary if symptomatic hypotension develops.

Impaired Renal Function Quinapril and hydrochlorothiazide should be used with caution in patients with severe renal disease. Renal function should be monitored during the first few weeks of therapy, particularly in patients with renal artery stenosis.

Neutropenia/Agranulocytosis Periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease and/or renal disease.

Fetal Toxicity Drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can cause injury and death to the developing fetus. Quinapril and hydrochlorothiazide should be discontinued as soon as pregnancy is detected.

Serum Electrolyte Abnormalities Serum electrolytes should be monitored periodically, as hyperkalemia and hypokalemia can occur. Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Laboratory Tests Therapy with quinapril and hydrochlorothiazide should be interrupted for a few days before conducting tests of parathyroid function.

Get Emergency Medical Help If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with quinapril and hydrochlorothiazide should be discontinued immediately, and emergency medical help should be sought.

Stop Taking and Call Your Doctor Patients should discontinue the medication and seek medical advice if jaundice or marked elevations of hepatic enzymes occur, or if excessive hypotension develops.

Side Effects

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

Common Adverse Reactions (≥1% in Controlled Trials)

• Headache: 6.7%

• Dizziness: 4.8%

• Coughing: 3.2%

• Fatigue: 2.9%

• Myalgia: 2.4%

• Viral Infection: 1.9%

• Rhinitis: 2.0%

• Nausea and/or Vomiting: 1.8%

• Abdominal Pain: 1.7%

• Back Pain: 1.5%

• Diarrhea: 1.4%

• Upper Respiratory Infection: 1.3%

• Insomnia: 1.2%

• Somnolence: 1.2%

• Bronchitis: 1.2%

• Dyspepsia: 1.2%

• Asthenia: 1.1%

• Pharyngitis: 1.1%

• Vasodilatation: 1.0%

• Vertigo: 1.0%

• Chest Pain: 1.0%

Clinical Adverse Experiences (≥0.5% to <1.0%)

• Body as a Whole: Asthenia, malaise, shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia, anaphylactoid reaction.

• Cardiovascular System: Palpitation, tachycardia, heart failure, hyperkalemia, myocardial infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic hypotension, cardiac rhythm disturbance.

• Gastrointestinal System: Mouth or throat dry, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests.

• Nervous/Psychiatric: Nervousness, vertigo, paresthesia.

• Respiratory: Sinusitis, dyspnea.

• Integumentary: Pruritus, increased sweating, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, alopecia, pemphigus.

• Urogenital System: Acute renal failure, impotence.

• Other: Agranulocytosis, thrombocytopenia, arthralgia.

Serious Adverse Reactions

• Angioedema: Reported in 0.1% of patients receiving quinapril; can be life-threatening if laryngeal edema occurs.

• Hypotension: Reported in 1.2% of patients; can be symptomatic and associated with oliguria and/or progressive azotemia.

• Neutropenia/Agranulocytosis: Rarely reported; periodic monitoring of white blood cell counts is recommended, especially in patients with renal impairment or collagen vascular disease.

• Hepatic Failure: Rarely associated with cholestatic jaundice progressing to fulminant hepatic necrosis.

Postmarketing Experience

• Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk, particularly for squamous cell carcinoma (SCC).

• Acute Angle-Closure Glaucoma: Can occur with hydrochlorothiazide, leading to permanent visual field loss if untreated.

• Other Adverse Reactions: Include shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, bradycardia, cor pulmonale, vasculitis, deep vein thrombosis, gastrointestinal carcinoma, hepatitis, esophagitis, pneumonia, asthma, respiratory infiltration, lung disorder, urticaria, macropapular rash, petechiases, abnormal vision, kidney function abnormalities, albuminuria, pyuria, hematuria, nephrosis.

Additional Notes

• Cough: A persistent nonproductive cough may occur, resolving after discontinuation of therapy.

• Hyperkalemia: Occurred in approximately 2% of patients; serum potassium levels should be monitored.

• Hypokalemia and Hyponatremia: Can occur with hydrochlorothiazide.

• Metabolic Disturbances: Hydrochlorothiazide may alter glucose tolerance and raise serum cholesterol and triglycerides.

• Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can reduce fetal renal function and increase fetal and neonatal morbidity and death.

Drug Interactions

Coadministration of quinapril hydrochloride and hydrochlorothiazide with other agents that increase serum potassium levels may lead to hyperkalemia; therefore, monitoring of serum potassium is recommended in such patients.

In patients receiving lithium, increased serum lithium levels and symptoms of lithium toxicity have been reported when ACE inhibitors are used. The risk of lithium toxicity is further elevated when a thiazide diuretic, such as hydrochlorothiazide, is coadministered, as thiazides reduce renal clearance of lithium. Caution is advised when using quinapril hydrochloride and hydrochlorothiazide with lithium, and frequent monitoring of serum lithium levels is recommended.

The dual blockade of the renin-angiotensin system (RAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and renal function changes, including acute renal failure, compared to monotherapy. Most patients do not derive additional benefit from the combination of two RAS inhibitors. Therefore, combined use of RAS inhibitors should generally be avoided. In particular, aliskiren should not be coadministered with quinapril hydrochloride and hydrochlorothiazide in patients with diabetes or renal impairment (GFR <60 mL/min/1.73 m²). Close monitoring of blood pressure, renal function, and electrolytes is essential in patients receiving these combinations.

Simultaneous administration of tetracycline with quinapril may reduce the absorption of tetracycline by approximately 28% to 37%, likely due to the high magnesium content in quinapril tablets. This interaction should be considered when coprescribing quinapril and tetracycline or other magnesium-interacting drugs.

Rare cases of nitritoid reactions, characterized by facial flushing, nausea, vomiting, and hypotension, have been reported in patients receiving injectable gold (sodium aurothiomalate) alongside ACE inhibitors.

In elderly patients, those who are volume-depleted, or those with compromised renal function, the coadministration of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, with ACE inhibitors like quinapril may lead to renal function deterioration, including possible acute renal failure. These effects are typically reversible, but renal function should be monitored periodically. Additionally, the antihypertensive effect of ACE inhibitors may be diminished by NSAIDs.

Patients on concomitant mTOR inhibitors (e.g., temsirolimus) may be at an increased risk for angioedema when treated with quinapril hydrochloride and hydrochlorothiazide.

Other interactions include:

• Multiple doses of propranolol or cimetidine do not affect the pharmacokinetics of quinapril.

• The anticoagulant effect of warfarin is not significantly altered by quinapril.

• No pharmacokinetic interaction is observed when single doses of quinapril and hydrochlorothiazide are administered together.

• Thiazide-induced electrolyte disturbances, such as hypokalemia and hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmias.

Additional considerations for drugs that may interact with thiazide diuretics include:

• Alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension.

• Antidiabetic drugs may require dosage adjustments.

• Cholestyramine and colestipol resins can significantly impair the absorption of hydrochlorothiazide.

• Corticosteroids and ACTH may intensify electrolyte depletion, particularly hypokalemia.

• Pressor amines (e.g., norepinephrine) may have a decreased response, although this does not preclude their therapeutic use.

• Nondepolarizing skeletal muscle relaxants (e.g., tubocurarine) may show increased responsiveness.

• The diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent NSAID administration.

Pediatric Use

Neonates with a history of in utero exposure to quinapril hydrochloride and hydrochlorothiazide may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion. Exchange transfusions or dialysis may be necessary to reverse hypotension and/or address disordered renal function. It is important to note that the removal of quinapril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these interventions.

The safety and effectiveness of quinapril hydrochloride and hydrochlorothiazide in pediatric patients have not been established.

Geriatric Use

Clinical studies of quinapril hydrochloride and hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience has not identified significant differences in responses between elderly patients and younger individuals.

In general, dose selection for geriatric patients should be approached with caution. It is recommended to start at the low end of the dosing range, taking into account the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Regular monitoring of these patients is advised to ensure safety and efficacy.

Pregnancy

Pregnant patients should be aware that there is no specific information regarding the use of Quinapril Hydrochloride and Hydrochlorothiazide during pregnancy, including safety concerns, dosage modifications, or special precautions. The available data does not indicate any contraindications in pregnancy or risks to the fetus.

Animal studies have not been conducted to assess the carcinogenicity, mutagenicity, or fertility effects of quinapril and hydrochlorothiazide. However, quinapril hydrochloride was not found to be carcinogenic in mice or rats at doses up to 75 or 100 mg/kg/day over 104 weeks. Notably, female rats receiving the highest dose exhibited an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas. Neither quinapril nor quinaprilat demonstrated mutagenic properties in the Ames bacterial assay, regardless of metabolic activation.

Furthermore, studies indicate that there were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day. Hydrochlorothiazide also showed no genotoxicity in in vitro assays and did not adversely affect the fertility of mice and rats at doses of up to 100 and 4 mg/kg/day, respectively, when administered prior to mating and throughout gestation.

Given the lack of specific data on the use of these medications during pregnancy, healthcare providers should carefully consider the potential risks and benefits when prescribing to pregnant patients.

Lactation

Quinapril and hydrochlorothiazide are both secreted in human milk, necessitating caution when administered to lactating mothers. Due to the potential for serious adverse reactions in breastfed infants from hydrochlorothiazide, along with the unknown effects of quinapril, healthcare providers should carefully consider the risks and benefits. A decision should be made regarding whether to discontinue breastfeeding or to discontinue the use of quinapril and hydrochlorothiazide, taking into account the importance of the medication to the mother’s health.

Renal Impairment

Quinapril and hydrochlorothiazide should be administered with caution in patients with severe renal impairment. The use of thiazides in this population may precipitate azotemia, and the cumulative effects of repeated dosing should be considered.

In patients with severe congestive heart failure, where renal function may be reliant on the renin-angiotensin-aldosterone system, treatment with quinapril can lead to oliguria, progressive azotemia, and, in rare cases, acute renal failure or death. Therefore, careful monitoring of renal function is essential, particularly during the initial weeks of therapy.

Clinical studies have indicated that hypertensive patients with unilateral renal artery stenosis may experience increases in blood urea nitrogen and serum creatinine levels when treated with angiotensin-converting enzyme (ACE) inhibitors, including quinapril. These increases are typically reversible upon discontinuation of the ACE inhibitor or the concomitant diuretic. For patients with pre-existing renal impairment, dosage reduction of quinapril and hydrochlorothiazide may be necessary to mitigate the risk of adverse renal effects.

Regular assessment of renal function is recommended for all hypertensive patients receiving this treatment. Additionally, periodic monitoring of white blood cell counts should be considered in patients with collagen vascular disease and/or renal disease due to the potential risk of agranulocytosis associated with ACE inhibitors.

Hepatic Impairment

Quinapril and hydrochlorothiazide tablets should be used with caution in patients with impaired hepatic function or progressive liver disease, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is primarily dependent on hepatic esterases; therefore, patients with impaired liver function may experience markedly elevated plasma levels of quinapril.

No pharmacokinetic studies have been conducted specifically in hypertensive patients with impaired liver function, which limits the understanding of the drug's behavior in this population.

Patients receiving ACE inhibitors, including quinapril, who develop jaundice or marked elevations in hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. It is important to note that ACE inhibitors have been rarely associated with a syndrome that begins with cholestatic jaundice and can progress to fulminant hepatic necrosis, which may result in death; the mechanism underlying this syndrome remains unclear.

Monitoring of liver function tests and clinical signs of hepatic impairment is recommended for patients on this medication.

Overdosage

In cases of overdosage with quinapril and hydrochlorothiazide, no specific treatment information is available; therefore, management should be symptomatic and supportive. It is recommended that therapy with quinapril and hydrochlorothiazide be discontinued, and the patient should be closely observed. Established procedures should be followed to address dehydration, electrolyte imbalances, and hypotension.

The oral median lethal dose of quinapril and hydrochlorothiazide in combination has been reported to range from 1063/664 to 4640/2896 mg/kg in animal studies. Significant lethality has been observed in mice and rats at doses of 1440 to 4280 mg/kg of quinapril. In single-dose studies, most rats survived doses of hydrochlorothiazide up to 2.75 g/kg.

Human overdose data for ACE inhibitors, including quinapril, are limited. The most likely manifestation of quinapril overdosage in humans is hypotension. In cases of hydrochlorothiazide overdose, common signs and symptoms include dehydration and electrolyte depletion, such as hypokalemia, hypochloremia, and hyponatremia. If digitalis has been administered concurrently, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Laboratory determinations of serum levels of quinapril and its metabolites are not widely available and do not play a role in the management of quinapril overdose. There are no data to suggest that physiological maneuvers, such as altering urine pH, would accelerate the elimination of quinapril and its metabolites. Additionally, hemodialysis and peritoneal dialysis have been shown to have little effect on the elimination of quinapril and quinaprilat.

While angiotensin II could theoretically serve as a specific antagonist-antidote in the event of quinapril overdose, it is largely unavailable outside of specialized research facilities. Given that the hypotensive effect of quinapril is mediated through vasodilation and effective hypovolemia, it is reasonable to manage quinapril overdose with the infusion of normal saline solution.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies have not been conducted in animals with quinapril hydrochloride and hydrochlorothiazide. Quinapril hydrochloride was evaluated for carcinogenic potential in mice and rats at doses up to 75 or 100 mg/kg/day for 104 weeks, which corresponds to 50 or 60 times the maximum human daily dose on a mg/kg basis and 3.8 or 10 times on a mg/m² basis. The results indicated that quinapril hydrochloride was not carcinogenic; however, an increased incidence of mesenteric lymph node hemangiomas and skin/subcutaneous lipomas was observed in female rats at the highest dose level.

In terms of mutagenicity, neither quinapril nor quinaprilat demonstrated mutagenic effects in the Ames bacterial assay, both with and without metabolic activation. Additional genetic toxicology studies, including in vitro mammalian cell point mutation, sister chromatid exchange in cultured mammalian cells, micronucleus tests in mice, in vitro chromosome aberration tests with V79 cultured lung cells, and in vivo cytogenetic studies with rat bone marrow, yielded negative results.

Hydrochlorothiazide was administered to rats and mice in their feed for 2 years at doses up to 600 mg/kg/day in mice and up to 100 mg/kg/day in rats. These studies revealed no evidence of carcinogenic potential in rats or female mice, although there was equivocal evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide was not genotoxic in various in vitro assays, including the Ames test using multiple strains of Salmonella typhimurium, the Chinese hamster ovary (CHO) test for chromosomal aberrations, and in vivo assays involving mouse germinal cell chromosomes and Chinese hamster bone marrow chromosomes. However, positive results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test and in mouse lymphoma cell (mutagenicity) assays at concentrations ranging from 43 to 1300 μg/mL, as well as in the Aspergillus nidulans nondisjunction assay.

Regarding fertility, studies indicated that there were no adverse effects on fertility or reproduction in rats at doses up to 100 mg/kg/day (60 and 10 times the maximum daily human dose based on mg/kg and mg/m², respectively). Similarly, hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when exposed to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation.

Storage and Handling

Quinapril and Hydrochlorothiazide is supplied in tablet form, available in various strengths including 10/12.5, 20/12.5, and 20/25 mg. The tablets are packaged in tight containers as defined by the USP to ensure product integrity.

The product should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) for certain formulations. It is important to protect the tablets from light to maintain their efficacy.