Quinapril hydrochloride and hydrochlorothiazide tablet

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# Black Box Warning

# Overview
Quinapril hydrochloride and hydrochlorothiazide tablet is a diuretic that is FDA approved for the treatment of is indicated for the treatment of hypertension. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia and anaphylactoid reaction, bradycardia, cor pulmonale, vasculitis, and deep thrombosis, gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, diarrhea, acute myopia and acute angle closure glaucoma, anemia, weight loss, myopathy, myositis, arthritis, paralysis, hemiplegia, speech disorder, abnormal gait, meningism, amnesia, pneumonia, asthma, respiratory infiltration, lung disorder, urticaria, macropapular rash, petechiases, abnormal vision, kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- ACCURETIC is indicated for the treatment of hypertension. This fixed combination is not indicated for the initial therapy of hypertension.
- In using ACCURETIC, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease.
- Available data are insufficient to show that quinapril does not have a similar risk.
- Angioedema in Black Patients
- Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks.
- It should also be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Quinapril hydrochloride and hydrochlorothiazide tablet in adult patients.

### NonGuideline-Supported Use
- Congestive heart failure

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy not established in pediatric patients

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Quinapril hydrochloride and hydrochlorothiazide tablet in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Quinapril hydrochloride and hydrochlorothiazide tablet in pediatric patients.

# Contraindications
- ACCURETIC is contraindicated in patients who are hypersensitive to quinapril or hydrochlorothiazide and in patients with a history of angioedema related to previous treatment with an ACE inhibitor.
- Because of the hydrochlorothiazide components, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
- Do not co-administer ACCURETIC with aliskiren
- In patients with diabetes.

# Warnings
There is limited information regarding Quinapril hydrochloride and hydrochlorothiazide tablet Warnings' in the drug label.

# Adverse Reactions

## Clinical Trials Experience
There is limited information regarding Quinapril hydrochloride and hydrochlorothiazide tablet Clinical Trials Experience in the drug label.

## Postmarketing Experience
- Shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia and anaphylactoid reaction.
- Bradycardia, cor pulmonale, vasculitis, and deep thrombosis.
- Gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, and diarrhea.
- Acute myopia and acute angle closure glaucoma.
- Anemia.
- Weight loss.
- Myopathy, myositis, and arthritis.
- Paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia.
- Pneumonia, asthma, respiratory infiltration, and lung disorder.
- Urticaria, macropapular rash, and petechiases.
- Abnormal vision.
- Kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis.
- Hydrochlorothiazide has been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency.

# Drug Interactions
There is limited information regarding Quinapril hydrochloride and hydrochlorothiazide tablet Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): D
There is no FDA guidance on usage of Quinapril hydrochloride and hydrochlorothiazide tablet in women who are pregnant.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Quinapril hydrochloride and hydrochlorothiazide tablet in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Quinapril hydrochloride and hydrochlorothiazide tablet during labor and delivery.

### Nursing Mothers
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet in women who are nursing.

### Pediatric Use
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet in pediatric settings.

### Geriatic Use
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet in geriatric settings.

### Gender
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Quinapril hydrochloride and hydrochlorothiazide tablet in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Quinapril hydrochloride and hydrochlorothiazide tablet in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- As individual monotherapy, quinapril is an effective treatment of hypertension in once-daily doses of 10 to 80 mg and hydrochlorothiazide is effective in doses of 12.5 to 50 mg.
- In clinical trials of quinapril/hydrochlorothiazide combination therapy using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing dose of either component.
- The side effects of quinapril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of quinapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens that combine low doses of hydrochlorothiazide with quinapril produce minimal effects on serum potassium. In clinical trials of ACCURETIC, the average change in serum potassium was near zero in subjects who received HCTZ 6.25 mg in the combination, and the average subject who received 10 to 40/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.
- To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
- Patients whose blood pressures are not adequately controlled with quinapril monotherapy may instead be given ACCURETIC 10/12.5 or 20/12.5. Further increases of either or both components could depend on clinical response.
- The hydrochlorothiazide dose should generally not be increased until 2 to 3 weeks have elapsed. Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve blood pressure control with less electrolyte disturbance if they are switched to ACCURETIC 10/12.5 or 20/12.5.
- For convenience, patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide and experience no significant electrolyte disturbances may instead wish to receive ACCURETIC 20/25.
- Regimens of therapy with ACCURETIC need not take account of renal function as long as the patient's creatinine clearance is >30 mL/min/1.73 m2 (serum creatinine roughly 3 mg/dL or 265 mol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides. Therefore, ACCURETIC is not recommended for use in these patients.

### Monitoring
There is limited information regarding Quinapril hydrochloride and hydrochlorothiazide tablet Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Quinapril hydrochloride and hydrochlorothiazide tablet and IV administrations.

# Overdosage
- No specific information is available on the treatment of overdosage with ACCURETIC or quinapril monotherapy; treatment should be symptomatic and supportive.
- Therapy with ACCURETIC should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures.
- The oral median lethal dose of quinapril/hydrochlorothiazide in combination ranges from 1063/664 to 4640/2896 mg/kg in mice and rats.
- Doses of 1440 to 4280 mg/kg of quinapril cause significant lethality in mice and rats. In single-dose studies of hydrochlorothiazide, most rats survived doses up to 2.75 g/kg.
- Data from human overdoses of ACE inhibitors are scanty; the most likely manifestation of human quinapril overdosage is hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia).
- If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
- Laboratory determinations of serum levels of quinapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of quinapril overdose.
- No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of quinapril and its metabolites. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.
- Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of quinapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities.
- Because the hypotensive effect of quinapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat quinapril overdose by infusion of normal saline solution.

# Pharmacology

## Mechanism of Action
- The principal metabolite of quinapril, quinaprilat, is an inhibitor of ACE activity in human subjects and animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II.
- The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation.
- Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine, or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption.
- Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril alone resulted in mean increases in potassium of 0.07 mmol/L. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).
- While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension.
- Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated.
- Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts.
- Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium.
- The renin-aldolsterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics.
- The mechanism of the antihypertensive effect of thiazides is unknown.

## Structure
- ACCURETIC is a fixed-combination tablet that combines an angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a thiazide diuretic, hydrochlorothiazide.
- Quinapril hydrochloride is chemically described as 3S-2R*(R*)], 3R2-2-1-(ethoxycarbonyl)-3-phenylpropyl amino]-1-oxopropyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5. HCl and its structural formula is following.
- Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents.
- Hydrochlorothiazide is chemically described as: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8CIN3O4S2 and its structural formula is following.
- Hydrochlorothiazide is a white to off-white, crystalline powder which is slightly soluble in water but freely soluble in sodium hydroxide solution.
- ACCURETIC is available for oral use as fixed combination tablets in three strengths of quinapril with hydrochlorothiazide: 10 mg with 12.5 mg (ACCURETIC 10/12.5), 20 mg with 12.5 mg (ACCURETIC 20/12.5), and 20 mg with 25 mg (ACCURETIC 20/25).
- Inactive ingredients: candelilla wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide.

## Pharmacodynamics
- Single doses of 20 mg of quinapril provide over 80% inhibition of plasma ACE for 24 hours.
- Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20-mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg.
- Administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted.
- Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks.
- In multiple-dose studies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect.
- While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice-daily dosing tended to give a somewhat lower trough blood pressure than once-daily dosing with the same total dose. The antihypertensive effect of quinapril continues during long-term therapy, with no evidence of loss of effectiveness.
- Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction.
- Therapeutic effects of quinapril appear to be the same for elderly (65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. In patients with hypertension, quinapril 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics.
- After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Use of quinapril with a thiazide diuretic gives blood pressure lowering effect greater than that seen with either agent alone.
- In clinical trials of quinapril/hydrochlorothiazide using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects were sustained for at least 24 hours, and increased with increasing dose of either component.
- Although quinapril monotherapy is somewhat less effective in blacks than in non-blacks, the efficacy of combination therapy appears to be independent of race. By blocking the renin-angiotensin-aldosterone axis, administration of quinapril tends to reduce the potassium loss associated with the diuretic.
- In clinical trials of ACCURETIC, the average change in serum potassium was near zero when 2.5 to 40 mg of quinapril was combined with hydrochlorothiazide 6.25 mg, and the average subject who received 10 to 20/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.

## Pharmacokinetics
- The rate and extent of absorption of quinapril and hydrochlorothiazide from ACCURETIC tablets are not different, respectively, from the rate and extent of absorption of quinapril and hydrochlorothiazide from immediate-release monotherapy formulations, either administered concurrently or separately.
- Following oral administration of Accupril (quinapril monotherapy) tablets, peak plasma quinapril concentrations are observed within 1 hour.
- Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50% to 80%).
- The rate of quinapril absorption was reduced by 14% when ACCURETIC tablets were administered with a high-fat meal as compared to fasting, while the extent of absorption was not affected.
- The rate of hydrochlorothiazide absorption was reduced by 12% when ACCURETIC tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. Therefore, ACCURETIC may be administered without regard to food.
- Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose.
- Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is not metabolized.
- Its apparent volume of distribution is 3.6 to 7.8 L/kg, consistent with measured plasma protein binding of 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma.
- Some placental passage occurred when quinapril was administered to pregnant rats. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. Hydrochlorothiazide crosses the placenta freely but not the blood-brain barrier.
- Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours.
- Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.
- In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance.
- In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat is reduced in elderly patients (65 years) and in those with heart failure; this reduction is attributable to decrease in renal function.
- Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.
- The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5- to 80-mg doses and 40- to 160-mg in multiple daily doses.

## Nonclinical Toxicology
There is limited information regarding Quinapril hydrochloride and hydrochlorothiazide tablet Nonclinical Toxicology in the drug label.

# Clinical Studies
There is limited information regarding Quinapril hydrochloride and hydrochlorothiazide tablet Clinical Studies in the drug label.

# How Supplied
- ACCURETIC is available in tablets of three different strengths:
- 10/12.5 tablets: pink, scored elliptical, biconvex, film-coated tablets coded "PD 222" on one side. Each tablet contains 10 mg of quinapril and 12.5 mg of hydrochlorothiazide.
NDC 0071-0222-23: 90 tablet bottles
- 20/12.5 tablets: pink, scored triangular, film-coated tablets coded "PD 220" on one side. Each tablet contains 20 mg of quinapril and 12.5 mg of hydrochlorothiazide.
NDC 0071-0220-23: 90 tablet bottles
- 20/25 tablets: pink, round, biconvex, film-coated tablets coded "PD 223" on one side. Each tablet contains 20 mg of quinapril and 25 mg of hydrochlorothiazide.
NDC 0071-0223-23: 90 tablet bottles
- Dispense in tight containers as defined in the USP.

## Storage
- Store at Controlled Room Temperature 2025C

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Quinapril hydrochloride and hydrochlorothiazide tablet in the drug label.

# Precautions with Alcohol
Alcohol-Quinapril hydrochloride and hydrochlorothiazide tablet interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- QUINAPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE

# Look-Alike Drug Names
There is limited information regarding Quinapril hydrochloride and hydrochlorothiazide tablet Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price