Document
DailyMed Label: Quinapril Hydrochloride and Hydrochlorothiazide
Title
DailyMed Label: Quinapril Hydrochloride and Hydrochlorothiazide
Date
2010
Document type
DailyMed Prescription
Name
Quinapril Hydrochloride and Hydrochlorothiazide
Generic name
quinapril hydrochloride and hydrochlorothiazide
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-1802
Product information
NDC: 54868-1802
Product information
NDC: 54868-2847
Product information
NDC: 54868-2847
Product information
NDC: 54868-5475
Product information
NDC: 54868-5475
Description
Quinapril hydrochloride
and hydrochlorothiazide is a fixed-combination tablet that combines an
angiotensin-converting enzyme (ACE) inhibitor, quinapril hydrochloride, and a
thiazide diuretic, hydrochlorothiazide.
Quinapril hydrochloride
USP is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1-
(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinoline-carboxylic
acid, monohydrochloride. Its molecular formula is C 25 H 30 N 2 O 5 ·HCl and its structural formula is:
Quinapril hydrochloride
USP is a white to off-white powder with a pink cast at times that is freely
soluble in aqueous solvents.
Hydrochlorothiazide USP
is chemically described as: 6-Chloro-3,4-dihydro-2H-1,2,4-
benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is:
Hydrochlorothiazide USP
is a white to off-white, practically odorless, crystalline powder which is
slightly soluble in water, freely soluble in sodium hydroxide solution, in
n-butylamine, and in dimethylformamide, sparingly soluble in methanol, insoluble
in ether, in chloroform, and in dilute mineral acids.
Quinapril hydrochloride
and hydrochlorothiazide is available for oral use as fixed combination tablets
in three strengths of quinapril with hydrochlorothiazide: 10 mg/12.5 mg
containing10 mg of quinapril hydrochloride USP and 12.5 mg of
hydrochlorothiazide USP, 20 mg/12.5 mg containing 20 mg of quinapril
hydrochloride USP and 12.5 mg of hydrochlorothiazide USP and 20 mg/25 mg
containing 20 mg of quinapril hydrochloride USP and 25 mg of hydrochlorothiazide
USP. Inactive ingredients: crospovidone, iron oxide red, lecithin, magnesium
carbonate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol,
povidone, talc, titanium dioxide, xanthan gum.
image of chemical structure for quinapril hydrochloride
image of chemical structure for hydrochlorothiazide
Indications
Quinapril hydrochloride
and hydrochlorothiazide tablets are indicated for the treatment of hypertension.
This fixed combination is not indicated for the initial therapy of hypertension
(see DOSAGE AND ADMINISTRATION ).
In using quinapril
hydrochloride and hydrochlorothiazide, 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 (see WARNINGS:
Neutropenia/Agranulocytosis ).
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.
Dosage
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 (see
WARNINGS ) 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 quinapril hydrochloride and
hydrochlorothiazide, 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.
Therapy
Guided by Clinical Effect
Patients whose blood
pressures are not adequately controlled with quinapril monotherapy may instead
be given quinapril hydrochloride and hydrochlorothiazide tablets 10 mg/12.5 mg
or 20 mg/12.5 mg. 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 hydrochloro-thiazide, but who
experience significant potassium loss with this regimen, may achieve blood
pressure control with less electrolyte disturbance if they are switched to
quinapril hydrochloride and hydrochlorothiazide tablets 10 mg/12.5 mg or 20
mg/12.5 mg.
Replacement Therapy
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 quinapril hydrochloride and hydrochlorothiazide tablets
20 mg/25 mg.
Use in
Renal Impairment
Regimens of therapy with
quinapril hydrochloride and hydrochlorothiazide tablets need not take account of
renal function as long as the patient’s creatinine clearance is > 30
mL/min/1.73 m 2 (serum creatinine roughly ≤ 3 mg/dL or 265
µmol/L). In patients with more severe renal impairment, loop diuretics are
preferred to thiazides. Therefore, quinapril hydrochloride and
hydrochlorothiazide tablets are not recommended for use in these patients.
Contraindications
Quinapril hydrochloride
and hydrochlorothiazide tablets are 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.
Precautions
General
Derangements of Serum Electrolytes: In clinical trials,
hyperkalemia (serum potassium ≥ 5.8 mmol/L) occurred in approximately 2% of
patients receiving quinapril. In most cases, elevated serum potassium levels
were isolated values which resolved despite continued therapy. Less than 0.1% of
patients discontinued therapy due to hyperkalemia. Risk factors for the
development of hyperkalemia include renal insufficiency, diabetes mellitus, and
the concomitant use of potassium-sparing diuretics, potassium supplements,
and/or potassium-containing salt substitutes.
Treatment with thiazide
diuretics has been associated with hypokalemia, hyponatremia, and hypochloremic
alkalosis. These disturbances have sometimes been manifest as one or more of
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea,
and vomiting. Hypokalemia can also sensitize or exaggerate the response of the
heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in
patients with cirrhosis of the liver, in patients experiencing a brisk diuresis,
in patients who are receiving inadequate oral intake of electrolytes, and in
patients receiving concomitant therapy with corticosteroids or ACTH.
The opposite effects of
quinapril and hydrochlorothiazide on serum potassium will approximately balance
each other in many patients, so that no net effect upon serum potassium will be
seen. In other patients, one or the other effect may be dominant. Initial and
periodic determinations of serum electrolytes to detect possible electrolyte
imbalance should be performed at appropriate intervals.
Chloride deficits
secondary to thiazide therapy are generally mild and require specific treatment
only under extraordinary circumstances (e.g., in liver disease or renal
disease). Dilutional hyponatremia may occur in edematous patients in hot
weather; appropriate therapy is water restriction rather than administration of
salt, except in rare instances when the hyponatremia is life threatening. In
actual salt depletion, appropriate replacement is the therapy of choice.
Calcium excretion is
decreased by thiazides. In a few patients on prolonged thiazide therapy,
pathological changes in the parathyroid gland have been observed, with
hypercalcemia and hypophosphatemia. More serious complications of
hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration)
have not been seen.
Thiazides increase the
urinary excretion of magnesium, and hypomagnesemia may result.
Other
Metabolic Disturbances: Thiazide diuretics tend to reduce glucose
tolerance and to raise serum levels of cholesterol, triglycerides, and uric
acid. These effects are usually minor, but frank gout or overt diabetes may be
precipitated in susceptible patients.
Cough: Presumably due to the inhibition of the degradation of
endogenous bradykinin, persistent nonproductive cough has been reported with all
ACE inhibitors, resolving after discontinuation of therapy. ACE
inhibitor-induced cough should be considered in the differential diagnosis of
cough.
Surgery/Anesthesia: In patients undergoing surgery or during
anesthesia with agents that produce hypotension, quinapril will block the
angiotensin II formation that could otherwise occur secondary to compensatory
renin release. Hypotension that occurs as a result of this mechanism can be
corrected by volume expansion.
Information for Patients
Angioedema: Angioedema, including laryngeal edema, can occur
with treatment with ACE inhibitors, especially following the first dose.
Patients receiving quinapril hydrochloride and hydrochlorothiazide should be
told to report immediately any signs or symptoms suggesting angioedema (swelling
of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more
drug until after consulting with the prescribing physician.
Pregnancy: Female patients of childbearing age should be told
about the consequences of second- and third-trimester exposure to ACE
inhibitors, and they should also be told that these consequences do not appear
to have resulted from intrauterine ACE-inhibitor exposure that has been limited
to the first trimester. These patients should be asked to report pregnancies to
their physicians as soon as possible.
Symptomatic Hypotension: A patient receiving quinapril
hydrochloride and hydrochlorothiazide should be cautioned that lightheadedness
can occur, especially during the first days of therapy, and that it should be
reported to the prescribing physician. The patient should be told that if
syncope occurs, quinapril hydrochloride and hydrochlorothiazide should be
discontinued until the physician has been consulted.
All patients should be
cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or
vomiting can lead to an excessive fall in blood pressure because of reduction in
fluid volume, with the same consequences of lightheadedness and possible
syncope.
Patients planning to
undergo major surgery and/or general or spinal anesthesia should be told to
inform their physicians that they are taking an ACE inhibitor.
Hyperkalemia: A patient receiving quinapril hydrochloride and
hydrochlorothiazide should be told not to use potassium supplements or salt
substitutes containing potassium without consulting the prescribing
physician.
Neutropenia: Patients should be told to promptly report any
indication of infection (e.g., sore throat, fever) which could be a sign of
neutropenia.
NOTE:
As with many other drugs, certain advice to patients being treated with
quinapril is warranted. This information is intended to aid in the safe and
effective use of this medication. It is not a disclosure of all possible adverse
or intended effects.
Laboratory Tests
The hydrochlorothiazide
component of quinapril hydrochloride and hydrochlorothiazide may decrease serum
PBI levels without signs of thyroid disturbance.
Therapy with quinapril
hydrochloride and hydrochlorothiazide should be interrupted for a few days
before carrying out tests of parathyroid function.
Drug Interactions
Potassium Supplements and Potassium-Sparing Diuretics: As
noted above (“Derangements of Serum Electrolytes”), the net effect of quinapril
hydrochloride and hydrochlorothiazide may be to elevate a patient’s serum
potassium, to reduce it, or to leave it unchanged. Potassium-sparing diuretics
(spironolactone, amiloride, triamterene, and others) or potassium supplements
can increase the risk of hyperkalemia. If concomitant use of such agents is
indicated, they should be given with caution, and the patient’s serum potassium
should be monitored frequently.
Lithium: Increased serum lithium levels and symptoms of
lithium toxicity have been reported in patients receiving ACE inhibitors during
therapy with lithium. Because renal clearance of lithium is reduced by
thiazides, the risk of lithium toxicity is presumably raised further when, as in
therapy with quinapril hydrochloride and hydrochlorothiazide, a thiazide
diuretic is coadministered with the ACE inhibitor. Quinapril hydrochloride and
hydrochlorothiazide and lithium should be coadministered with caution, and
frequent monitoring of serum lithium levels is recommended.
Tetracycline and Other Drugs That Interact with Magnesium:
Simultaneous administration of tetracycline with quinapril reduced the
absorption of tetracycline by approximately 28% to 37%, possibly due to the high
magnesium content in quinapril tablets. This interaction should be considered if
coprescribing quinapril and tetracycline or other drugs that interact with
magnesium.
Other
Agents:
Drug interaction studies
of quinapril and other agents showed:
Multiple dose therapy with propranolol or cimetidine has no effect on the
pharmacokinetics of single doses of quinapril.
The anticoagulant effect of a single dose of warfarin (measured by
prothrombin time) was not significantly changed by quinapril coadministration
twice daily.
Quinapril treatment did not affect the pharmacokinetics of digoxin.
No pharmacokinetic interaction was observed when single doses of quinapril
and hydrochlorothiazide were administered concomitantly.
When administered
concurrently, the following drugs may interact with thiazide diuretics.
Alcohol, Barbiturates, or Narcotics—potentiation of orthostatic hypotension
may occur.
Antidiabetic Drugs (oral hypoglycemic agents and insulin)—dosage adjustments
of the antidiabetic drug may be required.
Cholestyramine and Colestipol Resin—absorption of hydrochlorothiazide is
impaired in the presence of anionic exchange resins. Single doses of either
cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its
absorption from the gastrointestinal tract by up to 85% and 43%,
respectively.
Corticosteroids, ACTH—intensified electrolyte depletion, particularly
hypokalemia.
Pressor Amines (e.g., norepinephrine)—possible decreased response to pressor
amines, but not sufficient to preclude their therapeutic use.
Skeletal Muscle Relaxants, Nondepolarizing (e.g., tubocurarine)—possible
increased responsiveness to the muscle relaxant.
Nonsteroidal Antiinflammatory Drugs—the diuretic, natriuretic, and
antihypertensive effects of thiazide diuretics may be reduced by concurrent
administration of nonsteroidal antiinflammatory agents.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Carcinogenicity,
mutagenicity, and fertility studies have not been conducted in animals with
quinapril hydrochloride and hydrochlorothiazide.
Quinapril hydrochloride
was not carcinogenic in mice or rats when given in doses up to 75 or 100
mg/kg/day (50 or 60 times the maximum human daily dose, respectively, on a mg/kg
basis and 3.8 or 10 times the maximum human daily dose on a mg/m 2 basis) for 104 weeks. Female rats given the highest dose
level had an increased incidence of mesenteric lymph node hemangiomas and
skin/subcutaneous lipomas. Neither quinapril nor quinaprilat were mutagenic in
the Ames bacterial assay with or without metabolic activation. Quinapril was
also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister chromatid
exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung
cells, and in an in vivo cytogenetic study with rat
bone marrow. 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 when
based on mg/kg and mg/m 2 , respectively).
Under the auspices of
the National Toxicology Program, rats and mice received hydrochlorothiazide 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 uncovered no evidence of a carcinogenic
potential of hydrochlorothiazide in rats or female mice, but there was
“equivocal” evidence of hepatocarcinogenicity in male mice. Hydrochlorothiazide
was not genotoxic in in vitro assays using strains TA
98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella
typhimurium (the Ames test); in the Chinese hamster ovary (CHO) test for
chromosomal aberrations; or in vivo assays using
mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and
the Drosophila sex-linked recessive lethal trait
gene. Positive test results were obtained in the in vitro
CHO sister chromatid exchange (clastogenicity) test and in the mouse
lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide
of 43 to 1300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an
unspecified concentration of hydrochlorothiazide.
Hydrochlorothiazide had
no adverse effects on the fertility of mice and rats of either sex in studies
wherein these species were exposed, via their diets, to doses of up to 100 and 4
mg/kg/day, respectively, prior to mating and throughout gestation.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third
trimesters): See WARNINGS: Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Because quinapril and
hydrochlorothiazide are secreted in human milk, caution should be exercised when
quinapril hydrochloride and hydrochlorothiazide is administered to a nursing
woman.
Because of the potential
for serious adverse reactions in nursing infants from hydrochlorothiazide and
the unknown effects of quinapril in infants, a decision should be made whether
to discontinue nursing or to discontinue quinapril hydrochloride and
hydrochlorothiazide, taking into account the importance of the drug to the
mother.
Geriatric Use
Clinical studies of
quinapril HCl/hydrochlorothiazide did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of
the dosing range, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy.
Pediatric Use
Safety and effectiveness
of quinapril hydrochloride and hydrochlorothiazide in children have not been
established.
Adverse reactions
How supplied
Quinapril hydrochloride
and hydrochlorothiazide tablets are available in three different strengths:
10
mg/12.5 mg tablets: pink colored, capsule shaped, biconvex, film-coated
tablets, debossed with "RX" and "161" on either side of the scoreline on one
side and a deep breakline on the other side. Each tablet contains 10 mg of
quinapril and 12.5 mg of hydrochlorothiazide.
NDC-54868-1802-0 Bottles
of 30
20
mg/12.5 mg tablets: pink colored, capsule shaped, biconvex, film-coated
tablets, debossed with "RX" and "162" on either side of the scoreline on one
side and a deep breakline on the other side. Each tablet contains 20 mg of
quinapril and 12.5 mg of hydrochlorothiazide.
NDC 54868-2847-1 Bottles of 10
NDC 54868-2847-0 Bottles of 30
20
mg/25 mg tablets: pink colored, round biconvex, film-coated tablets,
debossed with "RX 163" on one side and plain on the other side. Each tablet
contains 20 mg of quinapril and 25 mg of hydrochlorothiazide
NDC 54868-5475-0 Bottles of 30
Dispense in tight
containers as defined in the USP.
Store at 20 - 25° C (68
- 77° F) (See USP Controlled Room Temperature).
Manufactured for:
Ranbaxy Pharmaceuticals
Inc.
Jacksonville, FL 32257
USA
by: Ohm Laboratories
Inc
North Brunswick, NJ
08902
January 2006
Repackaging and Relabeling by: Physicians Total Care, Inc. Tulsa, OK 74146
Clinical 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 (see PRECAUTIONS ). 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-aldosterone 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.
Pharmacokinetics and Metabolism: The rate and extent of
absorption of quinapril and hydrochlorothiazide from quinapril hydrochloride and
hydrochlorothiazide 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 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 quinapril hydrochloride and
hydrochlorothiazide 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 quinapril hydrochloride
and hydrochlorothiazide tablets were administered with a high-fat meal, while
the extent of absorption was not significantly affected. Therefore, quinapril
hydrochloride and hydrochlorothiazide 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 (see DOSAGE AND ADMINISTRATION ). 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.
Pharmacodynamics and Clinical Effects: 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 (see
WARNINGS ).
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 quinapril
hydrochloride and hydrochlorothiazide, 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.
Package label
Quinapril hydrochloride and hydrochlorothiazide tablets
10 mg/12.5 mg
Quinapril hydrochloride and hydrochlorothiazide tablets
20 mg /12.5 mg
Quinapril hydrochloride and hydrochlorothiazide tablets
20 mg/25 mg
image of 10/12.5 mg package label
image of 20/12.5 mg package label
image of 20/25 mg package label
1 organization
1 product
Organization
Physicians Total Care, Inc.