function (including acute renal failure) compared to monotherapy. most patients receiving the combination of two ras inhibitors do not obtain any additional benefit compared to monotherapy. in general, avoid combined use of ras inhibitors. closely monitor blood pressure, renal function and electrolytes in patients on quinapril and hydrochlorothiazide and other agents that affect the ras. do not co-administer aliskiren with quinapril and hydrochlorothiazide in patients with diabetes. avoid concomitant use of aliskiren with quinapril and hydrochlorothiazide in patients with renal impairment (gfr <60 ml/min/1.73 m 2 ). 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. gold nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ace inhibitor therapy. non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors (cox-2 inhibitors) in patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of nsaids, including selective cox-2 inhibitors, with ace inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. these effects are usually reversible. monitor renal function periodically in patients receiving quinapril and nsaid therapy. the antihypertensive effect of ace inhibitors, including quinapril may be attenuated by nsaids. agents that inhibit mtor or other drugs known to cause angioedema: patients taking concomitant mtor inhibitor (e.g., temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema . 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. digoxin: thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (see precautions ). 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 (see precautions ). 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. non-steroidal anti-inflammatory drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents.

d pressure education program’s joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. this fixed combination is not indicated for the initial therapy of hypertension (see dosage and administration ). in using quinapril and hydrochlorothiazide tablets, 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.

diately, the patient treated in accordance with accepted medical care, and carefully observed until the swelling disappears. in instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 ml) should be promptly administered ( see precautions and adverse reactions ). patients taking concomitant mammalian target of rapamycin (mtor inhibitor) (e.g., temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. intestinal angioedema intestinal angioedema has been reported in patients treated with ace inhibitors. these patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and c-1 esterase levels were normal. the angioedema was diagnosed by procedures including abdominal ct scan or ultrasound, or at surgery, and symptoms resolved after stopping the ace inhibitor. intestinal angioedema should be included in the differential diagnosis of patients on ace inhibitors presenting with abdominal pain. patients with a history of angioedema patients with a history of angioedema unrelated to ace inhibitor therapy may be at increased risk of angioedema while receiving an ace inhibitor (see also contraindications ). anaphylactoid reactions during desensitization two patients undergoing desensitizing treatment with hymenoptera venom while receiving ace inhibitors sustained life-threatening anaphylactoid reactions. in the same patients, these reactions were avoided when ace inhibitors were temporarily withheld, but they reappeared upon inadvertent challenge. anaphylactoid reactions during membrane exposure anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ace inhibitor. anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. hepatic failure rarely, ace inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. the mechanism of this syndrome is not understood. patients receiving ace inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ace inhibitor and receive appropriate medical follow-up. hypotension quinapril and hydrochlorothiazide can cause symptomatic hypotension, probably not more frequently than either monotherapy. it was reported in 1.2% of 1,571 patients receiving quinapril and hydrochlorothiazide during clinical trials. like other ace inhibitors, quinapril has been only rarely associated with hypotension in uncomplicated hypertensive patients. symptomatic hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis or severe volume and/or salt depletion of any etiology. volume and/or salt depletion should be corrected before initiating therapy with quinapril and hydrochlorothiazide. quinapril and hydrochlorothiazide should be used cautiously in patients receiving concomitant therapy with other antihypertensives. the thiazide component of quinapril and hydrochlorothiazide may potentiate the action of other antihypertensive drugs, especially ganglionic or peripheral adrenergic-blocking drugs. the antihypertensive effects of the thiazide component may also be enhanced in the postsympathectomy patients. in patients at risk of excessive hypotension, therapy with quinapril and hydrochlorothiazide should be started under close medical supervision. such patients should be followed closely for the first 2 weeks of treatment and whenever the dosage of quinapril or diuretic is increased. similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident. if excessive hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of normal saline. quinapril and hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume. if symptomatic hypotension develops, a dose reduction or discontinuation of quinapril and hydrochlorothiazide may be necessary. impaired renal function quinapril and hydrochlorothiazide should be used with caution in patients with severe renal disease. thiazides may precipitate azotemia in such patients, and the effects of repeated dosing may be cumulative. when the renin-angiotensin-aldosterone system is inhibited by quinapril, changes in renal function may be anticipated in susceptible individuals. in patients with severe congestive heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors (including quinapril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. in clinical studies in hypertensive patients with unilateral renal artery stenosis, treatment with ace inhibitors was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of ace inhibitor, concomitant diuretic, or both. when such patients are treated with quinapril and hydrochlorothiazide, renal function should be monitored during the first few weeks of therapy. some quinapril-treated hypertensive patients with no apparent preexisting renal vascular diseases have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when quinapril has been given concomitantly with a diuretic. this is more likely to occur in patients with pre-existing renal impairment. dosage reduction of quinapril and hydrochlorothiazide may be required. evaluation of the hypertensive patients should also include assessment of the renal function ( see dosage and administration ). neutropenia/agranulocytosis another ace inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. available data from clinical trials of quinapril are insufficient to show that, in patients without prior reactions to other ace inhibitors, quinapril does not cause agranulocytosis at similar rates. as with other ace inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. fetal toxicity use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. when pregnancy is detected, discontinue quinapril and hydrochlorothiazide as soon as possible. these adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. if oligohydramnios is observed, discontinue quinapril and hydrochlorothiazide, unless it is considered life-saving for the mother. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to quinapril and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia (see precautions, pediatric use ). intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that occurred in adults. no teratogenic effects of quinapril were seen in studies of pregnant rats and rabbits. on a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose. no teratogenic effects of quinapril and hydrochlorothiazide were seen in studies of pregnant rats and rabbits. on a mg/kg (quinapril/hydrochlorothiazide) basis, the doses used were up to 188/94 times (in rats) and 0.6/0.3 times (in rabbits) the maximum recommended human dose. impaired hepatic function quinapril and hydrochlorothiazide should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterases, patients with impaired liver function could develop markedly elevated plasma levels of quinapril. no normal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. systemic lupus erythematosus thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. acute angle-closure glaucoma with or without acute myopia and choroidal effusions: hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute angle-closure glaucoma and elevated intraocular pressure with or without a noticeable acute myopic shift and/or choroidal effusions. symptoms may include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. untreated, the angle-closure glaucoma may result in permanent visual field loss. the primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

s, brisk diuresis, or with concomitant use of drugs that lower serum potassium. monitor serum electrolytes periodically. other metabolic disturbances hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. monitor calcium levels in patients with hypercalcemia receiving quinapril and hydrochlorothiazide. 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.

in clinical trials of quinapril and hydrochlorothiazide tablets, 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 mg to 40 mg/12.5 mg 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 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 hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve blood pressure control with less electrolyte disturbance if they are switched to quinapril 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 and hydrochlorothiazide tablets 20 mg/25 mg. use in renal impairment regimens of therapy with quinapril 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 and hydrochlorothiazide tablets are not recommended for use in these patients.

y related to therapy or of unknown relationship to therapy occurring in 1% or more of the 943 patients treated with quinapril plus hydrochlorothiazide in controlled trials are shown below. percent of patients in controlled trials quinapril/hctz n = 943 placebo n = 100 headache 6.7 30 dizziness 4.8 4 coughing 3.2 2 fatigue 2.9 3 myalgia 2.4 5 viral infection 1.9 4 rhinitis 2 3 nausea and/or vomiting 1.8 6 abdominal pain 1.7 4 back pain 1.5 2 diarrhea 1.4 1 upper respiratory infection 1.3 4 insomnia 1.2 2 somnolence 1.2 0 bronchitis 1.2 1 dyspepsia 1.2 2 asthenia 1.1 1 pharyngitis 1.1 2 vasodilatation 1 1 vertigo 1 2 chest pain 1 2 clinical adverse experiences probably, possibly, or definitely related or of uncertain relationship to therapy occurring in ?0.5% to <1% (except as noted) of the patients treated with quinapril/hctz in controlled and uncontrolled trials (n=1571) and less frequent, clinically significant events seen in clinical trials or postmarketing experience (the rarer events are in italics) include (listed by body system): body as a whole: asthenia, malaise cardiovascular: palpitation, tachycardia, heart failure, hyperkalemia, myocardial infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic hypotension, cardiac rhythm disturbance gastrointestinal: mouth or throat dry, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests nervous/psychiatric: nervousness, vertigo, paresthesia respiratory: sinusitis, dyspnea integumentary: pruritus, sweating increased, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, alopecia, pemphigus urogenital system: other: acute renal failure, impotence agranulocytosis, thrombocytopenia, arthralgia angioedema: angioedema has been reported in 0.1% of patients receiving quinapril (0.1%) (see warnings ). postmarketing experience the following serious nonfatal adverse events, regardless of their relationship to quinapril and hctz combination tablets, have been reported during extensive postmarketing experience: non-melanoma skin cancer: hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. in a study conducted in the sentinel system, increased risk was predominantly for squamous cell carcinoma (scc) and in white patients taking large cumulative doses. the increased risk for scc in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ?50,000 mg the risk increase was approximately 1 additional scc case for every 6,700 patients per year. body as a whole: shock, accidental injury, neoplasm, cellulitis, ascites, generalized edema, hernia and anaphylactoid reaction. cardiovascular system: bradycardia, cor pulmonale, vasculitis, and deep vein thrombosis. digestive system: gastrointestinal carcinoma, cholestatic jaundice, hepatitis, esophagitis, vomiting, and diarrhea. eye disorders: acute myopia and acute angle closure glaucoma (see warnings ). hemic system: anemia. metabolic and nutritional disorders: weight loss. musculoskeletal system: myopathy, myositis, and arthritis. nervous system: paralysis, hemiplegia, speech disorder, abnormal gait, meningism, and amnesia. respiratory system: pneumonia, asthma, respiratory infiltration, and lung disorder. skin and appendages: urticaria, macropapular rash, and petechiases. special senses: abnormal vision. urogenital system: kidney function abnormal, albuminuria, pyuria, hematuria, and nephrosis. quinapril monotherapy has been evaluated for safety in 4960 patients. in clinical trials adverse events which occurred with quinapril were also seen with quinapril and hydrochlorothiazide. in addition, the following were reported for quinapril at an incidence >0.5%: depression, back pain, constipation, syncope, and amblyopia. 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. body as a whole: weakness. cardiovascular: orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics). digestive: pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia. neurologic: vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness. musculoskeletal: muscle spasm. hematologic: aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia. renal: renal failure, renal dysfunction, interstitial nephritis (see warnings ). metabolic: hyperglycemia, glycosuria, and hyperuricemia. hypersensitivity: necrotizing angiitis, stevens-johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. clinical laboratory test findings serum electrolytes: see precautions . creatinine, blood urea nitrogen increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 3% and 4%, respectively, of patients treated with quinapril and hydrochlorothiazide. most increases were minor and reversible, which can occur in patients with essential hypertension but most frequently in patients with renal artery stenosis (see precautions ). pbi and tests of parathyroid function: see precautions . hematology: see warnings . other (causal relationships unknown) other clinically important changes in standard laboratory tests were rarely associated with quinapril and hydrochlorothiazide administration. elevations in uric acid, glucose, magnesium, cholesterol, triglyceride, and calcium (see precautions ) have been reported.

function (including acute renal failure) compared to monotherapy. most patients receiving the combination of two ras inhibitors do not obtain any additional benefit compared to monotherapy. in general, avoid combined use of ras inhibitors. closely monitor blood pressure, renal function and electrolytes in patients on quinapril and hydrochlorothiazide and other agents that affect the ras. do not co-administer aliskiren with quinapril and hydrochlorothiazide in patients with diabetes. avoid concomitant use of aliskiren with quinapril and hydrochlorothiazide in patients with renal impairment (gfr <60 ml/min/1.73 m 2 ). 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. gold nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ace inhibitor therapy. non-steroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors (cox-2 inhibitors) in patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of nsaids, including selective cox-2 inhibitors, with ace inhibitors, including quinapril, may result in deterioration of renal function, including possible acute renal failure. these effects are usually reversible. monitor renal function periodically in patients receiving quinapril and nsaid therapy. the antihypertensive effect of ace inhibitors, including quinapril may be attenuated by nsaids. agents that inhibit mtor or other drugs known to cause angioedema: patients taking concomitant mtor inhibitor (e.g., temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema . 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. digoxin: thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events (see precautions ). 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 (see precautions ). 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. non-steroidal anti-inflammatory drugs—the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents.

e 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-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. pharmacokinetics and metabolism the rate and extent of absorption of quinapril and hydrochlorothiazide from quinapril 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 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 and hydrochlorothiazide tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. therefore, quinapril 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 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.

t 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.

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continue quinapril and hydrochlorothiazide until the physician has been consulted. tell patients 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. tell patients planning to undergo major surgery and/ or general or spinal anesthesia to inform their physicians that they are taking an ace inhibitor. hyperkalemia tell patients receiving quinapril and hydrochlorothiazide not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. neutropenia tell patients to promptly report any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia. non-melanoma skin cancer: instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening. 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.