Quinapril Hydrochloride/Hydrochlorothiazide

WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin converting inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including quinapril) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors and has been seen in 0.1% of patients receiving quinapril. In two similarly sized US postmarketing quinapril trials that, combined, enrolled over 3,000 black patients and over 19,000 non-blacks, angioedema was reported in 0.3% and 0.55% of blacks (in Study 1 and 2, respectively) and 0.39% and 0.17% of non-blacks. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with quinapril and hydrochlorothiazide should be discontinued immediately, 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.