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Basic Drug Info
Drug Name:Quinaretic
Manufacturer:Actavis Totowa LLC
Other Info:QUINARETIC® (Quinapril Hydrochloride and Hydrochlorothiazide Tablets) 8263-07Rx Only



Clinical Trials:


Indications and Usage

QUINARETIC is indicated for the treatment of hypertension.

This fixed combination is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION). In using QUINARETIC, 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.
Hypertensive disease -- Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.

Agranulocytosis -- A decrease in the number of GRANULOCYTES; (BASOPHILS; EOSINOPHILS; and NEUTROPHILS).

COLLAGEN VASCULAR DISEASE --

Angioedema -- Swelling involving the deep DERMIS, subcutaneous, or submucosal tissues, representing localized EDEMA. Angioedema often occurs in the face, lips, tongue, and larynx.

Contraindications
QUINARETIC 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.
Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.

Angioedema -- Swelling involving the deep DERMIS, subcutaneous, or submucosal tissues, representing localized EDEMA. Angioedema often occurs in the face, lips, tongue, and larynx.

Anuria -- Absence of urine formation. It is usually associated with complete bilateral ureteral (URETER) obstruction, complete lower urinary tract obstruction, or unilateral ureteral obstruction when a solitary kidney is present.

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 0.30% 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 QUINARETIC 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). 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: QUINARETIC can cause symptomatic hypotension, probably not more frequently than either monotherapy.

It was reported in 1.2% of 1,571 patients receiving QUINARETIC 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 QUINARETIC. QUINARETIC should be used cautiously in patients receiving concomitant therapy with other antihypertensives.

The thiazide component of QUINARETIC 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 QUINARETIC 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.

QUINARETIC treatment usually can be continued following restoration of blood pressure and volume.

If symptomatic hypotension develops, a dose reduction or discontinuation of QUINARETIC may be necessary. Impaired Renal Function: QUINARETIC 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 QUINARETIC, 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 QUINARETIC 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/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women.

Several dozen cases have been reported in the world literature.

When pregnancy is detected, QUINARETIC should be discontinued as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE inhibitor exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of quinapril as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative ACE inhibitors will be found.

In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, quinapril should be discontinued unless it is considered life-saving for the mother.

Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia.

If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.

Exchange transfusion or peritoneal dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Removal of quinapril, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means. 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 QUINARETIC 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: QUINARETIC 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.

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