FDA label c47cbdce-8ace-47dd-a5e6-963e700af58f

USE IN PREGNANCY When used in pregnancy, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, benazepril hydrochloride and hydrochlorothiazide should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril and hydrochlorothiazide) 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 angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with benazepril and hydrochlorothiazide should be discontinued and appropriate therapy instituted immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 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. 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 rechallenge. 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. Hypotension Benazepril and hydrochlorothiazide can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with benazepril and hydrochlorothiazide. Benazepril and hydrochlorothiazide should be used cautiously in patients receiving concomitant therapy with other antihypertensives. The thiazide component of benazepril 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 patient. In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and (rarely) with acute renal failure and death. In such patients, benazepril and hydrochlorothiazide therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased. If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Benazepril and hydrochlorothiazide treatment usually can be continued following restoration of blood pressure and volume. Impaired Renal Function Benazepril 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 benazepril, 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 benazepril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In a small study of hypertensive patients with unilateral or bilateral renal artery stenosis , treatment with benazepril was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of benazepril therapy, concomitant diuretic therapy, or both. When such patients are treated with benazepril and hydrochlorothiazide, renal function should be monitored during the first few weeks of therapy. Some benazepril-treated hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when benazepril has been given concomitantly with a diuretic. Dosage reduction of benazepril and hydrochlorothiazide may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION ). Neutropenia/Agranulocytosis Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients (incidence probably less than once per 10,000 exposures) but more frequently (incidence possibly as great as once per 1,000 exposures) in patients with renal impairment, especially those who also have collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of benazepril are insufficient to show that benazepril does not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function. 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, benazepril and hydrochlorothiazide should be discontinued as soon as possible and monitoring of the fetal development should be performed on a regular basis. 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. In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated with a potentially increased risk of birth defects. In women planning to become pregnant, ACE inhibitors (including benazepril and hydrochlorothiazide) should not be used. Women of child-bearing age should be made aware of the potential risk and ACE inhibitors (including benazepril and hydrochlorothiazide) should only be given after careful counseling and consideration of individual risks and benefits. Rarely (probably less often than once in every thousand pregnancies), no alternative to 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, benazepril 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 means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers, but experience is limited. Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. No teratogenic effects were seen when benazepril and hydrochlorothiazide were administered to pregnant rats at a dose ratio of 4:5. On a mg/kg basis, the doses used were up to 167 times the maximum recommended human dose. Similarly, no teratogenic effects were seen when benazepril and hydrochlorothiazide were administered to pregnant mice at total doses up to 160 mg/kg/day, with benazepril:hydrochlorothiazide ratios of 15:1. When hydrochlorothiazide was orally administered without benazepril to pregnant mice and rats during their respective periods of major organogenesis, at doses up to 3000 and 1000 mg/kg/day respectively, there was no evidence of harm to the fetus. Similarly, no teratogenic effects of benazepril were seen in studies of pregnant rats, mice, and rabbits; on a mg/kg basis, the doses used in these studies were 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose. 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. Impaired Hepatic Function Benazepril 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 (see Hepatic Failure , above). In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially unaltered. No formal 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.

ADVERSE REACTIONS Benazepril and hydrochlorothiazide has been evaluated for safety in over 2,500 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 200 were treated for more than 1 year. The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 7% of U.S. patients treated with benazepril and hydrochlorothiazide and in 4% of patients treated with placebo. The most common reasons for discontinuation of therapy with benazepril and hydrochlorothiazide in U.S. studies were cough (1%; see PRECAUTIONS ), "dizziness" (1%), headache (0.6%), and fatigue (0.6%). The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with benazepril and hydrochlorothiazide are shown in the table below. Reactions Possibly or Probably Drug Related Patients In U.S. Placebo-Controlled Studies Benazepril/HCTZ Placebo (N=665) (N=235) N % N % “Dizziness” 41 6.3 8 3.4 Fatigue 34 5.2 6 2.6 Postural Dizziness 23 3.5 1 0.4 Headache 20 3.1 10 4.3 Cough 14 2.1 3 1.3 Hypertonia 10 1.5 3 1.3 Vertigo 10 1.5 2 0.9 Nausea 9 1.4 2 0.9 Impotence 8 1.2 0 0.0 Somnolence 8 1.2 1 0.4 Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in 0.3% to 1% of patients treated with benazepril and hydrochlorothiazide were the following: Angioedema Edema of the lips or face without other manifestations of angioedema (0.3%). See WARNINGS, Head and Neck Angioedema . Cardiovascular Hypotension (seen in 0.6% of patients), postural hypotension (0.3%), palpitations, and flushing Gastrointestinal Vomiting, diarrhea, dyspepsia, anorexia, and constipation Neurologic and Psychiatric Insomnia, nervousness, paresthesia, libido decrease, dry mouth, taste perversion, and tinnitus Dermatologic Rash and sweating Other Gout, urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest pain and abdominal pain) Other adverse experiences reported in 0.3% or more of benazepril and hydrochlorothiazide patients in U.S. controlled clinical trials, and rarer events seen in postmarketing experience, were the following; asterisked entries occurred in more than 1% of patients (in some, a causal relationship to benazepril and hydrochlorothiazide is uncertain): Angioedema Edema of the lips or face without other manifestations of angioedema. See WARNINGS, Head and Neck Angioedema . Cardiovascular Syncope, peripheral vascular disorder, and tachycardia Body as a Whole Infection, back pain*, flu syndrome*, fever, chills, and neck pain Dermatologic Photosensitivity and pruritus Gastrointestinal Gastroenteritis, flatulence, and tooth disorder Neurologic and Psychiatric Hypesthesia, abnormal vision, abnormal dreams, and retinal disorder Respiratory Upper respiratory infection*, epistaxis, bronchitis, rhinitis*, sinusitis*, and voice alteration Other Conjunctivitis, arthritis, urinary tract infection, alopecia, and urinary frequency* Fetal/Neonatal Morbidity and Mortality See WARNINGS , Fetal/Neonatal Morbidity and Mortality Monotherapy with benazepril has been evaluated for safety in over 6,000 patients. In clinical trials, the observed adverse reactions to benazepril were similar to those seen in trials of benazepril and hydrochlorothiazide. In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia. Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors. Unknown frequency: small bowel angiodedema, anaphylactoid reactions, hyperkalemia, agranulocytosis, neutropenia. 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. Cardiovascular Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics) Digestive Pancreatitis, jaundice (intrahepatic cholestatic) (see WARNINGS ), 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, and thrombocytopenia 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 Minor reversible increases in serum creatinine were observed in patients with essential hypertension treated with benazepril and hydrochlorothiazide. Such increases occurred most frequently in patients with renal artery stenosis (see PRECAUTIONS ). PBI and Tests of Parathyroid Function See PRECAUTIONS Other (Causal Relationships Unknown) Other clinically important changes in standard laboratory tests were rarely associated with benazepril and hydrochlorothiazide administration. Elevations in blood urea nitrogen, uric acid, glucose, SGOT, and SGPT have been reported (see WARNINGS ). In the somewhat larger patient population exposed to benazepril monotherapy in U.S. trials, the same abnormalities were reported, together with scattered accounts of hyponatremia, melena, electrocardiographic changes, leukopenia, eosinophilia, and proteinuria.

<table border="1" ID="id_da46524e-dcbb-456a-9b8c-a57d5e2ed48c"> <caption ID="id_22d35903-1db7-4379-8c74-a57790a96ce7">Reactions Possibly or Probably Drug Related Patients In U.S. Placebo-Controlled Studies</caption> <col width="124px"/> <col width="124px"/> <col width="124px"/> <col width="124px"/> <col width="124px"/> <tbody> <tr ID="id_cb55f7b4-0c42-45be-ab0f-4b10b5aef9f2"> <td align="left" valign="top" styleCode="Toprule Botrule Lrule"> </td> <td align="left" valign="top" colspan="2" styleCode="Botrule"> <content styleCode="bold">Benazepril/HCTZ </content> </td> <td align="left" valign="top" colspan="2" styleCode="Botrule Rrule"> <content styleCode="bold">Placebo</content> </td> </tr> <tr ID="id_246adacd-3f59-420a-841f-2cbdb4488a04"> <td align="left" valign="top" styleCode="Lrule Botrule"> </td> <td align="left" valign="top" colspan="2" styleCode="Botrule"> <content styleCode="bold">(N=665) </content> </td> <td align="left" valign="top" colspan="2" styleCode="Botrule Rrule"> <content styleCode="bold">(N=235)</content> </td> </tr> <tr ID="id_e88cea0c-57c1-451d-b4a0-1388a740ad1c"> <td align="left" valign="top" styleCode="Lrule Botrule"> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">N</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">%</content> </td> <td align="center" valign="top" styleCode="Botrule"> <content styleCode="bold">N</content> </td> <td align="center" valign="top" styleCode="Botrule Rrule"> <content styleCode="bold">%</content> </td> </tr> <tr ID="id_3f0418f0-c07f-42ad-b250-6265a6c48333"> <td align="left" valign="top" styleCode="Lrule Botrule"> &#x201C;Dizziness&#x201D; </td> <td align="center" valign="top" styleCode="Botrule"> 41 </td> <td align="center" valign="top" styleCode="Botrule"> 6.3 </td> <td align="center" valign="top" styleCode="Botrule"> 8 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 3.4 </td> </tr> <tr ID="id_b45ca3c6-e6d4-4cba-bf47-4c86894fedbe"> <td align="left" valign="top" styleCode="Lrule Botrule"> Fatigue </td> <td align="center" valign="top" styleCode="Botrule"> 34 </td> <td align="center" valign="top" styleCode="Botrule"> 5.2 </td> <td align="center" valign="top" styleCode="Botrule"> 6 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 2.6 </td> </tr> <tr ID="id_dd7915a6-2527-4f38-a0da-2fee26799ae0"> <td align="left" valign="top" styleCode="Lrule Botrule"> Postural Dizziness </td> <td align="center" valign="top" styleCode="Botrule"> 23 </td> <td align="center" valign="top" styleCode="Botrule"> 3.5 </td> <td align="center" valign="top" styleCode="Botrule"> 1 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 0.4 </td> </tr> <tr ID="id_86d16a39-b216-413f-ae06-cde4f9521565"> <td align="left" valign="top" styleCode="Lrule Botrule"> Headache </td> <td align="center" valign="top" styleCode="Botrule"> 20 </td> <td align="center" valign="top" styleCode="Botrule"> 3.1 </td> <td align="center" valign="top" styleCode="Botrule"> 10 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 4.3 </td> </tr> <tr ID="id_5c96459a-adca-4713-a158-463e6adbc73e"> <td align="left" valign="top" styleCode="Lrule Botrule"> Cough </td> <td align="center" valign="top" styleCode="Botrule"> 14 </td> <td align="center" valign="top" styleCode="Botrule"> 2.1 </td> <td align="center" valign="top" styleCode="Botrule"> 3 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 1.3 </td> </tr> <tr ID="id_2c0b93f6-5073-4b6a-9fb6-2039ae4147b2"> <td align="left" valign="top" styleCode="Lrule Botrule"> Hypertonia </td> <td align="center" valign="top" styleCode="Botrule"> 10 </td> <td align="center" valign="top" styleCode="Botrule"> 1.5 </td> <td align="center" valign="top" styleCode="Botrule"> 3 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 1.3 </td> </tr> <tr ID="id_cd0b85f9-c90b-4ef2-89c5-7a0562bf0ff2"> <td align="left" valign="top" styleCode="Lrule Botrule"> Vertigo </td> <td align="center" valign="top" styleCode="Botrule"> 10 </td> <td align="center" valign="top" styleCode="Botrule"> 1.5 </td> <td align="center" valign="top" styleCode="Botrule"> 2 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 0.9 </td> </tr> <tr ID="id_cdb027ef-84a1-4b39-a18c-e950fa4aca04"> <td align="left" valign="top" styleCode="Lrule Botrule"> Nausea </td> <td align="center" valign="top" styleCode="Botrule"> 9 </td> <td align="center" valign="top" styleCode="Botrule"> 1.4 </td> <td align="center" valign="top" styleCode="Botrule"> 2 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 0.9 </td> </tr> <tr ID="id_3cbb075d-777f-49be-8fac-4a97326875f3"> <td align="left" valign="top" styleCode="Lrule Botrule"> Impotence </td> <td align="center" valign="top" styleCode="Botrule"> 8 </td> <td align="center" valign="top" styleCode="Botrule"> 1.2 </td> <td align="center" valign="top" styleCode="Botrule"> 0 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 0.0 </td> </tr> <tr ID="id_5f5c4680-9886-493c-8481-f9e15beec244"> <td align="left" valign="top" styleCode="Lrule Botrule"> Somnolence </td> <td align="center" valign="top" styleCode="Botrule"> 8 </td> <td align="center" valign="top" styleCode="Botrule"> 1.2 </td> <td align="center" valign="top" styleCode="Botrule"> 1 </td> <td align="center" valign="top" styleCode="Botrule Rrule"> 0.4 </td> </tr> </tbody> </table>