Principal Display Panel - 20mg/25mg

When pregnancy is detected, discontinue benazepril hydrochloride and hydrochlorothiazide tablets as soon as possible.   Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (see WARNINGS: Fetal Toxicity) .

Benazepril hydrochloride and hydrochlorothiazide tablets are indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION ).

Dose once daily. The dosage may then be increased after 2 to 3 weeks as needed to help achieve blood pressure goals. The maximum recommended dose is 20/25 mg.  Switch Therapy : A patient whose blood pressure is not adequately controlled with benazepril alone or with hydrochlorothiazide alone may be switched to combination therapy with benazepril hydrochloride and hydrochlorothiazide tablets. The usual recommended starting dose is 10 mg/12.5 mg once daily to control blood pressure. Replacement Therapy: The combination may be substituted for the titrated individual components.

Benazepril hydrochloride and hydrochlorothiazide tablets, USP 5 mg/6.25 mg are available for administration as white to off-white, round tablets, scored and engraved “APO” on one side, “5” over bisect “6.25” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0261-3) Bottles of 100 (NDC 60505-0261-1) Bottles of 1,000 (NDC 60505-0261-8) Benazepril hydrochloride and hydrochlorothiazide tablets, USP 10 mg/12.5 mg are available for administration as light pink, round, scored tablets, engraved “APO” on one side, “10” over bisect “12.5” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0262-3) Bottles of 100 (NDC 60505-0262-1) Bottles of 1,000 (NDC 60505-0262-8) Benazepril hydrochloride and hydrochlorothiazide tablets, USP 20 mg/12.5 mg are available for administration as greyish-violet, round, scored tablets, engraved “APO” on one side, “20” over bisect “12.5” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0263-3) Bottles of 100 (NDC 60505-0263-1) Bottles of 1,000 (NDC 60505-0263-8) Benazepril hydrochloride and hydrochlorothiazide tablets, USP 20 mg/25 mg are available for administration as reddish brown, round, scored tablets, engraved “APO” on one side, “20” over bisect “25” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0264-3) Bottles of 100 (NDC 60505-0264-1)  Bottles of 1,000 (NDC 60505-0264-8) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Dispense in a tight, light-resistant container [see USP]. APOTEX INC. BENAZEPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE TABLETS, USP 5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg and 20 mg/25 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 USA 33326 Rev. 14 August 2024

Benazepril hydrochloride and hydrochlorothiazide tablets are contraindicated in patients who are anuric. Benazepril hydrochloride and hydrochlorothiazide tablets are also contraindicated in patients who are hypersensitive to benazepril, to any other ACE inhibitor, to hydrochlorothiazide, or to other sulfonamide-derived drugs. Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma. Benazepril hydrochloride and hydrochlorothiazide tablets are also contraindicated in patients with a history of angioedema with or without previous ACE inhibitor treatment. Benazepril hydrochloride and hydrochlorothiazide tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer benazepril hydrochloride and hydrochlorothiazide tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNING and PRECAUTIONS ). Do not co-administer aliskiren with angiotensin receptor blockers, ACE inhibitors, including benazepril hydrochloride and hydrochlorothiazide tablets in patients with diabetes.

Benazepril hydrochloride, USP is a white to off-white crystalline powder, soluble ( > 100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino] -2,3,4,5-tetrahydro-2-oxo-1 H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is Its molecular formula is C 24 H 28 N 2 O 5 ·HCl, and its molecular weight is 460.96 g/mol. Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group. Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n -butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide’s chemical name is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural formula is Its molecular formula is C 7 H 8 ClN 3 O 4 S 2 , and its molecular weight is 297.74 g/mol. Hydrochlorothiazide is a thiazide diuretic. Benazepril hydrochloride and hydrochlorothiazide tablets, USP are a combination of benazepril hydrochloride, USP and hydrochlorothiazide, USP. The tablets are formulated for oral administration with a combination of 5, 10, or 20 mg of benazepril hydrochloride, USP and 6.25, 12.5, or 25 mg of hydrochlorothiazide, USP. The inactive ingredients of the tablets are black iron oxide (20 mg/12.5 mg), crospovidone, colloidal silicon dioxide, ferric oxide (10 mg/12.5 mg, 20 mg/12.5 mg and 20 mg/25 mg), hypromellose, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, titanium dioxide and zinc stearate.

Serum Electrolyte Abnormalities   In clinical trials of benazepril hydrochloride and hydrochlorothiazide tablets, the average change in serum potassium was near zero in subjects who received 5/6.25 mg or 20/12.5 mg, but the average subject who received 10/12.5 mg or 20/25 mg experienced a mild reduction in serum potassium, similar to that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.  Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. Metabolic Disturbances Hydrochlorothiazide   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.  Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium. Avoid using benazepril hydrochloride and hydrochlorothiazide tablets in patients with hypercalcemia. Cough : Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always 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, benazepril 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.

Neprilysin Inhibitors Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema. Interactions Common for Both Benazepril and Hydrochlorothiazide Potassium Supplements and Potassium-Sparing Diuretics : Concomitant use with benazepril hydrochloride and hydrochlorothiazide tablets may effect potassium levels. Monitor potassium periodically. mTOR (mammalian target of rapamycin) inhibitors: Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS ) . Lithium : Renal clearance of lithium is reduced by thiazides and increase the risk of lithium toxicity. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Monitor lithium levels when used concomitantly with benazepril hydrochloride and hydrochlorothiazide tablets. Dual Blockade of the Renin-Angiotensin System (RAS): Dual Blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypertension, hyperkalemia, and changes in renal 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 benazepril hydrochloride and hydrochlorothiazide tablets and other agents that affect the RAS. Do not coadminister aliskiren with benazepril hydrochloride and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with benazepril hydrochloride and hydrochlorothiazide tablets in patients with renal impairment (GFR < 60 mL/min). NSAIDs and Cox-2 selective agents : In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy. The antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.   Benazepril   Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions. Other ACE inhibitors have had less than additive effects with beta-adrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.  Interaction studies with warfarin and acenocoumarol have failed to identify any clinically important effects of benazepril on the serum concentrations or clinical effects of these anticoagulants. 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. Hydrochlorothiazide Ion exchange resins: Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of 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. Digitalis glycosides : Thiazide-induced hypokalemia or hypomagnesemia may predispose the patients to digoxin toxicity.  Skeletal muscle relaxants : Possible increased responsiveness to muscle relaxants such as curare derivatives. Antidiabetic agents: Dosage adjustment of antidiabetic drug may be required.  Antineoplastic agents (e.g., cyclophosphamide, methotrexate) : Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects. Drugs that alter gastrointestinal motility : The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics. Cyclosporin: Concomitant treatment with diuretics may increase the risk of hyperuricemia and gout-type complications. Alcohol, barbiturates or narcotics: Concomitant administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Pressor amines: Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline, but the clinical significance of this effect is not sufficient to preclude their use.

The hydrochlorothiazide component of benazepril hydrochloride and hydrochlorothiazide tablets may decrease serum PBI levels without signs of thyroid disturbance. Therapy with benazepril hydrochloride and hydrochlorothiazide tablets should be interrupted for a few days before carrying out tests of parathyroid function.

Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. A patient receiving benazepril hydrochloride and hydrochlorothiazide tablets should be told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drugs until after consulting with the prescribing physician. Pregnancy : Female patients of childbearing age should be told about the consequences of exposure to benazepril hydrochloride and hydrochlorothiazide tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension : A patient receiving benazepril hydrochloride and hydrochlorothiazide tablets should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patient should be told that if syncope occurs, benazepril hydrochloride and hydrochlorothiazide tablets should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Hyperkalemia: A patient receiving benazepril hydrochloride and hydrochlorothiazide tablets should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia. Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

Neonates with a history of in ute ro exposure to benazepril hydrochloride and hydrochlorothiazide tablets If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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 with another ACE inhibitor, but experience is limited.  Safety and effectiveness in pediatric patients have not been established.

Of the total number of patients who received benazepril hydrochloride and hydrochlorothiazide tablets in U.S. clinical studies of benazepril hydrochloride and hydrochlorothiazide tablets, 19% were 65 or older while about 1.5% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

Carcinogenesis, Mutagenicity, Fertility No evidence of carcinogenicity was found when benazepril was given to rats and mice for 104 weeks at doses up to 150 mg/kg/day. On a body-surface-area basis, this dose is 18 times (rats) and 9 times (mice) the maximum recommended human dose. No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50 to 500 mg/kg/day (6 to 61 times the maximum recommended dose on a body-surface-area basis), benazepril had no adverse effect on the reproductive performance of male and female rats. 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 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.

      Benazepril hydrochloride and hydrochlorothiazide tablets have been evaluated for safety in over 2500 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 hydrochloride and hydrochlorothiazide tablets and in 4% of patients treated with placebo. The most common reasons for discontinuation of therapy with benazepril hydrochloride and hydrochlorothiazide tablets in U.S. studies were cough (1.0%; see PRECAUTIONS ), “dizziness” (1.0%), 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 hydrochloride and hydrochlorothiazide tablets are shown in the table below. Reactions Possibly or Probably Drug Related Patients in U.S. Placebo-Controlled Studies Benazepril Hydrochloride and          Placebo Hydrochlorothiazide Tablets         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 1.0% of patients treated with benazepril hydrochloride and hydrochlorothiazide tablets were the following: Cardiovascular : Palpitations, 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: Urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest pain and abdominal pain). Other adverse experiences reported in 0.3% or more of benazepril hydrochloride and hydrochlorothiazide tablets patients in U.S. controlled clinical trials, and rarer events seen in post-marketing experience, were the following; asterisked entries occurred in more than 1% of patients (in some, a causal relationship to benazepril hydrochloride and hydrochlorothiazide tablets is uncertain): 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*. Post-Marketing Experience   The following adverse reactions have been identified during post-approval use of either benazepril or hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure: 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 ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.  Benazepril   Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia, eosinophilic pneumonitis . Hydrochlorothiazide Digestive: Pancreatitis, small bowel angioedema, 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, neutropenia and thrombocytopenia. Metabolic : Hyperglycemia, glycosuria, and hyperuricemia, pyrexia, asthenia, parathyroid gland changes with hypercalcemia and hypophosphatemia. Hypersensitivity : Anaphylactoid reactions, necrotizing angiitis, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Skin: Erythema multiforme including Stevens-Johnson syndrome, and exfoliative dermatitis including toxic epidermal necrolysis.

No specific information is available on the treatment of overdosage with benazepril hydrochloride and hydrochlorothiazide tablets; treatment should be symptomatic and supportive. Therapy with benazepril hydrochloride and hydrochlorothiazide tablets should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures. Single oral doses of 1 g/kg of benazepril caused reduced activity in mice, and doses of 3 g/kg were associated with significant lethality. Reduction of activity in rats was not seen until they had received doses of 5 g/kg, and doses of 6 g/kg were not lethal. In single-dose studies of hydrochlorothiazide, most rats survived doses up to 2.75 g/kg. Data from human overdoses of benazepril are scanty, but the most common manifestation of human benazepril overdosage is likely to be hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory determinations of serum levels of benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of benazepril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of benazepril and its metabolites. Benazeprilat is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see WARNINGS ). Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline solution.

In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2 to 4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20 mg to 80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6 to 12/4 to 7 mm Hg. The reductions at trough are about 50% of those seen at peak.  Four dose-response studies of benazepril monotherapy using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of benazepril was 10 mg; further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10 mg to 80 mg). In studies comparing the same daily dose of benazepril given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen. The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets. Benazepril-Hydrochlorothiazide   In 15 controlled clinical trials, 1453 healthy or hypertensive patients were exposed to benazepril and hydrochlorothiazide of which 459 were exposed for at least 6 months, 214 for at least 12 months and 25 for at least 24 months.  The combination of benazepril-hydrochlorothiazide resulted in mean placebo-adjusted decreases in sitting systolic and diastolic blood pressures of 10/6 mm Hg with 5/6.25 mg and 10/12.5 mg doses, and 20/10 mm Hg with 20/25 mg dose. In clinical trials of benazepril/hydrochlorothiazide using benazepril doses of 5/20 mg and hydrochlorothiazide doses of 6.25/25 mg, the antihypertensive effects were sustained for at least 24 hours, and they increased with increasing dose of either component. Although benazepril monotherapy is somewhat less effective in blacks than in nonblacks, the efficacy of combination therapy appears to be independent of race.

There are no human fertility data for hydrochlorothiazide. In animal studies, benazepril and hydrochlorothiazide alone or in combination had no effect on fertility and conception (see PRECAUTIONS, Non-Clinical Safety Data ).

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Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium (see PRECAUTIONS ). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of benazepril hydrochloride and hydrochlorothiazide tablets remains to be elucidated. While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.

Benazepril Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. For up to 4 hours after a 10-mg dose, pressor responses to exogenous angiotensin I were inhibited by 60% to 90%. In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.   Hydrochlorothiazide After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. Drug Interactions   Benazepril hydrochloride and hydrochlorothiazide tablets potentiate the antihypertensive action of other antihypertensive drugs (e.g., curare derivatives, guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors and ARBs and DRIs).

Representative sample of labeling (see HOW SUPPLIED section for complete listing: APOTEX CORP. NDC 60505-0261-1 Benazepril HCI and Hdrochlorothiazide Tablets 5 mg/6.25 mg, USP Benazepril Hydrochloride USP 5 mg Hydrochlorothiazide USP 6.25 mg Rx Only 100 Tablets

When pregnancy is detected, discontinue benazepril hydrochloride and hydrochlorothiazide tablets as soon as possible.   Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (see WARNINGS: Fetal Toxicity) .

Benazepril hydrochloride and hydrochlorothiazide tablets are indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION ).

Dose once daily. The dosage may then be increased after 2 to 3 weeks as needed to help achieve blood pressure goals. The maximum recommended dose is 20/25 mg.  Switch Therapy : A patient whose blood pressure is not adequately controlled with benazepril alone or with hydrochlorothiazide alone may be switched to combination therapy with benazepril hydrochloride and hydrochlorothiazide tablets. The usual recommended starting dose is 10 mg/12.5 mg once daily to control blood pressure. Replacement Therapy: The combination may be substituted for the titrated individual components.

Benazepril hydrochloride and hydrochlorothiazide tablets, USP 5 mg/6.25 mg are available for administration as white to off-white, round tablets, scored and engraved “APO” on one side, “5” over bisect “6.25” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0261-3) Bottles of 100 (NDC 60505-0261-1) Bottles of 1,000 (NDC 60505-0261-8) Benazepril hydrochloride and hydrochlorothiazide tablets, USP 10 mg/12.5 mg are available for administration as light pink, round, scored tablets, engraved “APO” on one side, “10” over bisect “12.5” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0262-3) Bottles of 100 (NDC 60505-0262-1) Bottles of 1,000 (NDC 60505-0262-8) Benazepril hydrochloride and hydrochlorothiazide tablets, USP 20 mg/12.5 mg are available for administration as greyish-violet, round, scored tablets, engraved “APO” on one side, “20” over bisect “12.5” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0263-3) Bottles of 100 (NDC 60505-0263-1) Bottles of 1,000 (NDC 60505-0263-8) Benazepril hydrochloride and hydrochlorothiazide tablets, USP 20 mg/25 mg are available for administration as reddish brown, round, scored tablets, engraved “APO” on one side, “20” over bisect “25” on the other side. They are supplied as follows: Bottles of 30 (NDC 60505-0264-3) Bottles of 100 (NDC 60505-0264-1)  Bottles of 1,000 (NDC 60505-0264-8) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light. Dispense in a tight, light-resistant container [see USP]. APOTEX INC. BENAZEPRIL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE TABLETS, USP 5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg and 20 mg/25 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 USA 33326 Rev. 14 August 2024

Benazepril hydrochloride and hydrochlorothiazide tablets are contraindicated in patients who are anuric. Benazepril hydrochloride and hydrochlorothiazide tablets are also contraindicated in patients who are hypersensitive to benazepril, to any other ACE inhibitor, to hydrochlorothiazide, or to other sulfonamide-derived drugs. Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma. Benazepril hydrochloride and hydrochlorothiazide tablets are also contraindicated in patients with a history of angioedema with or without previous ACE inhibitor treatment. Benazepril hydrochloride and hydrochlorothiazide tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer benazepril hydrochloride and hydrochlorothiazide tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNING and PRECAUTIONS ). Do not co-administer aliskiren with angiotensin receptor blockers, ACE inhibitors, including benazepril hydrochloride and hydrochlorothiazide tablets in patients with diabetes.

Serum Electrolyte Abnormalities   In clinical trials of benazepril hydrochloride and hydrochlorothiazide tablets, the average change in serum potassium was near zero in subjects who received 5/6.25 mg or 20/12.5 mg, but the average subject who received 10/12.5 mg or 20/25 mg experienced a mild reduction in serum potassium, similar to that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.  Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. Metabolic Disturbances Hydrochlorothiazide   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.  Thiazides decrease urinary calcium excretion and may cause mild elevation of serum calcium. Avoid using benazepril hydrochloride and hydrochlorothiazide tablets in patients with hypercalcemia. Cough : Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always 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, benazepril 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.

Neprilysin Inhibitors Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema. Interactions Common for Both Benazepril and Hydrochlorothiazide Potassium Supplements and Potassium-Sparing Diuretics : Concomitant use with benazepril hydrochloride and hydrochlorothiazide tablets may effect potassium levels. Monitor potassium periodically. mTOR (mammalian target of rapamycin) inhibitors: Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS ) . Lithium : Renal clearance of lithium is reduced by thiazides and increase the risk of lithium toxicity. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. Monitor lithium levels when used concomitantly with benazepril hydrochloride and hydrochlorothiazide tablets. Dual Blockade of the Renin-Angiotensin System (RAS): Dual Blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypertension, hyperkalemia, and changes in renal 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 benazepril hydrochloride and hydrochlorothiazide tablets and other agents that affect the RAS. Do not coadminister aliskiren with benazepril hydrochloride and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with benazepril hydrochloride and hydrochlorothiazide tablets in patients with renal impairment (GFR < 60 mL/min). NSAIDs and Cox-2 selective agents : In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy. The antihypertensive effect of benazepril and hydrochlorothiazide may be attenuated by NSAIDs.   Benazepril   Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, hydralazine, and naproxen without evidence of clinically important adverse interactions. Other ACE inhibitors have had less than additive effects with beta-adrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.  Interaction studies with warfarin and acenocoumarol have failed to identify any clinically important effects of benazepril on the serum concentrations or clinical effects of these anticoagulants. 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. Hydrochlorothiazide Ion exchange resins: Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4 to 6 hours after the administration of 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. Digitalis glycosides : Thiazide-induced hypokalemia or hypomagnesemia may predispose the patients to digoxin toxicity.  Skeletal muscle relaxants : Possible increased responsiveness to muscle relaxants such as curare derivatives. Antidiabetic agents: Dosage adjustment of antidiabetic drug may be required.  Antineoplastic agents (e.g., cyclophosphamide, methotrexate) : Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects. Drugs that alter gastrointestinal motility : The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g., atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics. Cyclosporin: Concomitant treatment with diuretics may increase the risk of hyperuricemia and gout-type complications. Alcohol, barbiturates or narcotics: Concomitant administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension. Pressor amines: Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline, but the clinical significance of this effect is not sufficient to preclude their use.

The hydrochlorothiazide component of benazepril hydrochloride and hydrochlorothiazide tablets may decrease serum PBI levels without signs of thyroid disturbance. Therapy with benazepril hydrochloride and hydrochlorothiazide tablets should be interrupted for a few days before carrying out tests of parathyroid function.

Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. A patient receiving benazepril hydrochloride and hydrochlorothiazide tablets should be told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drugs until after consulting with the prescribing physician. Pregnancy : Female patients of childbearing age should be told about the consequences of exposure to benazepril hydrochloride and hydrochlorothiazide tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension : A patient receiving benazepril hydrochloride and hydrochlorothiazide tablets should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patient should be told that if syncope occurs, benazepril hydrochloride and hydrochlorothiazide tablets should be discontinued until the physician has been consulted. All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Hyperkalemia: A patient receiving benazepril hydrochloride and hydrochlorothiazide tablets should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia. Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

Neonates with a history of in ute ro exposure to benazepril hydrochloride and hydrochlorothiazide tablets If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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 with another ACE inhibitor, but experience is limited.  Safety and effectiveness in pediatric patients have not been established.

Of the total number of patients who received benazepril hydrochloride and hydrochlorothiazide tablets in U.S. clinical studies of benazepril hydrochloride and hydrochlorothiazide tablets, 19% were 65 or older while about 1.5% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. A limited amount of data suggests that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.

Carcinogenesis, Mutagenicity, Fertility No evidence of carcinogenicity was found when benazepril was given to rats and mice for 104 weeks at doses up to 150 mg/kg/day. On a body-surface-area basis, this dose is 18 times (rats) and 9 times (mice) the maximum recommended human dose. No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50 to 500 mg/kg/day (6 to 61 times the maximum recommended dose on a body-surface-area basis), benazepril had no adverse effect on the reproductive performance of male and female rats. 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 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.

      Benazepril hydrochloride and hydrochlorothiazide tablets have been evaluated for safety in over 2500 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 hydrochloride and hydrochlorothiazide tablets and in 4% of patients treated with placebo. The most common reasons for discontinuation of therapy with benazepril hydrochloride and hydrochlorothiazide tablets in U.S. studies were cough (1.0%; see PRECAUTIONS ), “dizziness” (1.0%), 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 hydrochloride and hydrochlorothiazide tablets are shown in the table below. Reactions Possibly or Probably Drug Related Patients in U.S. Placebo-Controlled Studies Benazepril Hydrochloride and          Placebo Hydrochlorothiazide Tablets         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 1.0% of patients treated with benazepril hydrochloride and hydrochlorothiazide tablets were the following: Cardiovascular : Palpitations, 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: Urinary frequency, arthralgia, myalgia, asthenia, and pain (including chest pain and abdominal pain). Other adverse experiences reported in 0.3% or more of benazepril hydrochloride and hydrochlorothiazide tablets patients in U.S. controlled clinical trials, and rarer events seen in post-marketing experience, were the following; asterisked entries occurred in more than 1% of patients (in some, a causal relationship to benazepril hydrochloride and hydrochlorothiazide tablets is uncertain): 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*. Post-Marketing Experience   The following adverse reactions have been identified during post-approval use of either benazepril or hydrochlorothiazide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure: 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 ≥50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.  Benazepril   Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia, eosinophilic pneumonitis . Hydrochlorothiazide Digestive: Pancreatitis, small bowel angioedema, 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, neutropenia and thrombocytopenia. Metabolic : Hyperglycemia, glycosuria, and hyperuricemia, pyrexia, asthenia, parathyroid gland changes with hypercalcemia and hypophosphatemia. Hypersensitivity : Anaphylactoid reactions, necrotizing angiitis, respiratory distress (including pneumonitis and pulmonary edema), purpura, urticaria, rash, and photosensitivity. Skin: Erythema multiforme including Stevens-Johnson syndrome, and exfoliative dermatitis including toxic epidermal necrolysis.

No specific information is available on the treatment of overdosage with benazepril hydrochloride and hydrochlorothiazide tablets; treatment should be symptomatic and supportive. Therapy with benazepril hydrochloride and hydrochlorothiazide tablets should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures. Single oral doses of 1 g/kg of benazepril caused reduced activity in mice, and doses of 3 g/kg were associated with significant lethality. Reduction of activity in rats was not seen until they had received doses of 5 g/kg, and doses of 6 g/kg were not lethal. In single-dose studies of hydrochlorothiazide, most rats survived doses up to 2.75 g/kg. Data from human overdoses of benazepril are scanty, but the most common manifestation of human benazepril overdosage is likely to be hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory determinations of serum levels of benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of benazepril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of benazepril and its metabolites. Benazeprilat is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see WARNINGS ). Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline solution.

Benazepril hydrochloride, USP is a white to off-white crystalline powder, soluble ( > 100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino] -2,3,4,5-tetrahydro-2-oxo-1 H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is Its molecular formula is C 24 H 28 N 2 O 5 ·HCl, and its molecular weight is 460.96 g/mol. Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting enzyme inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group. Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n -butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide’s chemical name is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural formula is Its molecular formula is C 7 H 8 ClN 3 O 4 S 2 , and its molecular weight is 297.74 g/mol. Hydrochlorothiazide is a thiazide diuretic. Benazepril hydrochloride and hydrochlorothiazide tablets, USP are a combination of benazepril hydrochloride, USP and hydrochlorothiazide, USP. The tablets are formulated for oral administration with a combination of 5, 10, or 20 mg of benazepril hydrochloride, USP and 6.25, 12.5, or 25 mg of hydrochlorothiazide, USP. The inactive ingredients of the tablets are black iron oxide (20 mg/12.5 mg), crospovidone, colloidal silicon dioxide, ferric oxide (10 mg/12.5 mg, 20 mg/12.5 mg and 20 mg/25 mg), hypromellose, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, titanium dioxide and zinc stearate.

In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2 to 4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20 mg to 80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6 to 12/4 to 7 mm Hg. The reductions at trough are about 50% of those seen at peak.  Four dose-response studies of benazepril monotherapy using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of benazepril was 10 mg; further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10 mg to 80 mg). In studies comparing the same daily dose of benazepril given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen. The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets. Benazepril-Hydrochlorothiazide   In 15 controlled clinical trials, 1453 healthy or hypertensive patients were exposed to benazepril and hydrochlorothiazide of which 459 were exposed for at least 6 months, 214 for at least 12 months and 25 for at least 24 months.  The combination of benazepril-hydrochlorothiazide resulted in mean placebo-adjusted decreases in sitting systolic and diastolic blood pressures of 10/6 mm Hg with 5/6.25 mg and 10/12.5 mg doses, and 20/10 mm Hg with 20/25 mg dose. In clinical trials of benazepril/hydrochlorothiazide using benazepril doses of 5/20 mg and hydrochlorothiazide doses of 6.25/25 mg, the antihypertensive effects were sustained for at least 24 hours, and they increased with increasing dose of either component. Although benazepril monotherapy is somewhat less effective in blacks than in nonblacks, the efficacy of combination therapy appears to be independent of race.

There are no human fertility data for hydrochlorothiazide. In animal studies, benazepril and hydrochlorothiazide alone or in combination had no effect on fertility and conception (see PRECAUTIONS, Non-Clinical Safety Data ).

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Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium (see PRECAUTIONS ). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of benazepril hydrochloride and hydrochlorothiazide tablets remains to be elucidated. While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension. Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.

Benazepril Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. For up to 4 hours after a 10-mg dose, pressor responses to exogenous angiotensin I were inhibited by 60% to 90%. In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.   Hydrochlorothiazide After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. Drug Interactions   Benazepril hydrochloride and hydrochlorothiazide tablets potentiate the antihypertensive action of other antihypertensive drugs (e.g., curare derivatives, guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors and ARBs and DRIs).

Representative sample of labeling (see HOW SUPPLIED section for complete listing: APOTEX CORP. NDC 60505-0261-1 Benazepril HCI and Hdrochlorothiazide Tablets 5 mg/6.25 mg, USP Benazepril Hydrochloride USP 5 mg Hydrochlorothiazide USP 6.25 mg Rx Only 100 Tablets