Lotensin HCT

INDICATIONS AND USAGE Lotensin HCT USP is indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension ( see DOSAGE AND ADMINISTRATION ).

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 Lotensin HCT. The usual recommended starting dose is 10/12.5 mg once daily to control blood pressure. Replacement Therapy: The combination may be substituted for the titrated individual components.

CONTRAINDICATIONS Lotensin HCT is contraindicated in patients who are anuric. Lotensin HCT is 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. Lotensin HCT is also contraindicated in patients with a history of angioedema with or without previous ACE inhibitor treatment. Lotensin HCT is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer Lotensin HCT within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS and PRECAUTIONS ). Do not coadminister aliskiren with angiotensin receptor blockers, ACE inhibitors, including Lotensin HCT in patients with diabetes.

ADVERSE REACTIONS Lotensin HCT has 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 Lotensin HCT and in 4% of patients treated with placebo. The most common reasons for discontinuation of therapy with Lotensin HCT 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 Lotensin HCT are shown in the table below. Reactions Possibly or Probably Drug Related Patients in U.S. Placebo-Controlled Studies LOTENSIN HCT N = 665 Placebo 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 Lotensin HCT 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 Lotensin HCT 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 Lotensin HCT 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, t …

Drug Interactions 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 Lotensin HCT may effect potassium levels. Monitor potassium periodically. mTOR (mammalian target of rapamycin) inhibitor s : 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 Lotensin HCT. 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 Lotensin HCT and other agents that affect the RAS. Do not coadminister aliskiren with Lotensin HCT in patients with diabetes. Avoid use of aliskiren with Lotensin HCT 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 eff …

Mechanism of Action 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 Lotensin HCT 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.

DESCRIPTION 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 empirical formula is C 24 H 28 N 2 O 5 ·HCl, and its molecular weight is 460.96. 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 empirical formula is C 7 H 8 ClN 3 O 4 S 2 , and its molecular weight is 297.73. Hydrochlorothiazide is a thiazide diuretic. Lotensin HCT is a combination of benazepril and hydrochlorothiazide USP. The tablets are formulated for oral administration with a combination of 10 or 20 mg of benazepril and 12.5 or 25 mg of hydrochlorothiazide USP. The inactive ingredients of the tablets are cellulose compounds, crospovidone, hydrogenated castor oil, iron oxides (10/12.5 mg, 20/12.5 mg, and 20/25 mg tablets), lactose, polyethylene glycol, talc, and titanium dioxide. Benazepril hydrochloride structural formula. Hydrochlorothiazide structural formula.

OVERDOSAGE No specific information is available on the treatment of overdosage with Lotensin HCT; treatment should be symptomatic and supportive. Therapy with Lotensin HCT 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.

HOW SUPPLIED Lotensin HCT USP is available in tablets of three different strengths: Benazepril HCl Hydrochlorothiazide Tablet Color 10 mg 12.5 mg light pink 20 mg 12.5 mg grayish violet 20 mg 25 mg red Tablets of each strength are supplied in bottles that contain a desiccant and 100 tablets. The National Drug Codes for the various packages are: Dose Bottle of 100 Tablet Imprint 10/12.5 NDC 30698-452-01 452 20/12.5 NDC 30698-453-01 453 20/25 NDC 30698-454-01 454 Tablets are oblong and scored, with “LOTENSIN HCT” on one side and appropriate number imprinted on the other side. Storage: Do not store above 86°F (30°C). Protect from moisture and light. Dispense in a tight, light -resistant container (USP). Manufactured for and Distributed by: Validus Pharmaceuticals LLC Parsippany, NJ 07054 info@validuspharma.com www.validuspharma.com 1-866-982-5438 © 2023 Validus Pharmaceuticals LLC 60024-06 March 2023