Data from FDA - Curated by Marshall Pearce - Last updated 10 October 2017

Indication(s)

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 ).

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Advisory information

contraindications
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.
Special warnings and precautions
PRECAUTIONS General Serum Electrolyte Abnormalities In clinical trials of Lotensin HCT, 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. Hypomagnesema 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 Lotensin HCT 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. Information for Patients Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. A patient receiving Lotensin HCT 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 Lotensin HCT 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 Lotensin HCT 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, Lotensin HCT 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 Lotensin HCT 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. Laboratory Tests The hydrochlorothiazide component of Lotensin HCT may decrease serum PBI levels without signs of thyroid disturbance. Therapy with Lotensin HCT should be interrupted for a few days before carrying out tests of parathyroid function. 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 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 hyperuricaemia 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. Non-clinical safety data 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 50-500 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 - 1300 µg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay, using an unspecified concentration of hydrochlorothiazide. Fertility 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 ). Use in Specific Populations Nursing Mothers Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat. Thiazides, on the other hand, are definitely excreted into breast milk. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of benazepril in infants, a decision should be made whether to discontinue nursing or to discontinue Lotensin HCT, taking into account the importance of the drug to the mother. Geriatric Use Of the total number of patients who received Lotensin HCT in U.S. clinical studies of Lotensin HCT, 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. Pediatric Use Neonates with a history of in utero exposure to Lotensin HCT: 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. Renal Impairment Safety and effectiveness of Lotensin HCT in patients with severe renal impairment (CrCL ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCL 60-90 mL/min) or moderate (CrCL 30-60 mL/min) renal impairment. Hepatic Impairment No adjustment of the initial dose is required for patients with mild to moderate hepatic impairment (see CLINICAL PHARMACOLOGY ). Hydrochlorothiazide Minor alterations of fluid and electrolyte imbalance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
Adverse reactions
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: 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. Clinical Laboratory Test Findings Serum Electrolytes: s ee PRECAUTIONS . Creatinine and BUN: Minor reversible increases in serum creatinine and BUN were observed in patients with essential hypertension treated with Lotensin HCT. Such increases occurred most frequently in patients with renal artery stenosis (s ee PRECAUTIONS ). To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 (1-866-9VALIDUS) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing 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.
Pregnancy and lactation
Nursing Mothers Minimal amounts of unchanged benazepril and benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat. Thiazides, on the other hand, are definitely excreted into breast milk. Because of the potential for serious adverse reactions in nursing infants from hydrochlorothiazide and the unknown effects of benazepril in infants, a decision should be made whether to discontinue nursing or to discontinue Lotensin HCT, taking into account the importance of the drug to the mother.

Interactions

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 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 hyperuricaemia 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.

More information

Category Value
Authorisation number NDA020033
Agency product number N1SN99T69T
Orphan designation No
Product NDC 30698-454,30698-453,30698-452
Date Last Revised 25-08-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 898366
Marketing authorisation holder Validus Pharmaceuticals LLC
Warnings WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Lotensin HCT 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 ).