WARNING: FETAL TOXICITY
id: 378d793c-7843-48d4-92c2-5dd09b1f9ee6
displayName: Boxed Warning section
FDA Article Code: 34066-1
When pregnancy is detected, discontinue benazepril hydrochloride and hydrochlorothiazide 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
).
DESCRIPTION
id: d9947821-6e3c-4249-b194-47c075deae97
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
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-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is:
Its molecular formula is C24H28N2O5•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-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural formula is:
Its molecular formula is C7H8ClN3O4S2, and its molecular weight is 297.73. Hydrochlorothiazide is a thiazide diuretic.
The tablets are a combination of benazepril hydrochloride and hydrochlorothiazide USP. They are formulated for oral administration with a combination of 10 mg, or 20 mg of benazepril hydrochloride and 12.5 mg, or 25 mg of hydrochlorothiazide USP. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydrogenated castor oil, lactose monohydrate, poloxamer, polyethylene glycol, pregelatinized starch (corn), titanium dioxide and zinc stearate. The 10 mg/12.5 mg tablets also contain FD&C red No. 40, FD&C yellow No. 6, polyvinyl alcohol and talc. The 20 mg/12.5 mg tablets also contain FD&C blue No. 2, FD&C red No. 40, hypromellose and polysorbate. The 20 mg/25 mg tablets also contain FD&C red No. 40, hypromellose and polysorbate.
CLINICAL PHARMACOLOGY
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displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1
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 benazepril hydrochloride and hydrochlorothiazide 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.
INDICATIONS AND USAGE
id: cfa145dc-f80c-4da2-8811-a379dad29419
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9
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).
CONTRAINDICATIONS
id: 08d182bf-967d-4aed-890e-2aa912ee8df9
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3
Benazepril hydrochloride and hydrochlorothiazide is contraindicated in patients who are anuric.
Benazepril hydrochloride and hydrochlorothiazide 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.
Benazepril hydrochloride and hydrochlorothiazide is also contraindicated in patients with a history of angioedema with or without previous ACE inhibitor treatment.
Benazepril hydrochloride and hydrochlorothiazide is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer benazepril hydrochloride and hydrochlorothiazide 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 benazepril hydrochloride and hydrochlorothiazide in patients with diabetes.
WARNINGS
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displayName: WARNINGS SECTION
FDA Article Code: 34071-1
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including benazepril) may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with benazepril hydrochloride and hydrochlorothiazide should be discontinued and appropriate therapy instituted immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see
PRECAUTIONS
and
ADVERSE REACTIONS
).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., tesmsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema (see
PRECAUTIONS
).
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.
ADVERSE REACTIONS
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displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4
Benazepril hydrochloride and hydrochlorothiazide has been evaluated for safety in over 2,500 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 200 were treated for more than 1 year.
The reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 7% of U.S. patients treated with benazepril hydrochloride and hydrochlorothiazide and in 4% of patients treated with placebo.
The most common reasons for discontinuation of therapy with benazepril hydrochloride and hydrochlorothiazide 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 are shown in the table below.
Reactions Possibly or Probably Drug Related Patients in U.S. Placebo-Controlled Studies
|
Benazepril Hydrochloride and Hydrochlorothiazide
(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 benazepril hydrochloride and hydrochlorothiazide 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 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 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*.
OVERDOSAGE
id: 37127f5d-be99-4b31-892e-2683b79731b0
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5
No specific information is available on the treatment of overdosage with benazepril hydrochloride and hydrochlorothiazide; treatment should be symptomatic and supportive. Therapy with benazepril hydrochloride and hydrochlorothiazide 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.
DOSAGE AND ADMINISTRATION
id: bc6cc05d-8407-4ef5-8812-c7569762d179
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7
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 mg/25 mg.
HOW SUPPLIED
id: 8165df51-3f06-484c-982f-f90fe25a793e
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
Benazepril Hydrochloride and Hydrochlorothiazide Tablets, for oral administration, are available as
10 mg/12.5 mg
Pink, oblong, film-coated tablets, debossed “E 204″ on one side and scored on the other side and supplied as:
NDC 0832-0483-11 bottles of 100
20 mg/12.5 mg
Lavender, oblong, film-coated tablets, debossed “E 211″ on one side and scored on the other side and supplied as:
NDC 0832-0484-11 bottles of 100
20 mg/25 mg
Maroon, oblong, film-coated tablets, debossed “E 277″ on one side and scored on the other side and supplied as:
NDC 0832-0485-11 bottles of 100
Each strength is supplied in bottles that contain a desiccant.
Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Keep tightly closed.
KEEP THIS OUT OF THE REACH OF CHILDREN.
Manufactured for
UPSHER-SMITH LABORATORIES, LLC.
Maple Grove, MN 55369
© 2017 Upsher-Smith Laboratories, LLC.
46149826
Rev. October 2017
MF0483REV10/17
Package/Label Display Panel
id: c9176aad-4034-4499-969d-1d832d7a262b
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
NDC 0832-0483-11
Benazepril Hydrochloride and Hydrochlorothiazide Tablets
10 mg/12.5 mg
100 Tablets Rx only
UPSHER-SMITH
Package/Label Display Panel
id: 0641716a-7ae8-49c0-abc1-30ee850e8772
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
NDC 0832-0484-11
Benazepril Hydrochloride and Hydrochlorothiazide Tablets
20 mg/12.5 mg
100 Tablets Rx only
UPSHER-SMITH
Package/Label Display Panel
id: 14b6f8d9-dfa7-4b82-abaf-e5cc5a6256a6
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
NDC 0832-0485-11
Benazepril Hydrochloride and Hydrochlorothiazide Tablets
20 mg/25 mg
100 Tablets Rx only
UPSHER-SMITH
