Amlodipine Besylate and Benazepril Hydrochloride
Capsule · Oral
Uses
Amlodipine and benazepril hydrochloride capsules are a combination capsule of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin-converting enzyme (ACE) inhibitor. Amlodipine and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent. (1) 1.1 Hypertension Amlodipine and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.
Dosage and administration
Usual starting dose is 2.5/10 mg. (2.1) May be used as add-on therapy for patients not adequately controlled with either a dihydropyridine calcium channel blocker or an ACE inhibitor (2.2) Patients who experience edema with amlodipine may be switched to amlodipine and benazepril hydrochloride capsules containing a lower dose of amlodipine. (2.1) 2.1 General Considerations The recommended initial dose is amlodipine 2.5 mg/benazepril 10 mg orally once-daily. Begin therapy with amlodipine and benazepril hydrochloride capsules only after a patient has either (a) failed to achieve the desired antihypertensive effect with amlodipine or benazepril monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema. The antihypertensive effect of amlodipine and benazepril hydrochloride capsules is largely attained within 2 weeks. If blood pressure remains uncontrolled, the dose may be titrated up to amlodipine 10 mg/benazepril 40 mg once-daily. The dosing should be individualized and adjusted according to the patient’s clinical response. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups. 2.2 Replacement Therapy Amlodipine and benazepril hydrochloride capsules may be substituted for the titrated components.
Dosage forms and strengths
Amlodipine and benazepril hydrochloride capsules, USP are available as follows: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, and 10 mg/20 mg. Capsules (amlodipine mg/benazepril hydrochloride mg): 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 10 mg/20 mg (3)
Contraindications
Do not co-administer aliskiren with angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, including amlodipine and benazepril hydrochloride capsules in patients with diabetes. Amlodipine and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, to amlodipine, or to any of the excipients of amlodipine and benazepril hydrochloride capsules. Amlodipine and benazepril hydrochloride capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer amlodipine and benazepril hydrochloride capsules within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan [see Warnings and Precautions (5.1) ] . Do not co-administer aliskiren with ACE inhibitors, including amlodipine and benazepril hydrochloride capsules, in patients with diabetes. (4) Amlodipine and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema or patients who are hypersensitive to benazepril or to amlodipine. (4) Amlodipine and benazepril hydrochloride capsules are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer amlodipine and benazepril hydrochloride capsules within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan. (4)
Warnings and precautions
Anaphylactoid reactions, including angioedema (5.2) Myocardial infarction or increased angina in patients with obstructive coronary artery disease. (5.3) Assess for hypotension and hyperkalemia. (5.4 , 5.6) Titrate slowly in patients with impaired hepatic or severely impaired renal function. (5.5 , 5.7) 5.1 Fetal Toxicity Amlodipine and benazepril hydrochloride capsules can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue amlodipine and benazepril hydrochloride capsules as soon as possible [see Use in Specific Populations (8.1) ] . 5.2 Angioedema and Anaphylactoid Reactions Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with benazepril. This may occur at any time during treatment. Angioedema associated with edema of the larynx, tongue, or glottis can compromise the airway and be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with amlodipine and benazepril hydrochloride capsules and treat immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., administer subcutaneous epinephrine injection 1:1000 (0.3 to 0.5 mL), promptly [see Adverse Reactions (6)] . Patients with a history of angioedema may be at increased risk for angioedema while receiving amlodipine and benazepril hydrochloride capsules. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks. Patients receiving co-administration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema [see Drug Interactions (7) ] . 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 (wasp sting) venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. 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. 5.3 Increased Angina and/or Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease. 5.4 Hypotension Amlodipine and benazepril hydrochloride capsules can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure, or death. Symptomatic hypotension is most likely to occur in patients who have heart failure, severe aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy or have been volume or salt depleted as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume and salt depletion before starting therapy with benazepril. If hypotension occurs, place the patient in the supine position and give physiological saline intravenously if needed. Continue treatment with benazepril once blood pressure and volume have returned to normal. In patients with congestive heart failure, start amlodipine and benazepril hydrochloride capsules therapy under close medical supervision; follow closely for the first 2 weeks of treatment and whenever the dose of the benazepril component is increased or a diuretic is added or its dose increased. 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. 5.5 Impaired Renal Function Monitor renal function periodically in patients treated with amlodipine and benazepril hydrochloride capsules. Changes in renal function, including acute renal failure, can be caused by drugs that affect the RAS. Patients whose renal function may depend in part on the activity of the RAS (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or who are on Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) or ARBs may be at particular risk of developing acute renal failure on amlodipine and benazepril hydrochloride capsules. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on amlodipine and benazepril hydrochloride capsules. 5.6 Hyperkalemia Monitor serum potassium periodically in patients receiving amlodipine and benazepril hydrochloride capsules. Drugs that affect the RAS can cause hyperkalemia.
Side effects
Discontinuation because of adverse reactions occurred in 4% of amlodipine and benazepril hydrochloride capsules-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride capsules were cough and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Amlodipine and benazepril hydrochloride capsules have been evaluated for safety in over 2,991 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 400 were treated for more than 1 year. In a pooled analysis of 5 placebo-controlled trials involving amlodipine and benazepril hydrochloride capsules doses up to 5/20, 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 4% of patients treated with amlodipine and benazepril hydrochloride capsules and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride capsules in these studies were cough and edema (including angioedema). The peripheral edema associated with amlodipine use is dose-dependent. When benazepril is added to a regimen of amlodipine, the incidence of edema is substantially reduced. The addition of benazepril to a regimen of amlodipine should not be expected to provide additional antihypertensive effect in African-Americans. However, all patient groups benefit from the reduction in amlodipine-induced edema. The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with amlodipine and benazepril hydrochloride capsules are shown in the table below. Cough was the only adverse event with at least possible relationship to treatment that was more common on amlodipine and benazepril hydrochloride capsules (3.3%) than on placebo (0.2%). Percent Incidence in U. S. Placebo-controlled Trials Benazepril/Amlodipine Benazepril Amlodipine Placebo N = 760 N = 554 N = 475 N = 408 Cough 3.3 1.8 0.4 0.2 Headache 2.2 3.8 2.9 5.6 Dizziness 1.3 1.6 2.3 1.5 Edema* 2.1 0.9 5.1 2.2 *Edema refers to all edema, such as dependent edema, angioedema, facial edema. The incidence of edema was greater in patients treated with amlodipine monotherapy (5.1%) than in patients treated with amlodipine and benazepril hydrochloride capsules (2.1%) or placebo (2.2%). Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with amlodipine and benazepril hydrochloride capsules or in postmarketing experience were the following: Body as a Whole: Asthenia and fatigue. CNS: Insomnia, nervousness, anxiety, tremor, and decreased libido. Dermatologic: Flushing, hot flashes, rash, skin nodule, and dermatitis. Digestive: Dry mouth, nausea, abdominal pain, dyspepsia, and esophagitis. Hematologic: Neutropenia Musculoskeletal: cramps, and muscle cramps. Urogenital: Sexual problems, such as impotence, and polyuria. Monotherapies of benazepril and amlodipine have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of amlodipine and benazepril hydrochloride capsules. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, paresthesia, dysgeusia, orthostatic symptoms and hypotension, angina pectoris and arrhythmia, pruritus, photosensitivity reaction, arthralgia, arthritis, myalgia, blood urea nitrogen (BUN) increase, serum creatinine increase, renal impairment, vision impairment, agranulocytosis, neutropenia. Rare reports in association with use of amlodipine: gingival hyperplasia, tachycardia, jaundice, and hepatic enzyme elevations (mostly consistent with cholestasis severe enough to require hospitalization), leukocytopenia, allergic reaction, hyperglycemia, dysgeusia, hypoesthesia, paresthesia, syncope, peripheral neuropathy, hypertonia, visual impairment, diplopia, hypotension, vasculitis, rhinitis, gastritis, hyperhidrosis, pruritus, skin discoloration, urticaria, erythema multiform, muscle spasms, arthralgia, micturition disorder, nocturia, erectile dysfunction, malaise, weight decrease or gain. Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include: eosinophilic pneumonitis (ACE inhibitors) and gynecomastia (CCBs).
Drug interactions
Potassium supplements/potassium-sparing diuretics: hyperkalemia (7.1) Lithium: Increased serum lithium levels; toxicity symptoms (7.1) Injectable gold: facial flushing, nausea, vomiting, hypotension (7.1) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Risk of renal dysfunction, loss of antihypertensive effect (7.1) Do not exceed doses greater than 20 mg daily of simvastatin (7.1) mTOR inhibitors: increased risk of angioedema (7.1) Dual inhibition of the RAS: Increased risk of renal impairment, hypotension, and hyperkalemia (7.1) Neprilysin inhibitors: increased risk of angioedema (7.1) 7.1 Drug/Drug Interactions Amlodipine Simvastatin: Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily. CYP3A4 Inhibitors: Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A4 inhibitors to determine the need for dose adjustment. CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be monitored when amlodipine is co-administered with CYP3A4 inducers (e.g. rifampicin, St. John’s Wort). Benazepril Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, the patient’s serum potassium should be monitored frequently. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When co-administering amlodipine and benazepril hydrochloride capsules and lithium, frequent monitoring of serum lithium levels is recommended. 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. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration 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 ACE inhibitors, including benazepril, may be attenuated by NSAIDs. Antidiabetic Agents: In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral antidiabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly. Mammalian Target of Rapamycin (mTOR) Inhibitors: The risk of angioedema may be increased in patients receiving co-administration of ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus). 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 hypotension, 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 amlodipine and benazepril hydrochloride capsules and other agents that block the RAS. Do not co-administer aliskiren with amlodipine and benazepril hydrochloride capsules in patients with diabetes. Avoid use of aliskiren with amlodipine and benazepril hydrochloride capsules in patients with renal impairment [glomerular filtration rate (GFR) < 60 mL/min]. Neprilysin Inhibitor: Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema [see Warnings and Precautions (5.1) ] .
Use in specific populations
8.1 Pregnancy Risk Summary Amlodipine and benazepril hydrochloride capsules can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the RAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the RAS from other antihypertensive agents. When pregnancy is detected, discontinue amlodipine and benazepril hydrochloride capsules as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to amlodipine and benazepril hydrochloride for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to amlodipine and benazepril hydrochloride, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data Benazepril and Amlodipine: When rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, dystocia was observed at an increasing dose-related incidence at all doses tested. On a body surface area basis, the 2.5 mg/kg/day dose of amlodipine is twice the amlodipine dose delivered when the maximum recommended dose of amlodipine and benazepril hydrochloride is given to a 60 kg patient. Similarly, the 5 mg/kg/day dose of benazepril is approximately equivalent with the benazepril dose delivered when the maximum recommended dose of amlodipine and benazepril hydrochloride is given to a 60 kg patient. No teratogenic effects were seen when benazepril and amlodipine were administered in combination to pregnant rats or rabbits. Rats received doses of up to 50:25 mg (benazepril:amlodipine)/kg/day (12 times the MRHD on a body surface area basis, assuming a 60 kg patient). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent to the maximum recommended dose of amlodipine and benazepril hydrochloride given to a 60 kg patient). 8.2 Lactation Risk Summary Minimal amounts of unchanged benazepril and of 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. Limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine or benazepril on milk production. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In geriatric patients, exposure to amlodipine is increased, thus consider lower initial doses of amlodipine and benazepril hydrochloride capsules [see Clinical Pharmacology (12.3) ] . Of the total number of patients who received amlodipine and benazepril hydrochloride capsules in U.S. clinical studies of amlodipine and benazepril hydrochloride capsules, over 19% were 65 years or older while about 2% were 75 years or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment Exposure to amlodipine is increased in patients with hepatic insufficiency, thus consider using lower doses of amlodipine and benazepril hydrochloride capsules [see Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment In patients with severe renal impairment systemic exposure to benazepril is increased. The recommended dose of benazepril in this subgroup is 5 mg which is not an available strength with amlodipine and benazepril hydrochloride capsules. Amlodipine and benazepril hydrochloride capsules are not recommended in patients with severe renal impairment.
Pregnancy
8.1 Pregnancy Risk Summary Amlodipine and benazepril hydrochloride capsules can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the RAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the RAS from other antihypertensive agents. When pregnancy is detected, discontinue amlodipine and benazepril hydrochloride capsules as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to amlodipine and benazepril hydrochloride for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to amlodipine and benazepril hydrochloride, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data Benazepril and Amlodipine: When rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, dystocia was observed at an increasing dose-related incidence at all doses tested. On a body surface area basis, the 2.5 mg/kg/day dose of amlodipine is twice the amlodipine dose delivered when the maximum recommended dose of amlodipine and benazepril hydrochloride is given to a 60 kg patient. Similarly, the 5 mg/kg/day dose of benazepril is approximately equivalent with the benazepril dose delivered when the maximum recommended dose of amlodipine and benazepril hydrochloride is given to a 60 kg patient. No teratogenic effects were seen when benazepril and amlodipine were administered in combination to pregnant rats or rabbits. Rats received doses of up to 50:25 mg (benazepril:amlodipine)/kg/day (12 times the MRHD on a body surface area basis, assuming a 60 kg patient). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent to the maximum recommended dose of amlodipine and benazepril hydrochloride given to a 60 kg patient).
Pediatric use
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use In geriatric patients, exposure to amlodipine is increased, thus consider lower initial doses of amlodipine and benazepril hydrochloride capsules [see Clinical Pharmacology (12.3) ] . Of the total number of patients who received amlodipine and benazepril hydrochloride capsules in U.S. clinical studies of amlodipine and benazepril hydrochloride capsules, over 19% were 65 years or older while about 2% were 75 years or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Overdosage
Only a few cases of human overdose with amlodipine have been reported. One patient was asymptomatic after a 250 mg ingestion; another, who combined 70 mg of amlodipine with an unknown large quantity of a benzodiazepine, developed refractory shock and died. Human overdoses with any combination of amlodipine and benazepril have not been reported. In scattered reports of human overdoses with benazepril and other ACE inhibitors, there are no reports of death. Treatment: Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate. In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage and/or activated charcoal to remove the drug from the gastrointestinal tract (only if presented within 1 hour after ingestion of amlodipine and benazepril hydrochloride capsules). Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care. To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient. The most likely effect of overdose with amlodipine and benazepril hydrochloride capsules is vasodilation, with consequent hypotension and tachycardia. Simple repletion of central fluid volume (Trendelenburg positioning, infusion of crystalloids) may be sufficient therapy, but pressor agents (norepinephrine or high-dose dopamine) may be required. With abrupt return of peripheral vascular tone, overdoses of other dihydropyridine calcium channel blockers have sometimes progressed to pulmonary edema, and patients must be monitored for this complication. Analyses of bodily fluids for concentrations of amlodipine, benazepril, or their metabolites are not widely available. Such analyses are, in any event, not known to be of value in therapy or prognosis. No data are available to suggest physiologic maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of amlodipine, benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of amlodipine by hemodialysis or hemo-perfusion has not been reported, but amlodipine’s high protein binding makes it unlikely that these interventions will be of value. Angiotensin II could presumably serve as a specific antagonist-antidote to benazepril, but angiotensin II is essentially unavailable outside of scattered research laboratories.
Description
Amlodipine and benazepril hydrochloride capsules, USP are a combination of amlodipine besylate, USP and benazepril hydrochloride, USP. Benazepril hydrochloride, USP is a white to off-white crystalline powder, soluble (greater than 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 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 ACE inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group. Amlodipine besylate, USP is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Its chemical name is (R,S)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate; its structural formula is: Its empirical formula is C 20 H 25 ClN 2 O 5
• C 6 H 6 O 3 S, and its molecular weight is 567.1. Amlodipine besylate, USP is the besylate salt of amlodipine, a dihydropyridine calcium channel blocker. Amlodipine and benazepril hydrochloride capsules, USP are formulated in four different strengths for oral administration with a combination of amlodipine besylate, USP equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride, USP providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, and 10 mg/20 mg. The inactive ingredients of the capsules are colloidal silicon dioxide, crospovidone, dibasic calcium phosphate dihydrate, gelatin, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, siliconized talc, and titanium dioxide. The 2.5 mg/10 mg capsules also contain D&C Yellow #10. The 5 mg/10 mg capsules also contain D&C Yellow #10 and FD&C Yellow #6. The 5 mg/20 mg and 10 mg/20 mg capsules also contain D&C Red #28, FD&C Blue #1, and FD&C Red #40. The imprinting ink contains D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, n-butyl alcohol, propylene glycol, and shellac. Benazepril Structural Formula Amlodipine Besylate Structural Formula
Mechanism of action
12.1 Mechanism of Action Benazepril Benazepril and benazeprilat inhibit 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 and amlodipine for up to 56 weeks had elevations of serum potassium up to 0.2 mEq/L [see Warnings and Precautions (5.6) ] . 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 amlodipine and benazepril hydrochloride capsules 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. Amlodipine Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
How supplied
Amlodipine and benazepril hydrochloride capsules, USP are available as capsules containing amlodipine besylate, USP equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride, USP providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, and 10 mg/20 mg. All strengths are packaged with a desiccant in bottles of 100 capsules. Dose Capsule Color/Code NDC Code Bottle of 100 2.5 mg/10 mg Off-white round biconvex, film coated tablet, plain on both sides and white powder filled in ivory Opaque colored capsules imprinted with '2684' on the body and 'AN' on the cap in black ink. NDC 69238-2684-1 5 mg/10 mg Off-white round biconvex, film coated tablet, plain on both sides and white powder filled in buff opaque colored capsules imprinted with '2685' on the body and 'AN' on the cap in black ink. NDC 69238-2685-1 5 mg/20 mg Off-white round biconvex, film coated tablet, plain on both sides and white powder filled in pink opaque colored capsules imprinted with '2686' on the body and 'AN' on the cap in black ink NDC 69238-2686-1 10 mg/20 mg Off-white round biconvex, film coated tablet, plain on both sides and white powder filled in lavender Opaque colored capsules imprinted with '2687' on the body and 'AN' on the cap in black ink. NDC 69238-2687-1 Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP controlled room temperature]. Protect from moisture. Dispense in tight container (USP).
Patient information
Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Pregnancy: Advise female patients of childbearing age about the consequences of exposure to amlodipine and benazepril hydrochloride capsules during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to their healthcare provider. Tell patients that if syncope occurs to discontinue amlodipine and benazepril hydrochloride capsules until the physician has been consulted. Caution all patients 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 [see Warnings and Precautions (5.4) ] . Hyperkalemia: Advise patients not to use salt substitutes without consulting their healthcare provider [see Drug Interactions (7) ] . Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 03-2026-00
Label text from the FDA structured product label by Amneal Pharmaceuticals NY LLC (revised Mar 31, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Amlodipine Besylate in 48 products
- Benazepril Hydrochloride in 48 products
Amlodipine Besylate and Benazepril Hydrochloride NDC products (48)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 50090-5357 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | A-S Medication Solutions | ANDA |
| 50090-5389 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | A-S Medication Solutions | ANDA |
| 50090-5404 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | A-S Medication Solutions | ANDA |
| 50090-6185 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | A-S Medication Solutions | ANDA |
| 50090-6427 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | A-S Medication Solutions | ANDA |
| 50090-5137 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | A-S Medication Solutions | ANDA |
| 69238-2684 | Amlodipine Besylate 2.5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | Amneal Pharmaceuticals NY LLC | ANDA |
| 69238-2685 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | Amneal Pharmaceuticals NY LLC | ANDA |
| 69238-2686 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Amneal Pharmaceuticals NY LLC | ANDA |
| 69238-2687 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Amneal Pharmaceuticals NY LLC | ANDA |
| 68001-130 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | BluePoint Laboratories | ANDA |
| 68001-131 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | BluePoint Laboratories | ANDA |
| 68001-132 | Amlodipine Besylate 2.5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | BluePoint Laboratories | ANDA |
| 68001-133 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | BluePoint Laboratories | ANDA |
| 68001-134 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | BluePoint Laboratories | ANDA |
| 68001-135 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | BluePoint Laboratories | ANDA |
| 71335-3125 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Bryant Ranch Prepack | ANDA |
| 71335-3095 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Bryant Ranch Prepack | ANDA |
| 71335-3067 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Bryant Ranch Prepack | ANDA |
| 71335-3055 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Bryant Ranch Prepack | ANDA |
| 71335-2634 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | Bryant Ranch Prepack | ANDA |
| 71335-1946 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Bryant Ranch Prepack | ANDA |
| 55111-586 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Dr.Reddy's Laboratories Limited | ANDA |
| 55111-338 | Amlodipine Besylate 2.5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | Dr.Reddy's Laboratories Limited | ANDA |
| 55111-339 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | Dr.Reddy's Laboratories Limited | ANDA |
| 55111-340 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Dr.Reddy's Laboratories Limited | ANDA |
| 55111-587 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Dr.Reddy's Laboratories Limited | ANDA |
| 55111-341 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Dr.Reddy's Laboratories Limited | ANDA |
| 68180-756 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-760 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-759 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-758 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-757 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-459 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-463 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-472 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-473 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 68180-755 | Amlodipine Besylate 2.5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | Lupin Pharmaceuticals, Inc. | ANDA |
| 82868-041 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Northwind Health Company, LLC | ANDA |
| 51655-201 | Benazepril Hydrochloride 20 mg/1; Amlodipine Besylate 5 mg/1 Capsule | Northwind Health Company, LLC | ANDA |
| 72789-432 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | PD-Rx Pharmaceuticals, Inc. | ANDA |
| 72789-502 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | PD-Rx Pharmaceuticals, Inc. | ANDA |
| 68788-8818 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | Preferred Pharmaceuticals Inc. | ANDA |
| 70518-4499 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 10 mg/1 Capsule | REMEDYREPACK INC. | ANDA |
| 70518-4388 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | REMEDYREPACK INC. | ANDA |
| 70518-4386 | Amlodipine Besylate 5 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | REMEDYREPACK INC. | ANDA |
| 70518-4382 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 40 mg/1 Capsule | REMEDYREPACK INC. | ANDA |
| 70518-2566 | Amlodipine Besylate 10 mg/1; Benazepril Hydrochloride 20 mg/1 Capsule | REMEDYREPACK INC. | ANDA |
Amlodipine Besylate and Benazepril Hydrochloride recalls
- D-0542-2025 Aug 6, 2025 · Class II · Terminated
Labeling: Incorrect or Missing Lot and/or Exp Date: released with wrong expiry date as Feb.2027 instead of Jan.2027 - D-1434-2012 Aug 8, 2012 · Class II · Terminated
Adulterated Presence of Foreign Tablets: Dr. Reddy's Laboratories has received complaints of mislabeled bottles of Amlodipine Besylate and Benazepril Hydrochloride Capsules and Ciprofloxacin Tablets.
Frequently asked questions
What is Amlodipine Besylate and Benazepril Hydrochloride used for?
Amlodipine and benazepril hydrochloride capsules are a combination capsule of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin-converting enzyme (ACE) inhibitor. Amlodipine and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent. (1) 1.1 Hypertension…
What are the side effects of Amlodipine Besylate and Benazepril Hydrochloride?
Discontinuation because of adverse reactions occurred in 4% of amlodipine and benazepril hydrochloride capsules-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride capsules were cough and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or… See the full label for the complete list.
Who makes Amlodipine Besylate and Benazepril Hydrochloride?
Amlodipine Besylate and Benazepril Hydrochloride is listed by 10 labelers in the FDA NDC directory, including A-S Medication Solutions, Amneal Pharmaceuticals NY LLC, BluePoint Laboratories, Bryant Ranch Prepack.
Has Amlodipine Besylate and Benazepril Hydrochloride been recalled?
The FDA enforcement database lists 2 recalls for Amlodipine Besylate and Benazepril Hydrochloride, most recently D-0542-2025 (class ii): Labeling: Incorrect or Missing Lot and/or Exp Date: released with wrong expiry date as Feb.2027 instead of Jan.2027