FDA

Amlodipine Besylate and Benazepril Hydrochloride

Approved 5 Jul 2011OralCapsule

The FDA lists this product in 52 strengths and forms.

Indications

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 )

1.1Hypertension Amlodipine

and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.

Contraindications

Do not coadminister aliskiren with angiotensin receptor blockers (ARBs), ACE inhibitors, including amlodipine and benazepril hydrochloride in patients with diabetes. Amlodipine and benazepril hydrochloride is 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.

Amlodipine and benazepril hydrochloride is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer amlodipine and benazepril hydrochloride within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan. [see Warnings and Precautions ( 5.1 )]. Do not coadminister aliskiren with ACE inhibitors, including amlodipine and benazepril hydrochloride in patients with diabetes.

(4) Amlodipine and benazepril hydrochloride is contraindicated in patients with a history of angioedema or patients who are hypersensitive to benazepril or to amlodipine. (4) Amlodipine and benazepril hydrochloride is contraindicated in combination with a neprilysin inhibitor (e.g.,sacubitril). Do not administer amlodipine and benazepril hydrochloride within 36 hours of switching to or from a neprilysin inhibitor, e.g., sacubitril/valsartan.

( 5.1 )

Indications

1.1Hypertension Amlodipine

and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.

Contraindications

( 5.1 )

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 renin-angiotensin system (RAS): Increased risk of renal impairment, hypotension, and hyperkalemia (7.1) Neprilysin inhibitors: increased risk of angioedema (7.1)

7.1Drug/Drug Interactions Amlodipine

Simvastatin : Coadministration 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: Coadministration 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 coadministered 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 coadministering amlodipine and benazepril hydrochloride 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.

Non-Steroidal 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, 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 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 coadministration 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 and other agents that block the RAS. Do not co-administer aliskiren with amlodipine and benazepril hydrochloride in patients with diabetes.

Avoid use of aliskiren with amlodipine and benazepril hydrochloride 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 )].

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Amlodipine

and benazepril hydrochloride 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).

Adverse reactions

Discontinuation because of adverse reactions occurred in 4% of amlodipine and benazepril hydrochloride-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride were cough and edema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 has 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 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 and in 3% of patients treated with placebo. The most common reasons for discontinuation of therapy with amlodipine and benazepril hydrochloride 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 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 (3.3%) than on placebo (0.2%). Percent Incidence in U.S. Placebo-controlled Trials Benazepril/ Amlodipine N=760 Benazepril N=554 Amlodipine N=475 Placebo 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

1.5Edema* 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 (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 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.

6.2Postmarketing 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).

Amlodipine Besylate and Benazepril Hydrochloride

Indications

1.1Hypertension Amlodipine

Contraindications

Two medicines in one question?

Amlodipine Besylate and Benazepril Hydrochloride

Indications

1.1Hypertension Amlodipine

Contraindications

Two medicines in one question?

Warnings and precautions

5.1Fetal Toxicity Amlodipine

5.3Increased

5.4Hypotension Amlodipine

5.5Impaired Renal Function

5.6Hyperkalemia

5.7Hepatitis and Hepatic Failure

Interactions

7.1Drug/Drug Interactions Amlodipine

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Amlodipine

Adverse reactions

6.1Clinical Trials Experience

1.5Edema* 2.1 0.9 5.1

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information

At a glance