Amlodipine Besylate And Benazepril Hydrochloride

Amlodipine and benazepril hydrochloride capsule, is a combination capsule of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin converting-enzyme (ACE) inhibitor. Amlodipine and benazepril hydrochloride capsule, is indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent (

• Usual starting dose is 2.5/10 mg. (
  
  
  
  2.1 General Considerations

  The recommended initial dose of amlodipine and benazepril hydrochloride capsule, is 1 capsule of 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 capsule, 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.
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• 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)
  
  

Capsules (amlodipine/benazepril mg):  2.5/10, 5/10, 5/20, 5/40, 10/20, 10/40   (

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.

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.

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

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 capsules 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 capsules 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 capsules given to a 60 kg patient).

• Anaphylactoid reactions, including angioedema (
  
  
  
  5.1 Fetal Toxicity

  Amlodipine and benazepril hydrochloride 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 as soon as possible

  [see

  Use om Specific Populations

  ].
  ).
  
  
• Myocardial infarction or increased angina in patients with obstructive coronary artery disease (
  
  
  
  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 capsule 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 capsule. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

  Patients receiving coadministration 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

  [seeDrug 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.
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• Assess for hypotension and hyperkalemia (
  
  
  
  5.4 Hypotension

  Amlodipine and benazepril hydrochloride 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.
  ,
  
  
  5.8).
  
  
• Titrate slowly in patients with impaired hepatic or severely impaired renal function (
  
  
  
  5.6 Hyperkalemia

  Monitor serum potassium periodically in patients receiving amlodipine and benazepril hydrochloride. Drugs that affect the RAS can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium containing salt substitutes. In U.S. placebo-controlled trials of amlodipine and benazepril hydrochloride, hyperkalemia [serum potassium at least 0.5 mEq/L greater than the upper limit of normal(ULN)] not present at baseline occurred in approximately 1.5% of hypertensive patients receiving amlodipine and benazepril hydrochloride. Increases in serum potassium were generally reversible.
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  5.7 Hepatitis and Hepatic Failure

  There have been rare reports of predominantly cholestatic hepatitis and isolated cases of acute liver failure, some of them fatal, in patients on ACE inhibitors. The mechanism is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevation of hepatic enzymes should discontinue the ACE inhibitor and be kept under medical surveillance.
  ).