Amlodipine and benazepril: uses, appearance and warnings

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.

Amlodipine and benazepril hydrochloride capsules, USP are available as follows: 2.5/10 mg, 5/10 mg, 5/20 mg, 5/40 mg, 10/20 mg, and 10/40 mg. Capsules (amlodipine/benazepril hydrochloride mg): 2.5/10, 5/10, 5/20, 5/40, 10/20, 10/40 (3)

Amlodipine and Benazepril Hydrochloride Capsules, USP 2.5 mg*/10 mg are available as hard gelatin capsules with a white opaque body and a white opaque cap, imprinted “920” in black ink. They are supplied as follows: NDC 23155-920-01 Bottles of 100 NDC 23155-920-05 Bottles of 500 NDC 23155-920-10 Bottles of 1,000 Amlodipine and Benazepril Hydrochloride Capsules, USP 5 mg*/10 mg are available as hard gelatin capsules with a light brown opaque body and a light brown opaque cap, imprinted “921” in black ink. They are supplied as follows: NDC 23155-921-01 Bottles of 100 NDC 23155-921-05 Bottles of 500 NDC 23155-921-10 Bottles of 1,000 Amlodipine and Benazepril Hydrochloride Capsules, USP 5 mg*/20 mg are available as hard gelatin capsules with a pink opaque body and a pink opaque cap, imprinted “922” in black ink. They are supplied as follows: NDC 23155-922-01 Bottles of 100 NDC 23155-922-05 Bottles of 500 NDC 23155-922-10 Bottles of 1,000 Amlodipine and Benazepril Hydrochloride Capsules, USP 5 mg*/40 mg are available as hard gelatin capsules with a light blue opaque body and a light blue opaque cap, imprinted “923” in black ink. They are supplied as follows: NDC 23155-923-01 Bottles of 100 NDC 23155-923-05 Bottles of 500 NDC 23155-923-10 Bottles of 1,000 Amlodipine and Benazepril Hydrochloride Capsules, USP 10 mg*/20 mg are available as hard gelatin capsules with a amethyst opaque body and a amethyst opaque cap, imprinted “924” in black ink. They are supplied as follows: NDC 23155-924-01 Bottles of 100 NDC 23155-924-05 Bottles of 500 NDC 23155-924-10 Bottles of 1,000 Amlodipine and Benazepril Hydrochloride Capsules, USP 10 mg*/40 mg are available as hard gelatin capsules with a dark blue opaque body and a dark blue opaque cap, imprinted "925" in black ink. They are supplied as follows: NDC 23155-925-01 Bottles of 100 NDC 23155-925-05 Bottles of 500 NDC 23155-925-10 Bottles of 1,000 * Amlodipine equivalent Storage: Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture, heat and light. Dispense in a tight, light-resistant container as defined in the USP.

Do not coadminister 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 coadminister 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)

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 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 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 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 1:1,000 (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. 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 [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 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 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. 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. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on amlodipine and benazepril hydrochloride. 5.6 Hyperkalemia Monitor serum potassium periodically in patients receiving amlodipine and benazepril hydrochloride. Drugs that affect the RAS can cause hyperkalemia. …

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 Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) 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. …

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 : Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily. …