Amlopres L

Amlodipine Besylate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Amlopres L (Amlodipine Besylate) reviews

1 INDICATIONS AND USAGE

Amlopres L besylate and benazepril hydrochloride capsules are a combination tablet of Amlopres L (Amlodipine Besylate), a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin converting enzyme (ACE) inhibitor. Amlopres L (Amlodipine Besylate) besylate 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

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.

2 DOSAGE AND ADMINISTRATION

• Dose once-daily
• May be used as add-on therapy for patients not adequately controlled with either a dihydropyridine calcium channel blocker or an ACE inhibitor
• Patients who experience edema with Amlopres L (Amlodipine Besylate) may be switched to Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules containing a lower dose of Amlopres L (Amlodipine Besylate) (2.2)
• Start Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules at 2.5 mg/10 mg in patients ≥ 75 years old or in patients with hepatic impairment (2)

2.1 General considerations

The recommended initial dose of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsule is one capsule of Amlopres L (Amlodipine Besylate) 2.5 mg/benazepril 10 mg orally once daily.

It is usually appropriate to begin therapy with Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules only after a patient has either (a) failed to achieve the desired antihypertensive effect with Amlopres L (Amlodipine Besylate) or benazepril monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with Amlopres L (Amlodipine Besylate) therapy without developing edema.

The antihypertensive effect of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules is largely attained within 2 weeks. If blood pressure remains uncontrolled, the dose may be titrated up to Amlopres L (Amlodipine Besylate) 10 mg/benazepril 40 mg once daily. The dosing should be individualized and adjusted according to the patient’s clinical response.

Amlopres L (Amlodipine Besylate) is an effective treatment of hypertension in once-daily doses of 2.5 to 10 mg while benazepril is effective in doses of 10 to 80 mg. In clinical trials of amlodipine/benazepril combination therapy using Amlopres L (Amlodipine Besylate) doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of Amlopres L (Amlodipine Besylate) in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.

2.2 Dosage adjustment in renal impairment

Renal Impairment: Amlopres L besylate and benazepril hydrochloride capsules are not recommended in patients with creatinine clearance ≤ 30 mL/min. No dose adjustment of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are required in patients creatinine clearance > 30 mL/min (serum creatinine roughly ≤3 mg/dL or 265 μmol/L). [see Warnings and Precautions (5.7), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].

2.3 Replacement Therapy

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules may be substituted for the titrated components.

3 DOSAGE FORMS AND STRENGTHS

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are available as follows:

2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, and 10 mg/40 mg.

Capsules (amlodipine/benazepril mg): 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, 10 mg/40 mg (3)

4 CONTRAINDICATIONS

• Do not coadminister aliskiren with angiotensin receptor blockers, ACE inhibitors, including Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride in patients with diabetes (4)
• Amlopres L (Amlodipine Besylate) besylate 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, or Amlopres L (Amlodipine Besylate), or to any of the excipients of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride.

• Do not coadminister aliskiren with ARBs or ACEIs, including Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride in patients with diabetes (4)

• Amlopres L (Amlodipine Besylate) besylate 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, or to Amlopres L (Amlodipine Besylate). (4)

5 WARNINGS AND PRECAUTIONS

• Watch for anaphylactoid reactions, including angioedema (5.1).
• Warn patients with severe obstructive coronary artery disease about the risk of myocardial infarction or increased angina (5.2)
• Assess for hypotension and hyperkalemia (5.4) and (5.8)
• Avoid fetal or neonatal exposure (5.5)
• Titrate slowly in patients with impaired hepatic (5.6) or severely impaired renal (5.7) function

5.1 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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules) may be subject to a variety of adverse reactions, some of them serious. These reactions usually occur after one of the first few doses of the ACE inhibitor, but they sometimes do not appear until after months of therapy. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE 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, discontinue treatment with Amlopres L (Amlodipine Besylate) besylate 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)].

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.

5.2 Increased Angina and/or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Amlopres L, particularly in patients with severe obstructive coronary artery disease.

5.3 Patients with Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy

As with all other vasodilators, special caution is required when using Amlopres L (Amlodipine Besylate) in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

5.4 Hypotension

Amlopres L besylate and benazepril hydrochloride capsules can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume or salt depleted as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before starting therapy with benazepril. If hypotension occurs, the patient should be placed in the supine position and if necessary given physiological saline i.v. Treatment with benazepril can be continued once blood pressure and volume have returned to normal.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and (rarely) with acute renal failure and death. In such patients, start Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsule 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.

Symptomatic hypotension is also possible in patients with severe aortic stenosis.

5.5 Fetal Toxicity

Pregnancy Category D

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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride as soon as possible [see Use in Specific Populations ( 8.1 )].

5.6 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.

5.7 Impaired Renal Function

Monitor renal function periodically in patients treated with Amlopres L besylate and benazepril hydrochloride. Changes in renal function, including acute renal failure, can be caused by drugs that affect the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or who are on NSAIDS or angiotensin receptor blockers may be at particular risk of developing acute renal failure on Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride.

5.8 Hyperkalemia

Monitor serum potassium periodically in patients receiving Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride. Drugs that affect the renin-angiotensin system 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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) not present at baseline occurred in approximately 1.5% of hypertensive patients receiving Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride. Increases in serum potassium were generally reversible.

5.9 Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

5.10 Surgery/Anesthesia

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.

6 ADVERSE REACTIONS

Discontinuation because of adverse reactions occurred in 4% of Amlopres L besylate and benazepril hydrochloride capsule-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules were cough and edema. (6)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safetyAmlopres L (Amlodipine Besylate)tevapharm.com; 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.

Amlopres L (Amlodipine Besylate) besylate 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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsule doses up to 5 mg/20 mg, 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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules and in 3% of patients treated with placebo.

The most common reasons for discontinuation of therapy with Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules in these studies were cough and edema (including angioedema).

The peripheral edema associated with Amlopres L (Amlodipine Besylate) use is dose-dependent. When benazepril is added to a regimen of Amlopres L (Amlodipine Besylate), the incidence of edema is substantially reduced.

The addition of benazepril to a regimen of Amlopres L (Amlodipine Besylate) 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 Amlopres L (Amlodipine Besylate) besylate 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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules (3.3%) than on placebo (0.2%).

The incidence of edema was greater in patients treated with Amlopres L (Amlodipine Besylate) monotherapy (5.1%) than in patients treated with Amlopres L (Amlodipine Besylate) besylate 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 Amlopres L (Amlodipine Besylate) besylate 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, constipation, diarrhea, dyspepsia, and esophagitis.

Hematologic: Neutropenia

Metabolic and Nutritional: Hypokalemia.

Musculoskeletal: Back pain, musculoskeletal pain, cramps, and muscle cramps.

Respiratory: Pharyngitis.

Urogenital: Sexual problems such as impotence, and polyuria.

Monotherapies of benazepril and Amlopres L (Amlodipine Besylate) 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 Amlopres L (Amlodipine Besylate) besylate 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, BUN increase, serum creatinine increased, renal impairment, impaired vision, agranulocytosis, neutropenia.

Rare reports in association with use of Amlopres L (Amlodipine Besylate): gingival hyperplasia, tachycardia, jaundice, and hepatic enzyme elevations (mostly consistent with cholestasis severe enough to require hospitalization), leucocytopenia, allergic reaction, hyperglycemia, dysgeusia, hypoestheia, paresthesia, syncope, peripheral neuropathy, hypertonia, visual impairment, diplopia, hypotension, vasculitis, rhinitis, gastritis, hyperhidrosis, pruritis, 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). Other infrequently reported events included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, alopecia, upper respiratory tract infection, palpitations and somnolence.

7 DRUG INTERACTIONS

• Potassium supplements / Potassium-sparing diuretics: risk of hyperkalemia
• Lithium: Increased serum Lithium levels; toxicity symptoms (7.1)
• Injectable gold: facial flushing, nausea, vomiting, or hypotension may occur (7.1)
• NSAID: Risk of renal dysfunction, loss of antihypertensive effect ( 7.1 )
• If simvastatin is coadministered with Amlopres L (Amlodipine Besylate), do not exceed doses greater than 20 mg daily of simvastatin (7.1)
• Dual inhibition of the rennin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7.1)

7.1 Drug/Drug Interactions

Amlopres L (Amlodipine Besylate)

Simvastatin: Coadministration of simvastatin with Amlopres L (Amlodipine Besylate) increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on Amlopres L (Amlodipine Besylate) to 20 mg daily.

CYP3A4 Inhibitors: Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to Amlopres L (Amlodipine Besylate) and may require dose reduction. Monitor for symptoms of hypotension and edema when Amlopres L (Amlodipine Besylate) 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 Amlopres L (Amlodipine Besylate). Blood pressure should be monitored when Amlopres L (Amlodipine Besylate) is coadministered with CYP3A4 inducers.

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 Amlopres L (Amlodipine Besylate) besylate 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 Agents 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.

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. Closely monitor blood pressure, renal function and electrolytes in patients on Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride and other agents that block the RAS.

Do not coadminister aliskiren with Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride in patients with diabetes. Avoid use of aliskiren with Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride in patients with renal impairment (GFR <60 ml/min).

8 USE IN SPECIFIC POPULATIONS

Nursing Mothers: It is not known whether Amlopres L is excreted in human milk. Nursing or drug should be discontinued. (8.3)

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category D

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 Amlopres L besylate and benazepril hydrochloride capsules as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

8.2 Labor and Delivery

The effect of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules on labor and delivery has not been studied.

8.3 Nursing Mothers

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.

It is not known whether Amlopres L is excreted in human milk. Nursing or drug should be discontinued.

8.4 Pediatric Use

Neonates with a history of in utero exposure to Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers, but experience is limited.

8.5 Geriatric Use

In geriatrics, exposure to Amlopres L is increased, thus consider lower initial doses of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride .

Of the total number of patients who received Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules in U.S. clinical studies of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, over 19% were 65 or older while about 2% were 75 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 Amlopres L (Amlodipine Besylate) is increased in patients with hepatic insufficiency, thus consider using lower doses of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride .

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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules. Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are not recommended in patients with severe renal impairment. No dose adjustment of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride is needed in patients with mild or moderate impairment of renal function .

10 OVERDOSAGE

Only a few cases of human overdose with Amlopres L (Amlodipine Besylate) have been reported. One patient was asymptomatic after a 250 mg ingestion; another, who combined 70 mg of Amlopres L (Amlodipine Besylate) with an unknown large quantity of a benzodiazepine, developed refractory shock and died.

Human overdoses with any combination of Amlopres L (Amlodipine Besylate) 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 Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride).

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 Amlopres L (Amlodipine Besylate) besylate 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 Amlopres L (Amlodipine Besylate), 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 Amlopres L (Amlodipine Besylate), benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of Amlopres L (Amlodipine Besylate) 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.

11 DESCRIPTION

Benazepril hydrochloride 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:

C₂₄H₂₈N₂O₅-HCl M.W. 460.96

Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.

Amlopres L (Amlodipine Besylate) besylate 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:

C₂₀H₂₅ClN₂O₅-C₆H₆O₃S M.W. 567.1

Amlopres L (Amlodipine Besylate) besylate is the besylate salt of Amlopres L (Amlodipine Besylate), a dihydropyridine calcium channel blocker.

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are a combination of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride. The capsules are formulated in six different strengths for oral administration with a combination of Amlopres L (Amlodipine Besylate) besylate equivalent to 2.5 mg, 5 mg or 10 mg of Amlopres L (Amlodipine Besylate), with 10 mg, 20 mg or 40 mg of benazepril hydrochloride providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg and 10 mg/40 mg. The inactive ingredients of the capsules are black iron oxide, calcium phosphate dibasic anhydrous, colloidal silicon dioxide, corn starch, crospovidone, gelatin, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, pregelatinized starch, propylene glycol, shellac, sodium starch glycolate, and titanium dioxide. The imprinting ink may contain potassium hydroxide. In addition, the 5 mg/10 mg capsule contains red iron oxide and yellow iron oxide; the 5 mg/20 mg capsule contains D&C Red 28, FD&C Blue 1, and FD&C Red 40; the 10 mg/20 mg capsule contains FD&C Blue 1 and FD&C Red 3; and the 5 mg/40 mg and 10 mg/40 mg capsules contain FD&C Blue 1.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benazepril

Benazepril and benazeprilat inhibit angiotensin-converting enzyme 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 Amlopres L (Amlodipine Besylate) for up to 56 weeks had elevations of serum potassium up to 0.2 mEq/L [see Warnings and Precautions (5)].

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 Amlopres L (Amlodipine Besylate) besylate 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.

Amlopres L (Amlodipine Besylate)

Amlopres L (Amlodipine Besylate) 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 Amlopres L (Amlodipine Besylate) 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. Amlopres L (Amlodipine Besylate) 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 Amlopres L (Amlodipine Besylate). Within the physiologic pH range, Amlopres L (Amlodipine Besylate) 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.

Amlopres L (Amlodipine Besylate) 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.

12.2 Pharmacodynamics

Benazepril

Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. For up to 4 hours after a 10 mg dose, pressor responses to exogenous angiotensin I were inhibited by 60% to 90%.

Administration of benazepril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent, with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt and/or volume depleted [see Warnings and Precautions (5)].

The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets.

In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

Amlopres L (Amlodipine Besylate)

Following administration of therapeutic doses to patients with hypertension, Amlopres L (Amlodipine Besylate) produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with Amlopres L (Amlodipine Besylate) is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of Amlopres L (Amlodipine Besylate) resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with Amlopres L (Amlodipine Besylate) have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, Amlopres L (Amlodipine Besylate) has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when coadministered with beta-blockers to humans.

Amlopres L (Amlodipine Besylate) does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which Amlopres L (Amlodipine Besylate) was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Amlopres L (Amlodipine Besylate) has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

12.3 Pharmacokinetics

The rate and extent of absorption of benazepril and Amlopres L (Amlodipine Besylate) from Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are same as when administered as individual tablets. Absorption from the individual tablets is not influenced by the presence of food in the gastrointestinal tract; food effects on absorption from Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride have not been studied.

Absorption: Following oral administration of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, peak plasma concentrations of Amlopres L (Amlodipine Besylate) are reached in 6 to 12 hours. Absolute bioavailability has been calculated as between 64% and 90%. Following oral administration of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, the peak plasma concentrations of benazepril are reached in 0.5 to 2 hours. The cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat, which reaches peak plasma concentrations in 1.5 to 4 hours. The extent of absorption of benazepril is at least 37%. Amlopres L (Amlodipine Besylate) and benazepril exhibit dose proportional pharmacokinetics between the therapeutic dose range of 2.5 and 10 mg and 10 and 20 mg, respectively.

Distribution: The apparent volume of distribution of Amlopres L (Amlodipine Besylate) is about 21 L/kg. In vitro studies indicate that approximately 93% of circulating Amlopres L (Amlodipine Besylate) is bound to plasma proteins in hypertensive patients. The apparent volume of distribution of benazeprilat is about 0.7 L/kg. Approximately 93% of circulating Amlopres L (Amlodipine Besylate) is bound to plasma proteins, and the bound fraction of benazeprilat is slightly higher. On the basis of in vitro studies, benazeprilat’s degree of protein binding should be unaffected by age, by hepatic dysfunction, or-over the therapeutic concentration range-by concentration.

Metabolism: Amlopres L (Amlodipine Besylate) is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Benazepril is extensively metabolised to form benazeprilat as the main metabolite, which occur by enzymatic hydrolysis, mainly in the liver. Two minor metabolites are the acyl glucuronide conjugates of benazepril and benazeprilat.

Elimination: Amlopres L (Amlodipine Besylate) elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. 10% of unchanged drug and 60% of Amlopres L (Amlodipine Besylate) metabolites are excreted in urine. Effective elimination half-life of Amlopres L (Amlodipine Besylate) is 2 days. Benazepril is eliminated mainly by metabolic clearance. Benazeprilat is eliminated via the kidneys and the bile; renal excretion is the main route in patients with normal renal function. In the urine, benazepril accounts for less than 1 % and benazeprilat for about 20 % of an oral dose. Elimination of benazeprilat is biphasic with an initial half-life of about 3 hours and a terminal half-life of about 22 hours. Benazeprilat’s effective elimination half-life is 10 to 11 h, while that of Amlopres L (Amlodipine Besylate) is about 2 days, so steady-state levels of the two components are achieved after about a week of once-daily dosing.

Special populations

Geriatric patients: No specific clinical studies were performed to understand the impact of age on the pharmacokinetics of Amlopres L (Amlodipine Besylate) and benazepril as fixed dose combination. As individual component Amlopres L (Amlodipine Besylate) is extensively metabolized in the liver. In the elderly, clearance of Amlopres L (Amlodipine Besylate) is decreased with resulting increases in peak plasma levels, elimination half-life and area-under-the-plasma-concentration curve .

Hepatic impairment: Patients with hepatic insufficiency have decreased clearance of Amlopres L (Amlodipine Besylate) with a resulting increase in AUC of approximately 40 to 60%. Pharmacokinetics of benazepril is not significantly influenced by hepatic impairment .

Renal impairment : The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance > 30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance ≤ 30 mL/min, peak benazeprilat levels and the effective half-life increase, resulting in higher systemic exposures. Pharmacokinetics of Amlopres L (Amlodipine Besylate) is not significantly influenced by renal impairment .

Drug interactions

Amlopres L (Amlodipine Besylate)

In vitro data in human plasma indicate that Amlopres L (Amlodipine Besylate) has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine: Coadministration of Amlopres L (Amlodipine Besylate) with cimetidine did not alter the pharmacokinetics of Amlopres L (Amlodipine Besylate).

Grapefruit juice: Coadministration of 240 mL of grapefruit juice with a single oral dose of Amlopres L (Amlodipine Besylate) 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of Amlopres L (Amlodipine Besylate).

Maalox^® (antacid): Coadministration of the antacid Maalox with a single dose of Amlopres L (Amlodipine Besylate) had no significant effect on the pharmacokinetics of Amlopres L (Amlodipine Besylate).

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Amlopres L (Amlodipine Besylate). When Amlopres L (Amlodipine Besylate) and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin: Coadministration of multiple 10 mg doses of Amlopres L (Amlodipine Besylate) with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin: Coadministration of Amlopres L (Amlodipine Besylate) with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of Amlopres L (Amlodipine Besylate) had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Coadministration of Amlopres L (Amlodipine Besylate) with warfarin did not change the warfarin prothrombin response time.

Simvastatin: Coadministration of multiple doses of 10 mg of Amlopres L (Amlodipine Besylate) with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.

CYP3A inhibitors: Coadministration of a 180 mg daily dose of diltiazem with 5 mg Amlopres L (Amlodipine Besylate) in elderly hypertensive patients resulted in a 60% increase in Amlopres L (Amlodipine Besylate) systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change Amlopres L (Amlodipine Besylate) systemic exposure. However, strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of Amlopres L (Amlodipine Besylate) to a greater extent.

Benazepril

The pharmacokinetic properties of benazepril are not affected by hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, Amlopres L (Amlodipine Besylate), naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially affect the pharmacokinetics of these medications.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with this combination. However, these studies have been conducted with Amlopres L and benazepril alone. No adverse effects on fertility occurred when the benazepril:amlodipine combination was given orally to rats of either sex at doses up to 15:7.5 mg (benazepril:amlodipine)/kg/day, prior to mating and throughout gestation.

Benazepril

No evidence of carcinogenicity was found when benazepril was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body surface area, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg). No mutagenic activity was detected in the Ames test in bacteria, in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50 to 500 mg/kg/day (6 to 60 times the maximum recommended human dose on a body surface area basis), benazepril had no adverse effect on the reproductive performance of male and female rats.

Amlopres L (Amlodipine Besylate)

Rats and mice treated with Amlopres L (Amlodipine Besylate) maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5 mg, 1.25 mg, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a body surface area basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a body surface area basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.) Mutagenicity studies conducted with Amlopres L (Amlodipine Besylate) maleate revealed no drug-related effects at either the gene or chromosome level. There was no effect on the fertility of rats treated orally with Amlopres L (Amlodipine Besylate) maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a body surface area basis).

13.3 Reproductive Toxicity

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 Amlopres L (Amlodipine Besylate) is 3.6 times the Amlopres L (Amlodipine Besylate) dose delivered when the maximum recommended dose of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules is given to a 50 kg woman. Similarly, the 5 mg/kg/day dose of benazepril is approximately twice the benazepril dose delivered when the maximum recommended dose of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules is given to a 50 kg woman. No teratogenic effects were seen when benazepril and Amlopres L (Amlodipine Besylate) were administered in combination to pregnant rats or rabbits. Rats received doses of up to 50:25 mg (benazepril:amlodipine)/kg/day (24 times the maximum recommended human dose on a body surface area basis, assuming a 50 kg woman). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent to the maximum recommended dose of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules given to a 50 kg woman).

Benazepril

No teratogenic effects of benazepril were seen in studies of pregnant rats, mice, and rabbits. On a body surface area basis, the maximum doses used in these studies were 60 times (in rats), 9 times (in mice), and about equivalent to (in rabbits) the maximum recommended human dose (assuming a 50 kg woman).

Amlopres L (Amlodipine Besylate)

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with Amlopres L (Amlodipine Besylate) maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose [MRHD] of 10 mg Amlopres L (Amlodipine Besylate) on a body surface area basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5 fold) for rats receiving Amlopres L (Amlodipine Besylate) maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlopres L (Amlodipine Besylate) maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlopres L (Amlodipine Besylate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

14 CLINICAL STUDIES

Over 950 patients received Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules once daily in six double-blind, placebo-controlled studies. The antihypertensive effect of a single dose persisted for 24 hours, with peak reductions achieved 2 to 8 hours after dosing.

Once-daily doses of benazepril/amlodipine using benazepril doses of 10 to 20 mg and Amlopres L (Amlodipine Besylate) doses of 2.5 to 10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10 to 25/6 to 13 mmHg.

In two studies in patients not adequately controlled on either benazepril 40 mg alone (n = 329) or Amlopres L (Amlodipine Besylate) 10 mg alone (n = 812) once daily doses of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, 10 mg/40 mg further decreased seated blood pressure compared to the respective monotherapy alone.

Combination therapy was effective in blacks and nonblacks. Both components contributed to the antihypertensive efficacy in nonblacks, but virtually all of the antihypertensive effect in blacks could be attributed to the Amlopres L (Amlodipine Besylate) component. Among nonblack patients in placebo-controlled trials comparing Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules to the individual components, the blood pressure lowering effects of the combination were shown to be additive and in some cases synergistic.

During chronic therapy with Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, the maximum reduction in blood pressure with any given dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules have continued during therapy for at least 1 year. Abrupt withdrawal of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules have not been associated with a rapid increase in blood pressure.

16 HOW SUPPLIED/STORAGE AND HANDLING

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are available as capsules containing Amlopres L (Amlodipine Besylate) besylate equivalent to 2.5 mg, 5 mg or 10 mg of Amlopres L (Amlodipine Besylate), with 10 mg, 20 mg, or 40 mg of benazepril hydrochloride providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, and 10 mg/40 mg. All six strengths are packaged with a desiccant in bottles. They are available as follows:

2.5 mg/10 mg capsules: a hard gelatin capsule with a white opaque cap and body, filled with white to off-white powder, imprinted "TEVA" on the cap and "7370" on the body in bottles of 100.

5 mg/10 mg capsules: a hard gelatin capsule with an orange opaque cap and white opaque body, filled with white to off-white powder, imprinted "TEVA" on the cap and “7371” on the body in bottles of 100.

5 mg/20 mg capsules: a hard gelatin capsule with a pink opaque cap and white opaque body, filled with white to off-white powder, imprinted "TEVA" on the cap and “7372” on the body in bottles of 100.

5 mg/40 mg capsules: a hard gelatin capsule with a light turquoise blue opaque cap and light turquoise blue opaque body, filled with white to off-white powder, body and cap imprinting "TEVA" and “7670” in bottles of 100.

10 mg/20 mg capsules: a hard gelatin capsule with a blue violet opaque cap and body, filled with white to off-white powder, imprinted "TEVA" on the cap and “7373” on the body in bottles of 100.

10 mg/40 mg capsules: a hard gelatin capsule with a light blue opaque cap and light blue opaque body, filled with white to off-white powder, body and cap imprinting "TEVA" and “7671” in bottles of 100.

Store at 20° to 25°C (68° to 77°F). Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

17 PATIENT COUNSELING INFORMATION

Information for Patients

Female patients of childbearing age should be told about the consequences of exposure to Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. R 10/2012

PATIENT INFORMATION

Amlopres L (Amlodipine Besylate) Besylate and Benazepril Hydrochloride Capsules

2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, 10 mg/40 mg

Read this Patient Information leaflet before you start taking Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules and each time you get a refill. There may be new information. This leaflet does not replace talking with your doctor. If you have any questions, ask your doctor or pharmacist.

What is the most important information I should know about Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

• Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules can cause harm or death to an unborn baby.
• Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.
• If you get pregnant while taking Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, tell your doctor right away.

What are Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules contain two prescription medicines that work together to lower blood pressure: Amlopres L (Amlodipine Besylate) besylate (the active ingredient found in Norvasc^®), a calcium channel blocker, and benazepril hydrochloride (Lotensin^®), an ACE inhibitor. Your doctor will prescribe Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules only after other medicines haven’t worked.

High Blood Pressure (hypertension). Blood pressure is the force of blood in your blood vessels. You have high blood pressure when the force is too much. Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules can help your blood vessels relax so your blood pressure is lower.

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules have not been studied in children.

Who should not take Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

Don’t take Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules if you are allergic to any of the ingredients. There is a complete list at the end of this leaflet.

What should I tell my Doctor before taking Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

Tell your doctor about all your medical conditions, including if:

• you are pregnant or plan to become pregnant. See “What is the most important information I should know about Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?”
• you are breastfeeding. Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride may pass into your milk. Don’t breastfeed while you are taking Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules.
• you have a heart condition
• you have liver problems
• you have kidney problems
• you are about to have an operation (including dental surgery) or emergency treatment
• you are suffering from several episodes of vomiting or diarrhea
• you are treated for hyperkalemia (too much potassium in the blood)
• you are taking already a diuretic (a medicine to increase the amount of urine you produce)

Keep a list of your medicines with you, including vitamins and natural or herbal remedies, to show your doctor or pharmacist. Some of your other medicines and Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules could affect each other, causing serious side effects. Tell your doctor about all your medicines, especially:

• Simvastatin, (a medicine used to control elevated cholesterol)
• medicines for high blood pressure or heart failure
• water pills, extra potassium or a salt substitute
• Lithium (Eskalith^®, Lithobid^®)
• potassium-containing medicines, potassium supplements or salt substitutes containing potassium;
• ciclosporin, an immunosuppressant medicine used in transplanted patients to reduce the risk of organ rejection;
• indomethacin and other non-steroidal anti-inflammatory agents, medicines used to relieve pain and inflammation;
• insulin or oral antidiabetics, medicines that help a person with diabetes to control their level of glucose (sugar) in the blood;
• gold for the treatment of rheumatoid arthritis;
• probenecid, a medicine used to treat gout and hyperuricemia;
• medicines used to prevent and treat fungal skin infections (e.g. ketoconazole, itraconazole)
• medicines used to treat AIDS or HIV infections (e.g. ritonavir, indinavir)
• medicines used to treat bacterial infections (e.g. clarithromycin)

Avoid alcohol until you have discussed the matter with your doctor. Alcohol may make blood pressure fall more and/or increase the possibility of dizziness or fainting.

How do I take Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

• Take Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules exactly as your doctor tells you.
• Take Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules at the same time each day, with or without food.
• If you miss a dose, take it as soon as you remember. If it is more than 12 hours, just take your next dose at the regular time.
• Your doctor may test for kidney problems or check your blood potassium level.
• If you take too many Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, call your doctor or Poison Control Center, or go to the emergency room.
• Tell all your doctors or dentist you are taking Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules if you:
  

  - are going to have surgery
  

  - are getting allergy shots for bee stings
  

  - go for kidney dialysis
  

What are the possible side effects of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules can cause serious side effects including:

• serious allergic reactions that can be life threatening.

Stop Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules and get emergency help right away if you get:

• - swelling of your face, eyelids, lips, tongue or throat
• - have trouble swallowing
• - asthma (wheezing) or other breathing problems

These allergic reactions are rare but happen more times in people who are African-American.

• low blood pressure (hypotension). Low blood pressure is most likely to happen if you also take water pills, are on a low salt diet, get dialysis treatments, have heart problems or get sick with vomiting or diarrhea. Lie down if you feel faint or dizzy.
• liver problems. Call your doctor if:
  • you have nausea
  • you feel more tired or weaker than usual
  • you have itching
  • your skin or eyes look yellow
  • you have pain in your upper right stomach
  • you have flu-like symptoms
• kidney problems. Some people will have changes on blood tests for kidney function and need a lower dose of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules. Call your doctor if you get swelling in your feet, ankles, or hands or unexplained weight gain.
• more chest pain and heart attacks in people that already have severe heart problems. Get emergency help if you get worse chest pain or chest pain that does not go away.

The more common side effects of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are:

• dizziness, fainting on standing up
• cough (dry, non-productive, mainly at night, continuing)
• swelling of the feet, ankles, and hands

If any of these affects you severely, tell your doctor.

These are not all the side effects of Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules. For a complete list, ask your doctor or pharmacist.

How do I store Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

• Store Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules at 20° to 25°C (68° to 77°F).
• Keep Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules in a closed container in a dry place.
• Keep Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules and all medicines out of the reach of children.

General Information about Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules

Doctors can also use medicine for a condition that is not in the patient information leaflet. Take Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules the way your doctor tells you. Do not share them with other people. They may harm them.

For more information, ask your doctor or pharmacist, or call 1-866-832-8537, MEDICAL AFFAIRS.

What are the ingredients in Amlopres L (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

Active ingredients: Amlopres L (Amlodipine Besylate) besylate (the active ingredient found in Norvasc^®), benazepril hydrochloride (Lotensin^®)

Inactive ingredients: black iron oxide, calcium phosphate dibasic anhydrous, colloidal silicon dioxide, corn starch, crospovidone, gelatin, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, pregelatinized starch, propylene glycol, shellac, sodium starch glycolate, and titanium dioxide. The imprinting ink may contain potassium hydroxide. In addition, the 5 mg/10 mg capsule contains red iron oxide and yellow iron oxide; the 5 mg/20 mg capsule contains D&C Red 28, FD&C Blue 1, and FD&C Red 40; the 10 mg/20 mg capsule contains FD&C Blue 1 and FD&C Red 3; and the 5 mg/40 mg and 10 mg/40 mg capsules contain FD&C Blue 1.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. G 10/2012

Amlodipine/ Benazepril HCL 5/ 40mg Cap

benazepril hydrochloride structural formula Amlopres L (Amlodipine Besylate) besylate structural formula

Lisinopril:

• Amlopres L information
• Amlopres L indications
• Amlopres L warnings
• Amlopres L intake guidelines
• Amlopres L dosage
• Amlopres L overdose
• Amlopres L missed dose
• Amlopres L side effects
• Amlopres L drug reactions
• Amlopres L (Lisinopril) reviews

Amlopres L information

Amlopres L (Lisinopril) is a popular drug that belongs to a wide class of medicines generally known as ACE inhibitors (angiotensin converting enzyme inhibitors). This product is generally prescribed to patients who are suffering from congestive heart failure, high blood pressure or to patients who have recently suffered a heart attack.

Amlopres L indications

This medication is a well known medicine that is generally prescribed to patients who are suffering from heart medical conditions. However, this drug could also treat or prevent some other disorders that have not been mentioned in this guide. Ask your personal health care provider for more information about this product.

Amlopres L warnings

During your intake of Amlopres L (Lisinopril) it is forbidden to consume any products that contain alcohol, as this could lower your blood pressure even more, thus increasing this drug's side effects.

While you are using this medicine you should avoid taking potassium supplements or salt substitutes as this could harmfully interact with your treatment with this drug. Each patient who is following a treatment with this medicine should drink plenty of water (liquid) daily in order to prevent dehydration (this medical condition is triggered by some of this drug's side effects like diarrhea, vomiting, or heavy sweating), that could lead to electrolyte disorders, low blood pressure, or kidney failure.

Patients who are suffering from known allergic reaction to any of this product's component must not be allowed to start taking Amlopres L (Lisinopril). Before you start taking this product you should inform your personal health care specialist if you are allergic to any dyes, foods, preservatives or any other type of substances (this includes other medicines). Some medical conditions such as the following could harmfully interact with a treatment with this drug:

liver disease;

kidney disorder;

diabetes;

congestive heart failure;

connective tissue disorders like scleroderma, Sjogren's syndrome, lupus, Marfan syndrome, or rheumatoid arthritis.

Patients who suffer from any of the medical disorders that have been listed above should not be allowed to start a treatment with Amlopres L (Lisinopril) or should be prescribed a lower dose of this product. They should undergo special medical exams during their intake of this medicine, in order to enable their doctor to closely monitor the treatment with this drug.

Amlopres L (Lisinopril) is a category D FDA pregnancy medicine. Therefore, a treatment with it during pregnancy could severely harm a growing fetus. If you are pregnant you should ask your personal physician whether you may start using this medicine or not. Female patients should use an effective non hormonal contraceptive method (such as condoms, diaphragm) during their treatment with this medicine. If you accidentally become pregnant you must stop using this drug at once and alert your personal health care provider as soon as possible. It has not been determined whether this drug's main components are able to pass into the patient's breast milk or not. However, if you are nursing an infant, it is best to ask your doctor if you may start taking the medication.

Amlopres L intake guidelines

Before you start taking Amlopres L (Lisinopril) you should ask your personal health care provider to give you precise directions regarding how and when you should take your doses of this medicine. You should not disobey from any of your physician's directions. If you have further questions regarding your intake of this product you should refer to a nurse or to a pharmacist and ask them for additional explanations.

Each dose of the medicine should be taken in with a full glass of liquid (water). Because this drug is not known to be a stomach irritant, it is safe to take it either with or without food. In order to check to see if your treatment with this medicine is actually improving your medical disorder, you should probably undergo regular blood medical tests. Avoid missing any of your scheduled appointments with your physician.

In case you have to undergo surgery during your treatment with this medicine you should alert your surgeon that you are currently taking Amlopres L (Lisinopril) (you might have to stop your treatment with it for a while - before and after the operation). If you are taking this medicine to treat hypertension, you must not stop using this product without your personal physician's approval even if you already feel better.

Amlopres L dosage

You should ask your personal health care provider to give you the exact dose of this product that you should take in. Do not change the either the dose or the dosing schedule that you doctor advised you to follow without his or her consent. During your treatment with this product, your personal physician might want to change your initial dose of Amlopres L (Lisinopril) (this depends on how your organism has responded to your treatment with this medicine).

Amlopres L overdose

If you suspect that you might be suffering from an overdose with this product you should seek medical attention at once. The average Amlopres L (Lisinopril) overdose symptoms include light-headedness, dizziness, or fainting.

Amlopres L missed dose

If you miss one of your doses of Amlopres L (Lisinopril) you should ask your physician for further instructions.

Amlopres L side effects

A treatment with Amlopres L (Lisinopril) could trigger any of these side effects:

fainting, light-headedness;

urinating less or more than normally;

chills, fever, flu symptoms, body aches;

tiredness, and uneven or pounding heartbeats;

chest pain;

rapid weight gain, swelling.

cough;

drowsiness, dizziness, headache;

vomiting, nausea, upset stomach, diarrhea;

skin rash or itching.

Amlopres L drug reactions

During your treatment with Amlopres L (Lisinopril) you should avoid taking any of these medicines:lithium;

potassium supplements;

salt substitutes;

insulin;

aspirin;

diuretics