Amlopres Z

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 Z (Amlodipine Besylate) reviews

1 INDICATIONS AND USAGE

Amlopres Z besylate and benazepril hydrochloride capsules are a combination tablet of Amlopres Z (Amlodipine Besylate), a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin converting enzyme (ACE) inhibitor. Amlopres Z (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 Z (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 Z (Amlodipine Besylate) may be switched to Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules containing a lower dose of Amlopres Z (Amlodipine Besylate) (2.2)
• Start Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsule is one capsule of Amlopres Z (Amlodipine Besylate) 2.5 mg/benazepril 10 mg orally once daily.

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

The antihypertensive effect of Amlopres Z (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 Z (Amlodipine Besylate) 10 mg/benazepril 40 mg once daily. The dosing should be individualized and adjusted according to the patient’s clinical response.

Amlopres Z (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 Z (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 Z (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 Z besylate and benazepril hydrochloride capsules are not recommended in patients with creatinine clearance ≤ 30 mL/min. No dose adjustment of Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules may be substituted for the titrated components.

3 DOSAGE FORMS AND STRENGTHS

Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride in patients with diabetes (4)
• Amlopres Z (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 Z (Amlodipine Besylate), or to any of the excipients of Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride.

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

• Amlopres Z (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 Z (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 Z (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 Z (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 Z, 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 Z (Amlodipine Besylate) in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

5.4 Hypotension

Amlopres Z 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 Z (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 Z (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 Z 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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride.

5.8 Hyperkalemia

Monitor serum potassium periodically in patients receiving Amlopres Z (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 Z (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 Z (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 Z besylate and benazepril hydrochloride capsule-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with Amlopres Z (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 Z (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 Z (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 Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules in these studies were cough and edema (including angioedema).

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

The addition of benazepril to a regimen of Amlopres Z (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 Z (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 Z (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 Z (Amlodipine Besylate) monotherapy (5.1%) than in patients treated with Amlopres Z (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 Z (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 Z (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 Z (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 Z (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 Z (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 Z (Amlodipine Besylate)

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

CYP3A4 Inhibitors: Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to Amlopres Z (Amlodipine Besylate) and may require dose reduction. Monitor for symptoms of hypotension and edema when Amlopres Z (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 Z (Amlodipine Besylate). Blood pressure should be monitored when Amlopres Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride and other agents that block the RAS.

Do not coadminister aliskiren with Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride in patients with diabetes. Avoid use of aliskiren with Amlopres Z (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 Z 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 Z 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 Z (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 Z (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 Z (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 Z 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 Z (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 Z is increased, thus consider lower initial doses of Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride .

Of the total number of patients who received Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules in U.S. clinical studies of Amlopres Z (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 Z (Amlodipine Besylate) is increased in patients with hepatic insufficiency, thus consider using lower doses of Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules. Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are not recommended in patients with severe renal impairment. No dose adjustment of Amlopres Z (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 Z (Amlodipine Besylate) have been reported. One patient was asymptomatic after a 250 mg ingestion; another, who combined 70 mg of Amlopres Z (Amlodipine Besylate) with an unknown large quantity of a benzodiazepine, developed refractory shock and died.

Human overdoses with any combination of Amlopres Z (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 Z (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 Z (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 Z (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 Z (Amlodipine Besylate), benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of Amlopres Z (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 Z (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 Z (Amlodipine Besylate) besylate is the besylate salt of Amlopres Z (Amlodipine Besylate), a dihydropyridine calcium channel blocker.

Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are a combination of Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride. The capsules are formulated in six different strengths for oral administration with a combination of Amlopres Z (Amlodipine Besylate) besylate equivalent to 2.5 mg, 5 mg or 10 mg of Amlopres Z (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 Z (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 Z (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 Z (Amlodipine Besylate)

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

Following administration of therapeutic doses to patients with hypertension, Amlopres Z (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 Z (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 Z (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 Z (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 Z (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 Z (Amlodipine Besylate) does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which Amlopres Z (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 Z (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 Z (Amlodipine Besylate) from Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride have not been studied.

Absorption: Following oral administration of Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, peak plasma concentrations of Amlopres Z (Amlodipine Besylate) are reached in 6 to 12 hours. Absolute bioavailability has been calculated as between 64% and 90%. Following oral administration of Amlopres Z (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 Z (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 Z (Amlodipine Besylate) is about 21 L/kg. In vitro studies indicate that approximately 93% of circulating Amlopres Z (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 Z (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 Z (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 Z (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 Z (Amlodipine Besylate) metabolites are excreted in urine. Effective elimination half-life of Amlopres Z (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 Z (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 Z (Amlodipine Besylate) and benazepril as fixed dose combination. As individual component Amlopres Z (Amlodipine Besylate) is extensively metabolized in the liver. In the elderly, clearance of Amlopres Z (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 Z (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 Z (Amlodipine Besylate) is not significantly influenced by renal impairment .

Drug interactions

Amlopres Z (Amlodipine Besylate)

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

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

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

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

Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of Amlopres Z (Amlodipine Besylate). When Amlopres Z (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 Z (Amlodipine Besylate) with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin: Coadministration of Amlopres Z (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 Z (Amlodipine Besylate) had no significant effect on the pharmacokinetics of ethanol.

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

Simvastatin: Coadministration of multiple doses of 10 mg of Amlopres Z (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 Z (Amlodipine Besylate) in elderly hypertensive patients resulted in a 60% increase in Amlopres Z (Amlodipine Besylate) systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change Amlopres Z (Amlodipine Besylate) systemic exposure. However, strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of Amlopres Z (Amlodipine Besylate) to a greater extent.

Benazepril

The pharmacokinetic properties of benazepril are not affected by hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, Amlopres Z (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 Z 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 Z (Amlodipine Besylate)

Rats and mice treated with Amlopres Z (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 Z (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 Z (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 Z (Amlodipine Besylate) is 3.6 times the Amlopres Z (Amlodipine Besylate) dose delivered when the maximum recommended dose of Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules is given to a 50 kg woman. No teratogenic effects were seen when benazepril and Amlopres Z (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 Z (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 Z (Amlodipine Besylate)

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with Amlopres Z (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 Z (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 Z (Amlodipine Besylate) maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlopres Z (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 Z (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 Z (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 Z (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 Z (Amlodipine Besylate) 10 mg alone (n = 812) once daily doses of Amlopres Z (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 Z (Amlodipine Besylate) component. Among nonblack patients in placebo-controlled trials comparing Amlopres Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules have continued during therapy for at least 1 year. Abrupt withdrawal of Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are available as capsules containing Amlopres Z (Amlodipine Besylate) besylate equivalent to 2.5 mg, 5 mg or 10 mg of Amlopres Z (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 Z (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 Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

• Amlopres Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, tell your doctor right away.

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

Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules contain two prescription medicines that work together to lower blood pressure: Amlopres Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules can help your blood vessels relax so your blood pressure is lower.

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

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

Don’t take Amlopres Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?”
• you are breastfeeding. Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride may pass into your milk. Don’t breastfeed while you are taking Amlopres Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

• Take Amlopres Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules exactly as your doctor tells you.
• Take Amlopres Z (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 Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules?

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

• serious allergic reactions that can be life threatening.

Stop Amlopres Z (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 Z (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 Z (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 Z (Amlodipine Besylate) besylate and benazepril hydrochloride capsules. For a complete list, ask your doctor or pharmacist.

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

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

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

Active ingredients: Amlopres Z (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 Z (Amlodipine Besylate) besylate structural formula

Losartan Potassium:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Patient information
• Amlopres Z (Losartan Potassium) reviews

INDICATIONS AND USAGE

Hypertension

Amlopres Z Tablets, USP is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics.

Hypertensive Patients with Left Ventricular Hypertrophy

Amlopres Z (Losartan Potassium) Tablets USP is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. (See PRECAUTIONS , Race and CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race .)

Nephropathy in Type 2 Diabetic Patients

Amlopres Z (Losartan Potassium) is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥ 300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Amlopres Z (Losartan Potassium) reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation) (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects ).

CONTRAINDICATIONS

Amlopres Z (Losartan Potassium) Tablets USP is contraindicated in patients who are hypersensitive to any component of this product.

WARNINGS

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, Amlopres Z tablets should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Amlopres Z (Losartan Potassium) tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Amlopres Z (Losartan Potassium) tablets should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Amlopres Z (Losartan Potassium) has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Hypotension - Volume-Depleted Patients

In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with Amlopres Z (Losartan Potassium). These conditions should be corrected prior to administration of Amlopres Z (Losartan Potassium) tablets, or a lower starting dose should be used (see DOSAGE AND ADMINISTRATION ).

PRECAUTIONS

General

Hypersensitivity: Angioedema.

See ADVERSE REACTIONS , Post-Marketing Experience.

Impaired Hepatic Function

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with impaired liver function.

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with Amlopres Z (Losartan Potassium); in some patients, these changes in renal function were reversible upon discontinuation of therapy.

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with Amlopres Z (Losartan Potassium).

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Similar effects have been reported with Amlopres Z (Losartan Potassium); in some patients, these effects were reversible upon discontinuation of therapy.

Electrolyte Imbalance

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with Amlopres Z as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see ADVERSE REACTIONS ).

Information for Patients

Pregnancy: Female patients of childbearing age should be told about the consequences of second-and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

Potassium Supplements: A patient receiving Amlopres Z (Losartan Potassium) tablets should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician (see PRECAUTIONS , Drug Interactions ).

Drug Interactions: No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite. (See CLINICAL PHARMACOLOGY , Drug Interactions .) In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Lithium: As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) including Selective Cyclooxygenase-2 Inhibitors(COX-2Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function co-administration of NSAIDS, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving losartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including losartan may be attenuated by NSAIDs, including selective COX-2 inhibitors.

Dual blockade of the renin-angiotensin-aldosterone system: Dual blockade of the renin-angiotensin-aldosterone system is associated with increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure). Closely monitor blood pressure, renal function, and electrolytes in patients on Amlopres Z (Losartan Potassium) Tablets and ACE inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Amlopres Z was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160- and 90-times (rats) and 30- and 15-times (mice) the exposure of a 50 kg human given 100 mg per day.

Amlopres Z (Losartan Potassium) was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of Amlopres Z (Losartan Potassium) up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNING , Fetal/Neonatal Morbidity and Mortality .

Nursing Mothers

It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Antihypertensive effects of Amlopres Z have been established in hypertensive pediatric patients aged 6 to 16 years. There are no data on the effect of Amlopres Z (Losartan Potassium) on blood pressure in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m² (see CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects and DOSAGE AND ADMINISTRATION).

Geriatric Use

Of the total number of patients receiving Amlopres Z (Losartan Potassium) in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Race

In the LIFE study, Black patients with hypertension and left ventricular hypertrophy had a lower risk of stroke on atenolol than on Amlopres Z (Losartan Potassium). Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study does not provide evidence that the benefits of Amlopres Z (Losartan Potassium) on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients. (See CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects ; Reduction in the Risk of Stroke .)

ADVERSE REACTIONS

Hypertension

Amlopres Z has been evaluated for safety in more than 3300 adult patients treated for essential hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year. In general, treatment with Amlopres Z (Losartan Potassium) was well-tolerated. The overall incidence of adverse experiences reported with Amlopres Z (Losartan Potassium) was similar to placebo.

In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 2.3 percent of patients treated with Amlopres Z (Losartan Potassium) and 3.7 percent of patients given placebo.

The following table of adverse events is based on four 6- to 12-week, placebo-controlled trials involving over 1000 patients on various doses (10-150 mg) of losartan and over 300 patients given placebo. All doses of losartan are grouped because none of the adverse events appeared to have a dose-related frequency. The adverse experiences reported in ≥1% of patients treated with Amlopres Z (Losartan Potassium) and more commonly than placebo are shown in the table below.

The following adverse events were also reported at a rate of 1% or greater in patients treated with losartan, but were as, or more frequent, in the placebo group: asthenia/fatigue, edema/swelling, abdominal pain, chest pain, nausea, headache, pharyngitis, diarrhea, dyspepsia, myalgia, insomnia, cough, sinus disorder.

Adverse events occurred at about the same rates in men and women, older and younger patients, and Black and non-Black patients.

A patient with known hypersensitivity to aspirin and penicillin, when treated with Amlopres Z (Losartan Potassium), was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.

Superficial peeling of palms and hemolysis were reported in one subject.

In addition to the adverse events above, potentially important events that occurred in at least two patients/subjects exposed to losartan or other adverse events that occurred in <1% of patients in clinical studies are listed below. It cannot be determined whether these events were causally related to losartan: Body as a Whole: facial edema, fever, orthostatic effects, syncope; Cardiovascular: angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation; Digestive: anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting; Hematologic: anemia; Metabolic: gout; Musculoskeletal: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness; Nervous System/Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, decreased libido, memory impairment, migraine, nervousness, paresthesia, peripheral neuropathy, panic disorder, sleep disorder, somnolence, tremor, vertigo; Respiratory: dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion; Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria; Special Senses: blurred vision, burning/stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity; Urogenital: impotence, nocturia, urinary frequency, urinary tract infection.

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown below.

† Demographics = (89% caucasian, 64% female)

†† Demographics = (90% caucasian, 51% female)

These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in post-marketing experience.

Pediatric Patients: No relevant differences between the adverse experience profile for pediatric patients and that previously reported for adult patients were identified.

Hypertensive Patients with Left Ventricular Hypertrophy

In the LIFE study, adverse events with Amlopres Z (Losartan Potassium) were similar to those reported previously for patients with hypertension.

Nephropathy in Type 2 Diabetic Patients

In the RENAAL study involving 1513 patients treated with Amlopres Z tablets or placebo, the overall incidences of reported adverse experiences were similar for the two groups. Amlopres Z (Losartan Potassium) tablets was generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo (19% for Amlopres Z (Losartan Potassium) tablets, 24% for placebo). The adverse experiences, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with Amlopres Z (Losartan Potassium) tablets and occurring more commonly than placebo, on a background of conventional antihypertensive therapy, are shown in the table below.

Post-Marketing Experience

The following additional adverse reactions have been reported in post-marketing experience:

Digestive: Hepatitis (reported rarely).

General Disorders and Administration Site Conditions : Malaise.

Hemic: Thrombocytopenia (reported rarely).

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported. Anaphylactic reactions have been reported.

Metabolic and Nutrition: Hyperkalemia, hyponatremia have been reported with losartan.

Musculoskeletal: Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Nervous system disorders: Dysgeusia

Respiratory: Dry cough.

Skin: Erythroderma

Laboratory Test Findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Amlopres Z (Losartan Potassium).

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with Amlopres Z (Losartan Potassium) alone (see PRECAUTIONS , Impaired Renal Function ).

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.11 grams percent and 0.09 volume percent, respectively) occurred frequently in patients treated with Amlopres Z (Losartan Potassium) alone, but were rarely of clinical importance. No patients were discontinued due to anemia.

Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with Amlopres Z (Losartan Potassium) alone, one patient (<0.1%) was discontinued due to these laboratory adverse experiences.

OVERDOSAGE

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m² basis.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither losartan nor its active metabolite can be removed by hemodialysis.

DOSAGE AND ADMINISTRATION

Adult Hypertensive Patients

Amlopres Z tablets may be administered with other antihypertensive agents, and with or without food.

Dosing must be individualized. The usual starting dose of Amlopres Z (Losartan Potassium) tablets is 50 mg once daily, with 25 mg used in patients with possible depletion of intravascular volume (e.g., patients treated with diuretics) (see WARNINGS , Hypotension - Volume-Depleted Patients ) and patients with a history of hepatic impairment (see PRECAUTIONS , General ). Amlopres Z (Losartan Potassium) tablets can be administered once or twice daily with total daily doses ranging from 25 mg to 100 mg.

If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Hypertension).

If blood pressure is not controlled by Amlopres Z (Losartan Potassium) alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Hypertension ).

No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis.

Pediatric Hypertensive Patients ≥ 6 years of age

The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total) administered as a tablet or a suspension (see Preparation of Suspension). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects , and WARNINGS , Hypotension - Volume-Depleted Patients .)

Amlopres Z (Losartan Potassium) is not recommended in pediatric patients <6 years of age or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m² (see CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects , and PRECAUTIONS ).

Preparation of Suspension

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg Amlopres Z (Losartan Potassium) tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus ** and Ora-Sweet SF **. Add 190 mL of the 50/50 Ora-Plus /Ora-Sweet SF mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

Hypertensive Patients with Left Ventricular Hypertrophy

The usual starting dose is 50 mg of Amlopres Z (Losartan Potassium) tablets once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of Amlopres Z (Losartan Potassium) should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke ).

Nephropathy in Type 2 Diabetic Patients

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Nephropathy in Type 2 Diabetic Patients). Amlopres Z (Losartan Potassium) may be administered with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).

HOW SUPPLIED

Amlopres Z Tablets USP 25 mg

White, round, biconvex film-coated tablets with “APO” debossed on one side and “LS” over “25” on the other side. Supplied in the following presentations

Bottles of 30 (NDC 60505-3160-3)

Bottles of 90 (NDC 60505-3160-9)

Bottles of 1000 (NDC 60505-3160-8)

Unit dose Blisters of 100 (10x10s) (NDC 60505-3160-0)

Amlopres Z (Losartan Potassium) Tablets USP 50 mg

White to off white, round, biconvex, film-coated, scored tablets debossed “APO” on one side and “LS” bisect “50” on the other side. Supplied in the following presentations

Bottles of 30 (NDC 60505-3161-3)

Bottles of 90 (NDC 60505-3161-9)

Bottles of 1000 (NDC 60505-3161-8)

Unit dose Blisters of 100 (10x10s) (NDC 60505-3161-0)

Amlopres Z (Losartan Potassium) Tablets USP 100 mg

White, oval, biconvex film-coated tablets with “APO” debossed on one side and “LS100” on the other side. Supplied in the following presentations

Bottles of 30 (NDC 60505-3162-3)

Bottles of 90 (NDC 60505-3162-9)

Bottles of 1000 (NDC 60505-3162-8)

Unit dose Blisters of 100 (10x10s) (NDC 60505-3162-0)

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in a tight, light resistant container.

** Trademark of Paddock Laboratories, Inc

APOTEX CORP.

Amlopres Z (Losartan Potassium) TABLETS USP

25 mg, 50 mg and 100 mg

Revised: May 2012

PATIENT INFORMATION

Amlopres Z Tablets USP

25 mg, 50 mg, 100 mg

Read the Patient Information that comes with Amlopres Z (Losartan Potassium) Tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition and treatment.

What is the most important information I should know about Amlopres Z (Losartan Potassium) Tablets?

Do not take Amlopres Z (Losartan Potassium) Tablets if you are pregnant or plan to become pregnant. Amlopres Z (Losartan Potassium) Tablets can harm your unborn baby causing injury and even death. Stop taking Amlopres Z (Losartan Potassium) Tablets if you become pregnant and call your doctor right away. If you plan to become pregnant, talk to your doctor about other treatment options before taking Amlopres Z (Losartan Potassium) Tablets.

What is Amlopres Z Tablets?

Amlopres Z (Losartan Potassium) Tablets is a prescription medicine called an angiotensin receptor blocker (ARB). It is used:

• Alone or with other blood pressure medicines to lower high blood pressure (hypertension).
• To lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy. Amlopres Z (Losartan Potassium) Tablets may not help Black patients with this problem.
• To slow the worsening of diabetic kidney disease (nephropathy) in patients with type 2 diabetes who have or had high blood pressure.

Amlopres Z (Losartan Potassium) Tablets has not been studied in children less than 6 years old or in children with certain kidney problems.

High Blood Pressure (hypertension). Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Amlopres Z (Losartan Potassium) Tablets can help your blood vessels relax so your blood pressure is lower.

Left Ventricular Hypertrophy (LVH). is an enlargement of the walls of the left chamber of the heart (the heart’s main pumping chamber). LVH can happen from several things. High blood pressure is the most common cause of LVH.

Type 2 Diabetes with Nephropathy. Type 2 diabetes is a type of diabetes that happens mainly in adults. If you have diabetic nephropathy it means that your kidneys do not work properly because of damage from the diabetes.

Who should not take Amlopres Z Tablets?

• 
  

  Do not take Amlopres Z (Losartan Potassium) Tablets if you are allergic to any of the ingredients in Amlopres Z (Losartan Potassium) Tablets. See the end of this leaflet for a complete list of ingredients in Amlopres Z (Losartan Potassium) Tablets.
  

What should I tell my doctor before taking Amlopres Z Tablets?

Tell your doctor about all of your medical conditions including if you:

• 
  

  Are pregnant or planning to become pregnant. See "What is the most important information I should know about Amlopres Z (Losartan Potassium) Tablets?”
  

• 
  

  Are breast-feeding. It is not known if Amlopres Z (Losartan Potassium) Tablets passes into your breast milk. You should choose either to take Amlopres Z (Losartan Potassium) Tablets or breast-feed, but not both.
  

• 
  

  are vomiting a lot or having a lot of diarrhea
  

• 
  

  have liver problems
  

• 
  

  have kidney problems
  

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Amlopres Z Tablets and certain other medicines may interact with each other. Especially tell your doctor if you are taking:

• 
  

  potassium supplements
  

• 
  

  salt substitutes containing potassium
  

• 
  

  water pills (diuretics)
  

• 
  

  Medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs NSAIDs including COX-2 inhibitors.
  

• other medicines to reduce blood pressure.

How should I take Amlopres Z (Losartan Potassium) Tablets?

• 
  

  Take Amlopres Z (Losartan Potassium) Tablets exactly as prescribed by your doctor. Your doctor may change your dose if needed.
  

• Amlopres Z (Losartan Potassium) Tablets
  

  can be taken with or without food.
  

• 
  

  If you miss a dose, take it as soon as you remember. If it is close to your next dose, donot take the missed dose. Just take the next dose at your regular time.
  

• 
  

  If you take too much Amlopres Z (Losartan Potassium) Tablets, call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away.
  

What are the possible side effects of Amlopres Z Tablets?

Amlopres Z (Losartan Potassium) Tablets may cause the following side effects that may be serious:

• 
  

  Injury or death of unborn babies. See "What is the most important information I should know about Amlopres Z (Losartan Potassium) Tablets?”
  

• 
  

  Allergic reaction. Symptoms of an allergic reaction are swelling of the face, lips, throat or tongue. Get emergency medical help right away and stop taking Amlopres Z (Losartan Potassium) Tablets.
  

• Low blood pressure (hypotension). Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. Call your doctor right away.
• 
  

  For people who already have kidney problems, you may see a worsening in how well your kidneys work. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain.
  

The most common side effects of Amlopres Z Tablets in people with high blood pressure are:

• “colds” (upper respiratory infection)
• dizziness
• stuffy nose
• back pain

The most common side effects of Amlopres Z (Losartan Potassium) Tablets in people with type 2 diabetes with diabetic kidney disease are:

• diarrhea
• tiredness
• low blood sugar
• chest pain
• high blood potassium
• low blood pressure

Tell your doctor if you get any side effect that bothers you or that won’t go away.

This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist.

How do I store Amlopres Z Tablets?

• 
  

  Store Amlopres Z (Losartan Potassium) Tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F), Dispense in a tight; light – resistant container.
  

• 
  

  Keep Amlopres Z (Losartan Potassium) Tablets in a tightly closed container that protects the medicine from light.
  

• 
  

  Keep Amlopres Z (Losartan Potassium) Tablets and all medicines out of the reach of children.
  

General information about Amlopres Z Tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Amlopres Z (Losartan Potassium) Tablets for a condition for which it was not prescribed. Do not give Amlopres Z (Losartan Potassium) Tablets to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about Amlopres Z (Losartan Potassium) Tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Amlopres Z (Losartan Potassium) Tablets that is written for health professionals.

What are the ingredients in Amlopres Z Tablets?

Active ingredients: Amlopres Z (Losartan Potassium)

Inactive ingredients: Lactose monohydrate, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose 6 cp, hydroxy propyl cellulose, titanium dioxide and carnauba wax.

Rx only

APOTEX CORP.

Amlopres Z (Losartan Potassium) TABLETS USP

25 mg, 50 mg and 100 mg

Revised: May 2012

Amlopres Z (Losartan Potassium) 25mg Tablet