Nebilong-AM

Amlodipine:

• 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
• Nebilong-AM (Amlodipine) reviews

1 INDICATIONS AND USAGE

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

Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) may be switched to Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules containing a lower dose of Nebilong-AM (Amlodipine) (2.2)
• Start Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsule is one capsule of Nebilong-AM (Amlodipine) 2.5 mg/benazepril 10 mg orally once daily.

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

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

Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of Nebilong-AM (Amlodipine) 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: Nebilong-AM besylate and benazepril hydrochloride capsules are not recommended in patients with creatinine clearance ≤ 30 mL/min. No dose adjustment of Nebilong-AM (Amlodipine) 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

Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules may be substituted for the titrated components.

3 DOSAGE FORMS AND STRENGTHS

Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride in patients with diabetes (4)
• Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine), or to any of the excipients of Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride.

• Do not coadminister aliskiren with ARBs or ACEIs, including Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride in patients with diabetes (4)

• Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine). (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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM, 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 Nebilong-AM (Amlodipine) in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

5.4 Hypotension

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

5.8 Hyperkalemia

Monitor serum potassium periodically in patients receiving Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM besylate and benazepril hydrochloride capsule-treated patients and 3% of placebo-treated patients. The most common reasons for discontinuation of therapy with Nebilong-AM (Amlodipine) 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.safetyNebilong-AM (Amlodipine)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.

Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules and in 3% of patients treated with placebo.

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

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

The addition of benazepril to a regimen of Nebilong-AM (Amlodipine) should not be expected to provide additional antihypertensive effect in African-Americans. However, all patient groups benefit from the reduction in amlodipine-induced edema.

The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules (3.3%) than on placebo (0.2%).

The incidence of edema was greater in patients treated with Nebilong-AM (Amlodipine) monotherapy (5.1%) than in patients treated with Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine): 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 Nebilong-AM (Amlodipine), 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

Nebilong-AM (Amlodipine)

Simvastatin: Coadministration of simvastatin with Nebilong-AM (Amlodipine) increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on Nebilong-AM (Amlodipine) to 20 mg daily.

CYP3A4 Inhibitors: Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to Nebilong-AM (Amlodipine) and may require dose reduction. Monitor for symptoms of hypotension and edema when Nebilong-AM (Amlodipine) is coadministered with CYP3A4 inhibitors to determine the need for dose adjustment.

CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on Nebilong-AM (Amlodipine). Blood pressure should be monitored when Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride and other agents that block the RAS.

Do not coadminister aliskiren with Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride in patients with diabetes. Avoid use of aliskiren with Nebilong-AM (Amlodipine) 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 Nebilong-AM 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 Nebilong-AM 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

8.2 Labor and Delivery

The effect of Nebilong-AM (Amlodipine) 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 Nebilong-AM is excreted in human milk. Nursing or drug should be discontinued.

8.4 Pediatric Use

Neonates with a history of in utero exposure to Nebilong-AM (Amlodipine) 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 Nebilong-AM is increased, thus consider lower initial doses of Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride .

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

Human overdoses with any combination of Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine), 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 Nebilong-AM (Amlodipine), benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of Nebilong-AM (Amlodipine) 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.

Nebilong-AM (Amlodipine) 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

Nebilong-AM (Amlodipine) besylate is the besylate salt of Nebilong-AM (Amlodipine), a dihydropyridine calcium channel blocker.

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

Nebilong-AM (Amlodipine)

Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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. Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine). Within the physiologic pH range, Nebilong-AM (Amlodipine) 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.

Nebilong-AM (Amlodipine) 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.

Nebilong-AM (Amlodipine)

Following administration of therapeutic doses to patients with hypertension, Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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, Nebilong-AM (Amlodipine) 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.

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

Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) from Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride have not been studied.

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

Drug interactions

Nebilong-AM (Amlodipine)

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

Cimetidine: Coadministration of Nebilong-AM (Amlodipine) with cimetidine did not alter the pharmacokinetics of Nebilong-AM (Amlodipine).

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

Maalox^® (antacid): Coadministration of the antacid Maalox with a single dose of Nebilong-AM (Amlodipine) had no significant effect on the pharmacokinetics of Nebilong-AM (Amlodipine).

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

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

Digoxin: Coadministration of Nebilong-AM (Amlodipine) with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of Nebilong-AM (Amlodipine) had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Coadministration of Nebilong-AM (Amlodipine) with warfarin did not change the warfarin prothrombin response time.

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

Benazepril

The pharmacokinetic properties of benazepril are not affected by hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, Nebilong-AM (Amlodipine), 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 Nebilong-AM 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.

Nebilong-AM (Amlodipine)

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

Nebilong-AM (Amlodipine)

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Nebilong-AM (Amlodipine) 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. Nebilong-AM (Amlodipine) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

14 CLINICAL STUDIES

Over 950 patients received Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 10 mg alone (n = 812) once daily doses of Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) component. Among nonblack patients in placebo-controlled trials comparing Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules have continued during therapy for at least 1 year. Abrupt withdrawal of Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules have not been associated with a rapid increase in blood pressure.

16 HOW SUPPLIED/STORAGE AND HANDLING

Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules are available as capsules containing Nebilong-AM (Amlodipine) besylate equivalent to 2.5 mg, 5 mg or 10 mg of Nebilong-AM (Amlodipine), 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 Nebilong-AM (Amlodipine) 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

Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

• Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules, tell your doctor right away.

What are Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules contain two prescription medicines that work together to lower blood pressure: Nebilong-AM (Amlodipine) besylate (the active ingredient found in Norvasc^®), a calcium channel blocker, and benazepril hydrochloride (Lotensin^®), an ACE inhibitor. Your doctor will prescribe Nebilong-AM (Amlodipine) 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. Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules can help your blood vessels relax so your blood pressure is lower.

Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules have not been studied in children.

Who should not take Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

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

• Take Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules exactly as your doctor tells you.
• Take Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules can cause serious side effects including:

• serious allergic reactions that can be life threatening.

Stop Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules. For a complete list, ask your doctor or pharmacist.

How do I store Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

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

General Information about Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules

Doctors can also use medicine for a condition that is not in the patient information leaflet. Take Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate and benazepril hydrochloride capsules?

Active ingredients: Nebilong-AM (Amlodipine) 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 Nebilong-AM (Amlodipine) besylate structural formula

Nebivolol:

• 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
• Nebilong-AM (Nebivolol) reviews

1. INDICATIONS AND USAGE

Nebilong-AM is a beta-adrenergic blocking agent indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. (1.1)

1.1 Hypertension

Nebilong-AM (Nebivolol) is indicated for the treatment of hypertension, to lower blood pressure . Nebilong-AM (Nebivolol) may be used alone or in combination with other antihypertensive agents .

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Nebilong-AM (Nebivolol).

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

2. DOSAGE AND ADMINISTRATION

Can be taken with and without food. Individualize to the needs of the patient and monitor during up-titration.

• Hypertension: Most patients start at 5 mg once daily. Dose can be increased at 2-week intervals up to 40 mg. (2.1)

2.1 Hypertension

The dose of Nebilong-AM (Nebivolol) must be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial.

Renal Impairment

In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. Nebilong-AM (Nebivolol) has not been studied in patients receiving dialysis .

Hepatic Impairment

In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. Nebilong-AM (Nebivolol) has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population .

2.2 Subpopulations

Geriatric Patients

It is not necessary to adjust the dose in the elderly .

CYP2D6 Polymorphism

No dose adjustments are necessary for patients who are CYP2D6 poor metabolizers. The clinical effect and safety profile observed in poor metabolizers were similar to those of extensive metabolizers .

3. DOSAGE FORMS AND STRENGTHS

Nebilong-AM (Nebivolol) is available as tablets for oral administration containing Nebilong-AM (Nebivolol) hydrochloride equivalent to 2.5, 5, 10, and 20 mg of Nebilong-AM (Nebivolol).

Nebilong-AM (Nebivolol) tablets are triangular-shaped, biconvex, unscored, differentiated by color and are engraved with “FL” on one side and the number of mg (2 ½, 5, 10, or 20) on the other side.

Tablets: 2.5, 5, 10, 20 mg (3)

4. CONTRAINDICATIONS

Nebilong-AM (Nebivolol) is contraindicated in the following conditions:

• Severe bradycardia
• Heart block greater than first degree
• Patients with cardiogenic shock
• Decompensated cardiac failure
• Sick sinus syndrome (unless a permanent pacemaker is in place)
• Patients with severe hepatic impairment (Child-Pugh >B)
• Patients who are hypersensitive to any component of this product.

• Severe bradycardia (4)
• Heart block greater than first degree (4)
• Patients with cardiogenic shock (4)
• Decompensated cardiac failure (4)
• Sick sinus syndrome (unless a permanent pacemaker is in place) (4)
• Patients with severe hepatic impairment (Child-Pugh >B) (4)
• Hypersensitive to any component of this product (4)

5. WARNINGS AND PRECAUTIONS

• Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue
• Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia (5.5)

5.1 Abrupt Cessation of Therapy

Do not abruptly discontinue Nebilong-AM (Nebivolol) therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebilong-AM (Nebivolol) is planned, carefully observe and advise patients to minimize physical activity. Taper Nebilong-AM (Nebivolol) over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, re-start Nebilong-AM (Nebivolol) promptly, at least temporarily.

5.2 Angina and Acute Myocardial Infarction

Nebilong-AM was not studied in patients with angina pectoris or who had a recent MI.

5.3 Bronchospastic Diseases

In general, patients with bronchospastic diseases should not receive β-blockers.

5.4 Anesthesia and Major Surgery

Because beta-blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta-blockers should generally continue treatment throughout the perioperative period. If Nebilong-AM is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

The β-blocking effects of Nebilong-AM (Nebivolol) can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers.

5.5 Diabetes and Hypoglycemia

β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether Nebilong-AM (Nebivolol) has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities.

5.6 Thyrotoxicosis

β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

5.7 Peripheral Vascular Disease

β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

5.8 Non-dihydropyridine Calcium Channel Blockers

Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure in patients treated concomitantly with these agents.

5.9 Use with CYP2D6 Inhibitors

Nebilong-AM exposure increases with inhibition of CYP2D6 . The dose of Nebilong-AM (Nebivolol) may need to be reduced.

5.10 Impaired Renal Function

Renal clearance of Nebilong-AM (Nebivolol) is decreased in patients with severe renal impairment. Nebilong-AM (Nebivolol) has not been studied in patients receiving dialysis .

5.11 Impaired Hepatic Function

Metabolism of Nebilong-AM is decreased in patients with moderate hepatic impairment. Nebilong-AM (Nebivolol) has not been studied in patients with severe hepatic impairment .

5.12 Risk of Anaphylactic Reactions

While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

5.13 Pheochromocytoma

In patients with known or suspected pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker.

6. ADVERSE REACTIONS

Most common adverse reactions :

• Headache, fatigue

To report SUSPECTED ADVERSE REACTIONS, Contact Allergan at 1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience

Nebilong-AM (Nebivolol) has been evaluated for safety in patients with hypertension and in patients with heart failure. The observed adverse reaction profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population.

The data described below reflect worldwide clinical trial exposure to Nebilong-AM (Nebivolol) in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received Nebilong-AM (Nebivolol) for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year.

HYPERTENSION: In placebo-controlled clinical trials comparing Nebilong-AM (Nebivolol) with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with Nebilong-AM (Nebivolol) and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of Nebilong-AM (Nebivolol) were headache (0.4%), nausea (0.2%) and bradycardia (0.2%).

Table 1 lists treatment-emergent adverse reactions that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg, or 20-40 mg of Nebilong-AM (Nebivolol) and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with Nebilong-AM (Nebivolol) and greater than the rate for those treated with placebo in at least one dose group.

Listed below are other reported adverse reactions with an incidence of at least 1% in the more than 4300 patients treated with Nebilong-AM (Nebivolol) in controlled or open-label trials except for those already appearing in Table 1 , terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies.

Body as a Whole: asthenia.

Gastrointestinal System Disorders: abdominal pain

Metabolic and Nutritional Disorders: hypercholesterolemia

Nervous System Disorders: paraesthesia

6.2 Laboratory Abnormalities

In controlled monotherapy trials of hypertensive patients, Nebilong-AM was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count.

6.3 Postmarketing Experience

The following adverse reactions have been identified from spontaneous reports of Nebilong-AM (Nebivolol) received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to Nebilong-AM (Nebivolol). Adverse reactions common in the population have generally been omitted. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to Nebilong-AM (Nebivolol) exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second and third degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud's phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

7. Drug Interactions

• CYP2D6 enzyme inhibitors may increase Nebilong-AM levels (7.1)
• Reserpine or clonidine may produce excessive reduction of sympathetic activity. (7.2)
• Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. (7.3)
• Verapamil- or diltiazem-type calcium channel blockers may cause excessive reductions in heart rate, blood pressure, and cardiac contractility. (7.4)

7.1 CYP2D6 Inhibitors

Use caution when Nebilong-AM (Nebivolol) is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) .

7.2 Hypotensive Agents

Do not use Nebilong-AM with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of Nebilong-AM (Nebivolol) may produce excessive reduction of sympathetic activity. In patients who are receiving Nebilong-AM (Nebivolol) and clonidine, discontinue Nebilong-AM (Nebivolol) for several days before the gradual tapering of clonidine.

7.3 Digitalis Glycosides

Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

7.4 Calcium Channel Blockers

Nebilong-AM (Nebivolol) can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Category C.

Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period. At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given Nebilong-AM (Nebivolol) during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which Nebilong-AM (Nebivolol) was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

8.2 Labor and Delivery

Nebilong-AM (Nebivolol) caused prolonged gestation and dystocia at doses ≥ 5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when Nebilong-AM (Nebivolol) was given during the perinatal period (late gestation, parturition and lactation).

No studies of Nebilong-AM (Nebivolol) were conducted in pregnant women. Use Nebilong-AM (Nebivolol) during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

Studies in rats have shown that Nebilong-AM or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk.

Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, Nebilong-AM (Nebivolol) is not recommended during nursing.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility .

8.5 Geriatric Use

Of the 2800 patients in the U.S. sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.

8.6 Heart Failure

In a placebo-controlled trial of 2128 patients (1067 Nebilong-AM (Nebivolol), 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with Nebilong-AM (Nebivolol) compared to placebo. However, if heart failure worsens consider discontinuation of Nebilong-AM (Nebivolol).

10. OVERDOSAGE

In clinical trials and worldwide postmarketing experience there were reports of Nebilong-AM (Nebivolol) overdose. The most common signs and symptoms associated with Nebilong-AM (Nebivolol) overdosage are bradycardia and hypotension. Other important adverse reactions reported with Nebilong-AM (Nebivolol) overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse reactions associated with β-blocker overdose include bronchospasm and heart block.

The largest known ingestion of Nebilong-AM (Nebivolol) worldwide involved a patient who ingested up to 500 mg of Nebilong-AM (Nebivolol) along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhydrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered.

Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance Nebilong-AM (Nebivolol) clearance.

If overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping Nebilong-AM (Nebivolol), when clinically warranted:

Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.

Heart Block (second or third degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consider the use of inotropic and vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as a short acting inhaled β₂-agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required.

Supportive measures should continue until clinical stability is achieved. The half-life of low doses of Nebilong-AM (Nebivolol) is 12-19 hours.

Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.

11. DESCRIPTION

The chemical name for the active ingredient in Nebilong-AM (Nebivolol) (nebivolol) tablets is (1RS,1'RS)-1,1'-[(2RS,2'SR)-bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)]- 2,2'-iminodiethanol hydrochloride. Nebilong-AM (Nebivolol) is a racemate composed of d-Nebivolol and l-Nebivolol with the stereochemical designations of [SRRR]-nebivolol and [RSSS]-nebivolol, respectively. Nebivolol's molecular formula is (C₂₂H₂₅F₂NO₄-HCl) with the following structural formula:

Nebilong-AM (Nebivolol) hydrochloride is a white to almost white powder that is soluble in methanol, dimethylsulfoxide, and N,N-dimethylformamide, sparingly soluble in ethanol, propylene glycol, and polyethylene glycol, and very slightly soluble in hexane, dichloromethane, and methylbenzene.

Nebilong-AM (Nebivolol) as tablets for oral administration contains Nebilong-AM (Nebivolol) hydrochloride equivalent to 2.5, 5, 10, and 20 mg of Nebilong-AM (Nebivolol) base. In addition, Nebilong-AM (Nebivolol) contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Lake, FD&C Blue #2 Lake, FD&C Yellow #6 Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polysorbate 80, and sodium lauryl sulfate.

Structural Formula

12. CLINICAL PHARMACOLOGY

Nebilong-AM is a β-adrenergic receptor blocking agent. In extensive metabolizers (most of the population) and at doses less than or equal to 10 mg, Nebilong-AM (Nebivolol) is preferentially β₁ selective. In poor metabolizers and at higher doses, Nebilong-AM (Nebivolol) inhibits both β₁ - and β₂ - adrenergic receptors. Nebilong-AM (Nebivolol) lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, Nebilong-AM (Nebivolol) does not demonstrate α₁-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to β-blocking activity.

12.1 Mechanism of Action

The mechanism of action of the antihypertensive response of Nebilong-AM (Nebivolol) has not been definitively established. Possible factors that may be involved include: (1) decreased heart rate, (2) decreased myocardial contractility, (3) diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, (4) suppression of renin activity and (5) vasodilation and decreased peripheral vascular resistance.

12.3 Pharmacokinetics

Nebilong-AM is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to β-blocking activity.

Plasma levels of d–nebivolol increase in proportion to dose in EMs and PMs for doses up to 20mg. Exposure to l-nebivolol is higher than to d-nebivolol but l-nebivolol contributes little to the drug's activity as d-nebivolol's beta receptor affinity is > 1000-fold higher than l-nebivolol. For the same dose, PMs attain a 5-fold higher Cmax and 10-fold higher AUC of d-nebivolol than do EMs. d-Nebivolol accumulates about 1.5-fold with repeated once-daily dosing in EMs.

Absorption

Absorption of Nebilong-AM (Nebivolol) is similar to an oral solution. The absolute bioavailability has not been determined.

Mean peak plasma Nebilong-AM (Nebivolol) concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs.

Food does not alter the pharmacokinetics of Nebilong-AM (Nebivolol). Under fed conditions, Nebilong-AM (Nebivolol) glucuronides are slightly reduced. Nebilong-AM (Nebivolol) may be administered without regard to meals.

Distribution

The in vitro human plasma protein binding of Nebilong-AM (Nebivolol) is approximately 98%, mostly to albumin, and is independent of Nebilong-AM (Nebivolol) concentrations.

Metabolism

Nebilong-AM (Nebivolol) is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. Its stereospecific metabolites contribute to the pharmacologic activity .

Elimination

After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs. Essentially all Nebilong-AM (Nebivolol) was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates.

12.4 Pharmacokinetics in Special Populations

Hepatic Disease

d-Nebivolol peak plasma concentration increased 3-fold, exposure (AUC) increased 10-fold, and the apparent clearance decreased by 86% in patients with moderate hepatic impairment (Child-Pugh Class B). No formal studies have been performed in patients with severe hepatic impairment and Nebilong-AM (Nebivolol) should be contraindicated for these patients .

Renal Disease

The apparent clearance of Nebilong-AM (Nebivolol) was unchanged following a single 5 mg dose of Nebilong-AM (Nebivolol) in patients with mild renal impairment (ClCr 50 to 80 mL/min, n=7), and it was reduced negligibly in patients with moderate (ClCr 30 to 50 mL/min, n=9), but clearance was reduced by 53% in patients with severe renal impairment (ClCr <30 mL/min, n=5). No studies have been conducted in patients on dialysis .

12.5 Drug-Drug Interactions

Drugs that inhibit CYP2D6 can be expected to increase plasma levels of Nebilong-AM (Nebivolol). When Nebilong-AM (Nebivolol) is co-administered with an inhibitor or an inducer of this enzyme, monitor patients closely and adjust the Nebilong-AM (Nebivolol) dose according to blood pressure response. In vitro studies have demonstrated that at therapeutically relevant concentrations, d- and l-nebivolol do not inhibit any cytochrome P450 pathways.

Digoxin: Concomitant administration of Nebilong-AM (Nebivolol) (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or Nebilong-AM (Nebivolol) .

Warfarin: Administration of Nebilong-AM (Nebivolol) (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of Nebilong-AM (Nebivolol) or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, Nebilong-AM (Nebivolol) has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers.

Diuretics: No pharmacokinetic interactions were observed in healthy adults between Nebilong-AM (Nebivolol) (10 mg daily for 10 days) and furosemide (40 mg single dose), hydrochlorothiazide (25 mg once daily for 10 days), or spironolactone (25 mg once daily for 10 days).

Ramipril: Concomitant administration of Nebilong-AM (Nebivolol) (10 mg once daily) and ramipril (5 mg once daily) for 10 days in 15 healthy adult volunteers produced no pharmacokinetic interactions.

Losartan: Concomitant administration of Nebilong-AM (Nebivolol) (10 mg single dose) and losartan (50 mg single dose) in 20 healthy adult volunteers did not result in pharmacokinetic interactions.

Fluoxetine: Fluoxetine, a CYP2D6 inhibitor, administered at 20 mg per day for 21 days prior to a single 10 mg dose of Nebilong-AM (Nebivolol) to 10 healthy adults, led to an 8-fold increase in the AUC and 3-fold increase in C_max for d-nebivolol .

Histamine-2 Receptor Antagonists: The pharmacokinetics of Nebilong-AM (Nebivolol) (5 mg single dose) were not affected by the co-administration of ranitidine (150 mg twice daily). Cimetidine (400 mg twice daily) causes a 23% increase in the plasma levels of d-nebivolol.

Charcoal: The pharmacokinetics of Nebilong-AM (Nebivolol) (10 mg single dose) were not affected by repeated co-administration (4, 8, 12, 16, 22, 28, 36, and 48 hours after Nebilong-AM (Nebivolol) administration) of activated charcoal (Actidose-Aqua^®).

Sildenafil: The co-administration of Nebilong-AM (Nebivolol) and sildenafil decreased AUC and C_max of sildenafil by 21 and 23% respectively. The effect on the C_max and AUC for d-nebivolol was also small (< 20%). The effect on vital signs (e.g., pulse and blood pressure) was approximately the sum of the effects of sildenafil and Nebilong-AM (Nebivolol).

Other Concomitant Medications: Utilizing population pharmacokinetic analyses, derived from hypertensive patients, the following drugs were observed not to have an effect on the pharmacokinetics of Nebilong-AM (Nebivolol): acetaminophen, acetylsalicylic acid, atorvastatin, esomeprazole, ibuprofen, levothyroxine sodium, metformin, sildenafil, simvastatin, or tocopherol.

Protein Binding: No meaningful changes in the extent of in vitro binding of Nebilong-AM (Nebivolol) to human plasma proteins were noted in the presence of high concentrations of diazepam, digoxin, diphenylhydantoin, enalapril, hydrochlorothiazide, imipramine, indomethacin, propranolol, sulfamethazine, tolbutamide, or warfarin. Additionally, Nebilong-AM (Nebivolol) did not significantly alter the protein binding of the following drugs: diazepam, digoxin, diphenylhydantoin, hydrochlorothiazide, imipramine, or warfarin at their therapeutic concentrations.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study of Nebilong-AM (Nebivolol) in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m² basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of Nebilong-AM (Nebivolol) 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of Nebilong-AM (Nebivolol) in mice and not thought to be clinically relevant in man.

A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of Nebilong-AM (Nebivolol) on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of Nebilong-AM (Nebivolol) had no significant effect on ACTH-stimulated mean serum cortisol AUC_{0-120 min}, serum LH, or serum total testosterone.

Effects on spermatogenesis were seen in male rats and mice at ≥ 40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats the effects on spermatogenesis were not reversed and may have worsened during a four week recovery period. The effects of Nebilong-AM (Nebivolol) on sperm in mice, however, were partially reversible.

Mutagenesis: Nebilong-AM (Nebivolol) was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK^+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests).

14. CLINICAL STUDIES

14.1 Hypertension

The antihypertensive effectiveness of Nebilong-AM (Nebivolol) as monotherapy has been demonstrated in three randomized, double-blind, multi-center, placebo-controlled trials at doses ranging from 1.25 to 40 mg for 12 weeks (Studies 1, 2, and 3). A fourth placebo-controlled trial demonstrated additional antihypertensive effects of Nebilong-AM (Nebivolol) at doses ranging from 5 to 20 mg when administered concomitantly with up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) in patients with inadequate blood pressure control.

The three monotherapy trials included a total of 2016 patients (1811 Nebilong-AM (Nebivolol), 205 placebo) with mild to moderate hypertension who had baseline diastolic blood pressures (DBP) of 95 to 109 mmHg. Patients received either Nebilong-AM (Nebivolol) or placebo once daily for twelve weeks. Two of these monotherapy trials (Studies 1 and 2) studied 1716 patients in the general hypertensive population with a mean age of 54 years, 55% males, 26% non-Caucasians, 7% diabetics and 6% genotyped as PMs. The third monotherapy trial (Study 3) studied 300 Black patients with a mean age of 51 years, 45% males, 14% diabetics, and 3% as PMs.

Placebo-subtracted blood pressure reductions by dose for each study are presented in Table 2 . Most studies showed increasing response to doses above 5 mg.

Study 4 enrolled 669 patients with a mean age of 54 years, 55% males, 54% Caucasians, 29% Blacks, 15% Hispanics, 1% Asians, 14% diabetics, and 5% PMs. Nebilong-AM (Nebivolol), 5 mg to 20 mg, administered once daily concomitantly with stable doses of up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) resulted in significant additional antihypertensive effects over placebo compared to baseline blood pressure.

Effectiveness was similar in subgroups analyzed by age and sex. Effectiveness was established in Blacks, but as monotherapy the magnitude of effect was somewhat less than in Caucasians.

The blood pressure lowering effect of Nebilong-AM (Nebivolol) was seen within two weeks of treatment and was maintained over the 24-hour dosing interval.

There are no trials of Nebilong-AM (Nebivolol) demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

16. HOW SUPPLIED/STORAGE AND HANDLING

Nebilong-AM (Nebivolol) is available as tablets for oral administration containing Nebilong-AM (Nebivolol) hydrochloride equivalent to 2.5, 5, 10, and 20 mg of Nebilong-AM (Nebivolol).

Nebilong-AM (Nebivolol) tablets are triangular-shaped, biconvex, unscored, differentiated by color and are engraved with “FL” on one side and the number of mg (2 ½, 5, 10, or 20) on the other side. Nebilong-AM (Nebivolol) tablets are supplied in the following strengths and package configurations:

Store at 20° to 25°C (68° to 77°F) .

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

• Patient Advice

Advise patients to take Nebilong-AM (Nebivolol) regularly and continuously, as directed. Nebilong-AM (Nebivolol) can be taken with or without food. If a dose is missed, take the next scheduled dose only (without doubling it). Do not interrupt or discontinue Nebilong-AM (Nebivolol) without consulting the physician.

Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness.

Advise patients to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia.

Caution patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

Distributed by:

Allergan USA, Inc.

Irvine, CA 92612

Licensed from Mylan Laboratories, Inc.

Under license from Janssen Pharmaceutica N.V., Beerse, Belgium

Bystolic® is a registered trademark of Forest Laboratories, LLC, an Allergan affiliate.

Actidose®-Aqua is a registered trademark of Paddock Laboratories, LLC

© 2016 Allergan. All rights reserved.

PATIENT INFORMATION

Nebilong-AM (Nebivolol)^® (bi-STOL-ik)

(nebivolol) Tablets

Read the Patient Information that comes with Nebilong-AM (Nebivolol) before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Nebilong-AM (Nebivolol), ask your doctor or pharmacist.

WHAT IS Nebilong-AM (Nebivolol)?

Nebilong-AM (Nebivolol) is a kind of prescription medicine called a “beta-blocker”. Nebilong-AM (Nebivolol) treats:

• High blood pressure (hypertension)

Nebilong-AM (Nebivolol) can lower blood pressure when used by itself and with other medicines.

Nebilong-AM (Nebivolol) is not approved for children less than 18 years of age.

WHO SHOULD NOT TAKE Nebilong-AM (Nebivolol)?

Do not take Nebilong-AM (Nebivolol) if you:

• Have heart failure and are in the ICU or need medicines to keep up your blood circulation
• Have a slow heartbeat or your heart skips beats (irregular heartbeat)
• Have severe liver damage
• Are allergic to any ingredient in Nebilong-AM (Nebivolol). The active ingredient is Nebilong-AM (Nebivolol). See the end of this leaflet for a list of ingredients.

WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING Nebilong-AM (Nebivolol)?

Tell your doctor about all of your medical problems, including if you:

• Have asthma or other lung problems (such as bronchitis or emphysema)
• Have problems with blood flow in your feet and legs (peripheral vascular disease) Nebilong-AM (Nebivolol) can make symptoms of blood flow problems worse.
• Have diabetes and take medicine to control blood sugar
• Have thyroid problems
• Have liver or kidney problems
• Had allergic reactions to medications or have allergies
• Have a condition called pheochromocytoma
• Are pregnant or trying to become pregnant. It is not known if Nebilong-AM (Nebivolol) is safe for your unborn baby. Talk with your doctor about the best way to treat high blood pressure while you are pregnant.
• Are breastfeeding. It is not known if Nebilong-AM (Nebivolol) passes into your breast milk. You should not breastfeed while using Nebilong-AM (Nebivolol).
• Are scheduled for surgery and will be given anesthetic agents

Tell your doctor about all the medicines you take. Include prescription and non-prescription medicines, vitamins, and herbal products. Nebilong-AM (Nebivolol) and certain other medicines can affect each other and cause serious side effects.

Keep a list of all the medicines you take. Show this list to your doctor and pharmacist before you start a new medicine.

HOW SHOULD I TAKE Nebilong-AM (Nebivolol)?

• Do not suddenly stop taking Nebilong-AM (Nebivolol). You could have chest pain or a heart attack. If your doctor decides to stop Nebilong-AM (Nebivolol), your doctor may slowly lower your dose over time before stopping it completely.
• Take Nebilong-AM (Nebivolol) every day exactly as your doctor tells you. Your doctor will tell you how much Nebilong-AM (Nebivolol) to take and how often. Your doctor may start with a low dose and raise it over time.
• Do not stop taking Nebilong-AM (Nebivolol) or change your dose without talking with your doctor.
• Take Nebilong-AM (Nebivolol) with or without food.
• If you miss a dose, take your dose as soon as you remember, unless it is close to the time to take your next dose. Do not take 2 doses at the same time. Take your next dose at the usual time.
• If you take too much Nebilong-AM (Nebivolol), call your doctor or poison control center right away.

WHAT ARE POSSIBLE SIDE EFFECTS OF Nebilong-AM (Nebivolol)?

• Low blood pressure and feeling dizzy. If you feel dizzy, sit or lie down and tell your doctor right away.
• Tiredness
• Slow heartbeat
• Headache
• Leg swelling due to fluid retention (edema). Tell your doctor if you gain weight or have trouble breathing while taking Nebilong-AM (Nebivolol).

Tell your doctor if you have any side effects that bother you or don't go away.

HOW SHOULD I STORE Nebilong-AM (Nebivolol)?

• Store Nebilong-AM (Nebivolol) between 68° to 77°F (20° - 25°C).
• Safely throw away Nebilong-AM (Nebivolol) that is out of date or no longer needed.
• Keep Nebilong-AM (Nebivolol) and all medicines out of the reach of children.

GENERAL INFORMATION ABOUT Nebilong-AM (Nebivolol)

Doctors sometimes prescribe medicines for conditions not included in the patient information leaflets.

• Only use Nebilong-AM (Nebivolol) for the medical problem it was prescribed for.
• Do not give Nebilong-AM (Nebivolol) to other people, even if they have the same symptoms. It may harm them.

This leaflet summarizes the most important information about Nebilong-AM (Nebivolol). For more information:

• Talk with your doctor.
• Ask your doctor or pharmacist for information about Nebilong-AM (Nebivolol) that is written for healthcare professionals.
• Visit www. BYSTOLIC.com on the web or call 1-800-678-1605.

WHAT IS IN Nebilong-AM (Nebivolol)?

Active Ingredient: Nebilong-AM (Nebivolol)

Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Lake, FD&C Blue #2 Lake, FD&C Yellow #6 Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polysorbate 80, and sodium lauryl sulfate

WHAT IS 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 great.

High blood pressure makes the heart work harder to pump blood through the body and causes damage to the blood vessels. Nebilong-AM (Nebivolol) tablets can help your blood vessels relax so your blood pressure is lower. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack.

Rev. October 2016

Distributed by:

Allergan USA, Inc.

Irvine, CA 92612

Licensed from Mylan Laboratories, Inc.

Under license from Janssen Pharmaceutica N.V., Beerse, Belgium

Bystolic® is a registered trademark of Forest Laboratories, LLC, an Allergan affiliate.

Actidose®-Aqua is a registered trademark of Paddock Laboratories, LLC

© 2016 Allergan. All rights reserved.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 2.5 MG LABEL

Rx Only

NDC 0456-1402-30

Nebilong-AM (Nebivolol)^®

(nebivolol) tablets

2.5 mg/tablet

30 Tablets

FOREST PHARMACEUTICALS, INC.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 5 MG LABEL

Rx Only

NDC 0456-1405-90

Nebilong-AM (Nebivolol)^®

(nebivolol) tablets

5 mg/tablet

90 TABLETS

FOREST PHARMACEUTICALS, INC.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 10 MG LABEL

NDC 0456-1410-90

Nebilong-AM (Nebivolol)^®

(nebivolol) tablets

10 mg/tablet

90 TABLETS

FOREST PHARMACEUTICALS, INC.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 20 MG LABEL

NDC 0456-1420-90

Nebilong-AM (Nebivolol)^®

(nebivolol) tablets

20 mg/tablet

90 TABLETS

FOREST PHARMACEUTICALS, INC.