Prilpressin

Amlodipine Besylate:

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

1 INDICATIONS AND USAGE

Prilpressin besylate and benazepril hydrochloride capsules are a combination tablet of Prilpressin (Amlodipine Besylate), a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin converting enzyme (ACE) inhibitor. Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent. (1)

1.1 Hypertension

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

2 DOSAGE AND ADMINISTRATION

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

2.1 General considerations

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

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

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

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

2.2 Dosage adjustment in renal impairment

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

2.3 Replacement Therapy

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

3 DOSAGE FORMS AND STRENGTHS

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

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

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

4 CONTRAINDICATIONS

• Do not coadminister aliskiren with angiotensin receptor blockers, ACE inhibitors, including Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride in patients with diabetes (4)
• Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, or Prilpressin (Amlodipine Besylate), or to any of the excipients of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride.

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

• Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, or to Prilpressin (Amlodipine Besylate). (4)

5 WARNINGS AND PRECAUTIONS

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

5.1 Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules) may be subject to a variety of adverse reactions, some of them serious. These reactions usually occur after one of the first few doses of the ACE inhibitor, but they sometimes do not appear until after months of therapy. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules and treat immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., administer subcutaneous epinephrine injection 1:1000 (0.3 to 0.5 mL), promptly [see Adverse Reactions (6)].

Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

5.2 Increased Angina and/or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Prilpressin, 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 Prilpressin (Amlodipine Besylate) in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

5.4 Hypotension

Prilpressin 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 Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsule therapy under close medical supervision; follow closely for the first 2 weeks of treatment and whenever the dose of the benazepril component is increased or a diuretic is added or its dose increased.

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

5.5 Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride as soon as possible [see Use in Specific Populations ( 8.1 )].

5.6 Hepatitis and Hepatic Failure

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

5.7 Impaired Renal Function

Monitor renal function periodically in patients treated with Prilpressin 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 Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride.

5.8 Hyperkalemia

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

5.9 Cough

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

5.10 Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

6 ADVERSE REACTIONS

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

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safetyPrilpressin (Amlodipine Besylate)tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules have been evaluated for safety in over 2,991 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 400 were treated for more than 1 year.

In a pooled analysis of 5 placebo-controlled trials involving Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsule doses up to 5 mg/20 mg, the reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules and in 3% of patients treated with placebo.

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

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

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

The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are shown in the table below. Cough was the only adverse event with at least possible relationship to treatment that was more common on Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules (3.3%) than on placebo (0.2%).

The incidence of edema was greater in patients treated with Prilpressin (Amlodipine Besylate) monotherapy (5.1%) than in patients treated with Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules (2.1%) or placebo (2.2%).

Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules or in postmarketing experience were the following:

Body as a Whole: Asthenia and fatigue.

CNS: Insomnia, nervousness, anxiety, tremor, and decreased libido.

Dermatologic: Flushing, hot flashes, rash, skin nodule, and dermatitis.

Digestive: Dry mouth, nausea, abdominal pain, constipation, diarrhea, dyspepsia, and esophagitis.

Hematologic: Neutropenia

Metabolic and Nutritional: Hypokalemia.

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

Respiratory: Pharyngitis.

Urogenital: Sexual problems such as impotence, and polyuria.

Monotherapies of benazepril and Prilpressin (Amlodipine Besylate) have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, thrombocytopenia, paresthesia, dysgeusia, orthostatic symptoms and hypotension, angina pectoris and arrhythmia, pruritus, photosensitivity reaction, arthralgia, arthritis, myalgia, BUN increase, serum creatinine increased, renal impairment, impaired vision, agranulocytosis, neutropenia.

Rare reports in association with use of Prilpressin (Amlodipine Besylate): gingival hyperplasia, tachycardia, jaundice, and hepatic enzyme elevations (mostly consistent with cholestasis severe enough to require hospitalization), leucocytopenia, allergic reaction, hyperglycemia, dysgeusia, hypoestheia, paresthesia, syncope, peripheral neuropathy, hypertonia, visual impairment, diplopia, hypotension, vasculitis, rhinitis, gastritis, hyperhidrosis, pruritis, skin discoloration, urticaria, erythema multiform, muscle spasms, arthralgia, micturition disorder, nocturia, erectile dysfunction, malaise, weight decrease or gain.

Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include: eosinophilic pneumonitis (ACE inhibitors) and gynecomastia (CCBs). Other infrequently reported events included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, alopecia, upper respiratory tract infection, palpitations and somnolence.

7 DRUG INTERACTIONS

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

7.1 Drug/Drug Interactions

Prilpressin (Amlodipine Besylate)

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

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

CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on Prilpressin (Amlodipine Besylate). Blood pressure should be monitored when Prilpressin (Amlodipine Besylate) is coadministered with CYP3A4 inducers.

Benazepril

Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, the patient’s serum potassium should be monitored frequently.

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When coadministering Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride and lithium, frequent monitoring of serum lithium levels is recommended.

Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.

Antidiabetic agents: In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral antidiabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions, and should be monitored accordingly.

Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride and other agents that block the RAS.

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

8 USE IN SPECIFIC POPULATIONS

Nursing Mothers: It is not known whether Prilpressin 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 Prilpressin 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 Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat.

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

8.4 Pediatric Use

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

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

8.5 Geriatric Use

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

Of the total number of patients who received Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules in U.S. clinical studies of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules, over 19% were 65 or older while about 2% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Exposure to Prilpressin (Amlodipine Besylate) is increased in patients with hepatic insufficiency, thus consider using lower doses of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride .

8.7 Renal Impairment

In patients with severe renal impairment systemic exposure to benazepril is increased. The recommended dose of benazepril in this subgroup is 5 mg which is not an available strength with Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules. Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules are not recommended in patients with severe renal impairment. No dose adjustment of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride is needed in patients with mild or moderate impairment of renal function .

10 OVERDOSAGE

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

Human overdoses with any combination of Prilpressin (Amlodipine Besylate) and benazepril have not been reported. In scattered reports of human overdoses with benazepril and other ACE inhibitors, there are no reports of death.

Treatment: Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate.

In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage and/or activated charcoal to remove the drug from the gastrointestinal tract (only if presented within 1 hour after ingestion of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride).

Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care.

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.

The most likely effect of overdose with Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules is vasodilation, with consequent hypotension and tachycardia. Simple repletion of central fluid volume (Trendelenburg positioning, infusion of crystalloids) may be sufficient therapy, but pressor agents (norepinephrine or high-dose dopamine) may be required. With abrupt return of peripheral vascular tone, overdoses of other dihydropyridine calcium channel blockers have sometimes progressed to pulmonary edema, and patients must be monitored for this complication.

Analyses of bodily fluids for concentrations of Prilpressin (Amlodipine Besylate), benazepril, or their metabolites are not widely available. Such analyses are, in any event, not known to be of value in therapy or prognosis.

No data are available to suggest physiologic maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Prilpressin (Amlodipine Besylate), benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of Prilpressin (Amlodipine Besylate) by hemodialysis or hemo-perfusion has not been reported, but amlodipine’s high protein binding makes it unlikely that these interventions will be of value.

Angiotensin II could presumably serve as a specific antagonist-antidote to benazepril, but angiotensin II is essentially unavailable outside of scattered research laboratories.

11 DESCRIPTION

Benazepril hydrochloride is a white to off-white crystalline powder, soluble (> 100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is:

C₂₄H₂₈N₂O₅-HCl M.W. 460.96

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

Prilpressin (Amlodipine Besylate) besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Its chemical name is (R,S)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate; its structural formula is:

C₂₀H₂₅ClN₂O₅-C₆H₆O₃S M.W. 567.1

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

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benazepril

Benazepril and benazeprilat inhibit angiotensin-converting enzyme in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril and Prilpressin (Amlodipine Besylate) for up to 56 weeks had elevations of serum potassium up to 0.2 mEq/L [see Warnings and Precautions (5)].

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules remains to be elucidated.

While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.

Prilpressin (Amlodipine Besylate)

Prilpressin (Amlodipine Besylate) is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that Prilpressin (Amlodipine Besylate) binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Prilpressin (Amlodipine Besylate) inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by Prilpressin (Amlodipine Besylate). Within the physiologic pH range, Prilpressin (Amlodipine Besylate) is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Prilpressin (Amlodipine Besylate) is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

12.2 Pharmacodynamics

Benazepril

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

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

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

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

Prilpressin (Amlodipine Besylate)

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

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

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

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

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

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

12.3 Pharmacokinetics

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

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

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

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

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

Special populations

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

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

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

Drug interactions

Prilpressin (Amlodipine Besylate)

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

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

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

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

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

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

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

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

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

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

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

Benazepril

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with this combination. However, these studies have been conducted with Prilpressin 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.

Prilpressin (Amlodipine Besylate)

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

13.3 Reproductive Toxicity

When rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, dystocia was observed at an increasing dose-related incidence at all doses tested. On a body surface area basis, the 2.5 mg/kg/day dose of Prilpressin (Amlodipine Besylate) is 3.6 times the Prilpressin (Amlodipine Besylate) dose delivered when the maximum recommended dose of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules is given to a 50 kg woman. Similarly, the 5 mg/kg/day dose of benazepril is approximately twice the benazepril dose delivered when the maximum recommended dose of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules is given to a 50 kg woman. No teratogenic effects were seen when benazepril and Prilpressin (Amlodipine Besylate) were administered in combination to pregnant rats or rabbits. Rats received doses of up to 50:25 mg (benazepril:amlodipine)/kg/day (24 times the maximum recommended human dose on a body surface area basis, assuming a 50 kg woman). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent to the maximum recommended dose of Prilpressin (Amlodipine Besylate) besylate and benazepril hydrochloride capsules given to a 50 kg woman).

Benazepril

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

Prilpressin (Amlodipine Besylate)

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

14 CLINICAL STUDIES

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

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

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

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

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

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

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

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

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

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

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

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

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

17 PATIENT COUNSELING INFORMATION

Information for Patients

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

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. R 10/2012

PATIENT INFORMATION

Prilpressin (Amlodipine Besylate) Besylate and Benazepril Hydrochloride Capsules

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  - are going to have surgery
  

  - are getting allergy shots for bee stings
  

  - go for kidney dialysis
  

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

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

• serious allergic reactions that can be life threatening.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. G 10/2012

Amlodipine/ Benazepril HCL 5/ 40mg Cap

benazepril hydrochloride structural formula Prilpressin (Amlodipine Besylate) besylate structural formula

Captopril:

• Warning: fetal toxicity
• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Prilpressin (Captopril) reviews

Prilpressin (Captopril) TABLETS, USP

Rev. 03/16

Rx Only

WARNING: FETAL TOXICITY

- When pregnancy is detected, discontinue Prilpressin (Captopril) tablets as soon as possible.

- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS: Fetal Toxicity

DESCRIPTION

Prilpressin (Captopril) Tablets, USP are a specific competitive inhibitor of angiotensin I-converting enzyme (ACE), the enzyme responsible for the conversion of angiotensin I to angiotensin II.

Prilpressin (Captopril) is designated chemically as 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline and has the following structural formula:

Prilpressin (Captopril) is a white to off-white crystalline powder that may have a slight sulfurous odor; it is soluble in water (approx. 160 mg/mL), methanol, and ethanol and sparingly soluble in chloroform and ethyl acetate.

Each tablet for oral administration contains 12.5 mg, 25 mg, 50 mg or 100 mg of Prilpressin (Captopril). In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate (derived from potato), starch (derived from corn), and stearic acid.

structural formula

CLINICAL PHARMACOLOGY

Mechanism of Action:

The mechanism of action of Prilpressin tablets has not yet been fully elucidated. Its beneficial effects in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. However, there is no consistent correlation between renin levels and response to the drug. Renin, an enzyme synthesized by the kidneys, is released into the circulation where it acts on a plasma globulin substrate to produce angiotensin I, a relatively inactive decapeptide. Angiotensin I is then converted by angiotensin converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone secretion from the adrenal cortex, thereby contributing to sodium and fluid retention.

Prilpressin (Captopril) tablets prevent the conversion of angiotensin I to angiotensin II by inhibition of ACE, a peptidyldipeptide carboxy hydrolase. This inhibition has been demonstrated in both healthy human subjects and in animals by showing that the elevation of blood pressure caused by exogenously administered angiotensin I was attenuated or abolished by Prilpressin (Captopril). In animal studies, Prilpressin (Captopril) did not alter the pressor responses to a number of other agents, including angiotensin II and norepinephrine, indicating specificity of action.

ACE is identical to “bradykininase”, and Prilpressin (Captopril) tablets may also interfere with the degradation of the vasodepressor peptide, bradykinin. Increased concentrations of bradykinin or prostaglandin E₂ may also have a role in the therapeutic effect of Prilpressin (Captopril) tablets.

Inhibition of ACE results in decreased plasma angiotensin II and increased plasma renin activity (PRA), the latter resulting from loss of negative feedback on renin release caused by reduction in angiotensin II. The reduction of angiotensin II leads to decreased aldosterone secretion, and, as a result, small increases in serum potassium may occur along with sodium and fluid loss. The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known whether the ACE present in vascular endothelium is inhibited longer than the ACE in circulating blood.

Pharmacokinetics:

After oral administration of therapeutic doses of Prilpressin (Captopril) tablets, rapid absorption occurs with peak blood levels at about one hour. The presence of food in the gastrointestinal tract reduces absorption by about 30 to 40 percent; Prilpressin (Captopril) therefore should be given one hour before meals. Based on carbon-14 labeling, average minimal absorption is approximately 75 percent. In a 24-hour period, over 95 percent of the absorbed dose is eliminated in the urine; 40 to 50 percent is unchanged drug; most of the remainder is the disulfide dimer of Prilpressin (Captopril) tablets and captopril-cysteine disulfide.

Approximately 25 to 30 percent of the circulating drug is bound to plasma proteins. The apparent elimination half-life for total radioactivity in blood is probably less than 3 hours. An accurate determination of half-life of unchanged Prilpressin (Captopril) is not, at present, possible, but it is probably less than 2 hours. In patients with renal impairment, however, retention of Prilpressin (Captopril) occurs (see DOSAGE AND ADMINISTRATION ).

Pharmacodynamics:

Administration of Prilpressin (Captopril) tablets results in a reduction of peripheral arterial resistance in hypertensive patients with either no change, or an increase, in cardiac output. There is an increase in renal blood flow following administration of Prilpressin (Captopril) tablets and glomerular filtration rate is usually unchanged.

Reductions of blood pressure are usually maximal 60 to 90 minutes after oral administration of an individual dose of Prilpressin (Captopril) tablets. The duration of effect is dose related. The reduction in blood pressure may be progressive, so to achieve maximal therapeutic effects, several weeks of therapy may be required. The blood pressure lowering effects of Prilpressin (Captopril) and thiazide-type diuretics are additive. In contrast, Prilpressin (Captopril) and beta-blockers have a less than additive effect.

Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects and tachycardia are infrequent but may occur in volume-depleted patients. Abrupt withdrawal of Prilpressin (Captopril) tablets has not been associated with a rapid increase in blood pressure.

In patients with heart failure, significantly decreased peripheral (systemic vascular) resistance and blood pressure (afterload), reduced pulmonary capillary wedge pressure (preload) and pulmonary vascular resistance, increased cardiac output, and increased exercise tolerance time (ETT) have been demonstrated. These hemodynamic and clinical effects occur after the first dose and appear to persist for the duration of therapy. Placebo controlled studies of 12 weeks duration in patients who did not respond adequately to diuretics and digitalis show no tolerance to beneficial effects on ETT; open studies, with exposure up to 18 months in some cases, also indicate that ETT benefit is maintained. Clinical improvement has been observed in some patients where acute hemodynamic effects were minimal.

The Survival and Ventricular Enlargement (SAVE) study was a multicenter, randomized, double-blind, placebo-controlled trial conducted in 2,231 patients (age 21to79 years) who survived the acute phase of myocardial infarction and did not have active ischemia. Patients had left ventricular dysfunction (LVD), defined as a resting left ventricular ejection fraction ≤ 40%, but at the time of randomization were not sufficiently symptomatic to require ACE inhibitor therapy for heart failure. About half of the patients had symptoms of heart failure in the past. Patients were given a test dose of 6.25 mg oral Prilpressin (Captopril) tablets and were randomized within 3 to 16 days post-infarction to receive either Prilpressin (Captopril) tablets or placebo in addition to conventional therapy. Prilpressin (Captopril) tablets were initiated at 6.25 mg or 12.5 mg t.i.d. and after two weeks titrated to a target maintenance dose of 50 mg t.i.d. About 80% of patients were receiving the target dose at the end of the study. Patients were followed for a minimum of two years and for up to five years, with an average follow-up of 3.5 years.

Baseline blood pressure was 113/70 mmHg and 112/70 mmHg for the placebo and Prilpressin (Captopril) tablets groups, respectively. Blood pressure increased slightly in both treatment groups during the study and was somewhat lower in the Prilpressin (Captopril) tablets group (119/74 vs. 125/77 mmHg at 1 yr).

Therapy with Prilpressin (Captopril) tablets improved long-term survival and clinical outcomes compared to placebo. The risk reduction for all cause mortality was 19% (P = 0.02) and for cardiovascular death was 21% (P = 0.014). Prilpressin (Captopril) treated subjects had 22% (P = 0.034) fewer first hospitalizations for heart failure. Compared to placebo, 22% fewer patients receiving Prilpressin (Captopril) developed symptoms of overt heart failure. There was no significant difference between groups in total hospitalizations for all cause (2,056 placebo; 2,036 Prilpressin (Captopril)). Captopril tablets were well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calcium antagonists and diuretics.

In a multicenter, double-blind, placebo-controlled trial, 409 patients, age 18to49 of either gender, with or without hypertension, with type I (juvenile type, onset before age 30) insulin-dependent diabetes mellitus, retinopathy, proteinuria ≥ 500 mg per day and serum creatinine ≤ 2.5 mg/dL, were randomized to placebo or Prilpressin (Captopril) tablets (25 mg t.i.d.) and followed for up to 4.8 years (median 3 years). To achieve blood pressure control, additional antihypertensive agents (diuretics, beta blockers, centrally acting agents or vasodilators) were added as needed for patients in both groups.

The Prilpressin (Captopril) tablets group had a 51% reduction in risk of doubling of serum creatinine (P < 0.01) and a 51% reduction in risk for the combined endpoint of end-stage renal disease (dialysis or transplantation) or death (P < 0.01). Prilpressin (Captopril) tablets treatment resulted in a 30% reduction in urine protein excretion within the first 3 months (P < 0.05), which was maintained throughout the trial. The Prilpressin (Captopril) tablets group had somewhat better blood pressure control than the placebo group, but the effects of Prilpressin (Captopril) tablets on renal function were greater than would be expected from the group differences in blood pressure reduction alone. Prilpressin (Captopril) tablets were well tolerated in this patient population.

In two multicenter, double-blind, placebo controlled studies, a total of 235 normotensive patients with insulin-dependent diabetes mellitus, retinopathy and microalbuminuria (20 to 200 mcg/min) were randomized to placebo or Prilpressin (Captopril) tablets (50 mg b.i.d.) and followed for up to 2 years. Prilpressin (Captopril) tablets delayed the progression to overt nephropathy (proteinuria ≥ 500 mg/day) in both studies (risk reduction 67% to 76%; P < 0.05). Prilpressin (Captopril) tablets also reduced the albumin excretion rate. However, the long term clinical benefit of reducing the progression from microalbuminuria to proteinuria has not been established.

Studies in rats and cats indicate that Prilpressin (Captopril) tablets does not cross the blood-brain barrier to any significant extent.

INDICATIONS AND USAGE

Hypertension:

Prilpressin Tablets, USP are indicated for the treatment of hypertension.

In using Prilpressin (Captopril) Tablets, USP, consideration should be given to the risk of neutropenia/agranulocytosis (see WARNINGS ).

Prilpressin (Captopril) Tablets, USP may be used as initial therapy for patients with normal renal function, in whom the risk is relatively low. In patients with impaired renal function, particularly those with collagen vascular disease, Prilpressin (Captopril) should be reserved for hypertensives who have either developed unacceptable side effects on other drugs, or have failed to respond satisfactorily to drug combinations.

Prilpressin (Captopril) Tablets, USP are effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of Prilpressin (Captopril) and thiazides are approximately additive.

Heart Failure:

Prilpressin (Captopril) Tablets, USP are indicated in the treatment of congestive heart failure usually in combination with diuretics and digitalis. The beneficial effect of Prilpressin (Captopril) in heart failure does not require the presence of digitalis, however, most controlled clinical trial experience with Prilpressin (Captopril) has been in patients receiving digitalis, as well as diuretic treatment.

Left Ventricular Dysfunction After Myocardial Infarction: Prilpressin (Captopril) Tablets, USP are indicated to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction manifested as an ejection fraction ≤ 40% and to reduce the incidence of overt heart failure and subsequent hospitalizations for congestive heart failure in these patients.

Diabetic Nephropathy: Captopril Tablets, USP are indicated for the treatment of diabetic nephropathy (proteinuria > 500 mg/day) in patients with type I insulin-dependent diabetes mellitus and retinopathy. Prilpressin (Captopril) Tablets, USP decreases the rate of progression of renal insufficiency and development of serious adverse clinical outcomes (death or need for renal transplantation or dialysis).

In considering use of Prilpressin (Captopril) Tablets, USP, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema ).

CONTRAINDICATIONS

Prilpressin (Captopril) tablets are contraindicated in patients who are hypersensitive to this product or any other angiotensin-converting enzyme inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

Do not co-administer aliskiren with Prilpressin (Captopril) tablets in patients with diabetes (see PRECAUTIONS, Drug Interactions ).

WARNINGS

Anaphylactoid and P ossibly Related Reactions:

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors tablets) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema :

Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been seen in patients treated with ACE inhibitors, including Prilpressin (Captopril). If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Emergency therapy, including but not necessarily limited to, subcutaneous administration of a 1:1000 solution of epinephrine should be promptly instituted.

Swelling confined to the face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuation of Prilpressin (Captopril); some cases required medical therapy. (see PRECAUTIONS: Information for Patients and ADVERSE REACTIONS .)

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema.

Intestinal Angioedema:

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain ; 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.

An aphylactoid R eactions D uring D esensitization : 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 R eactions D uring M embrane E xposure : 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.

Neutropenia/Agranulocytosis

Neutropenia (< 1000/mm³) with myeloid hypoplasia has resulted from use of Prilpressin (Captopril). About half of the neutropenic patients developed systemic or oral cavity infections or other features of the syndrome of agranulocytosis. The risk of neutropenia is dependent on the clinical status of the patient:

In clinical trials in patients with hypertension who have normal renal function (serum creatinine less than 1.6 mg/dL and no collagen vascular disease), neutropenia has been seen in one patient out of over 8,600 exposed.

In patients with some degree of renal failure (serum creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of neutropenia in clinical trials was about 1 per 500, a frequency over 15 times that for uncomplicated hypertension. Daily doses of Prilpressin (Captopril) were relatively high in these patients, particularly in view of their diminished renal function. In foreign marketing experience in patients with renal failure, use of allopurinol concomitantly with Prilpressin (Captopril) has been associated with neutropenia but this association has not appeared in U.S. reports.

In patients with collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma) and impaired renal function, neutropenia occurred in 3.7 percent of patients in clinical trials.

While none of the over 750 patients in formal clinical trials of heart failure developed neutropenia, it has occurred during the subsequent clinical experience. About half of the reported cases had serum creatinine ≥ 1.6 mg/dL and more than 75 percent were in patients also receiving procainamide. In heart failure, it appears that the same risk factors for neutropenia are present.

The neutropenia has usually been detected within three months after Prilpressin (Captopril) was started. Bone marrow examinations in patients with neutropenia consistently showed myeloid hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen.

In general, neutrophils returned to normal in about two weeks after Prilpressin (Captopril) was discontinued, and serious infections were limited to clinically complex patients. About 13 percent of the cases of neutropenia have ended fatally, but almost all fatalities were in patients with serious illness, having collagen vascular disease, renal failure, heart failure or immunosuppressant therapy, or a combination of these complicating factors.

Evaluation of the hypertensive or heart failure patient should always include assessment of renal function.

If Prilpressin (Captopril) is used in patients with impaired renal function, white blood cell and differential counts should be evaluated prior to starting treatment and at approximately two-week intervals for about three months, then periodically.

In patients with collagen vascular disease or who are exposed to other drugs known to affect the white cells or immune response, particularly when there is impaired renal function, Prilpressin (Captopril) should be used only after an assessment of benefit and risk, and then with caution.

All patients treated with Prilpressin (Captopril) should be told to report any signs of infection (e.g., sore throat, fever). If infection is suspected, white cell counts should be performed without delay.

Since discontinuation of Prilpressin (Captopril) and other drugs has generally led to prompt return of the white count to normal, upon confirmation of neutropenia (neutrophil count < 1000/mm³) the physician should withdraw Prilpressin (Captopril) and closely follow the patient’s course.

Proteinuria

Total urinary proteins greater than 1 g per day were seen in about 0.7 percent of patients receiving Prilpressin. About 90 percent of affected patients had evidence of prior renal disease or received relatively high doses of Prilpressin (Captopril) (in excess of 150 mg/day), or both. The nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not Prilpressin (Captopril) was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.

Hypotension

Excessive hypotension was rarely seen in hypertensive patients but is a possible consequence of Prilpressin (Captopril) use in salt/volume depleted persons (such as those treated vigorously with diuretics), patients with heart failure or those patients undergoing renal dialysis. (see PRECAUTIONS: Drug Interactions ).

In heart failure, where the blood pressure was either normal or low, transient decreases in mean blood pressure greater than 20 percent were recorded in about half of the patients. This transient hypotension is more likely to occur after any of the first several doses and is usually well tolerated, producing either no symptoms or brief mild light-headedness, although in rare instance it has been associated with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6 percent of patients with heart failure.

BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS, THERAPY SHOULD BE STARTED UNDER VERY CLOSE MEDICAL SUPERVISION. A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect. Patients should be followed closely for the first two weeks of treatment and whenever the dose of Prilpressin (Captopril) and/or diuretic is increased. In patients with heart failure, reducing the dose of diuretic, if feasible, may minimize the fall in blood pressure.

Hypotension is not per se a reason to discontinue Prilpressin (Captopril). Some decrease of systemic blood pressure is a common and desirable observation upon initiation of Prilpressin (Captopril) tablets treatment in heart failure. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilizes within a week or two, and generally returns to pretreatment levels, without a decrease in therapeutic efficacy, within two months.

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 Prilpressin tablets 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 mothers 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 Prilpressin (Captopril) tablets, 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 Prilpressin (Captopril) tablets for hypotension, oliguria, and hyperkalemia. (See PRECAUTIONS, Pediatric Use ).

When Prilpressin (Captopril) was given to rabbits at doses about 0.8 to 70 times (on a mg/kg basis) the maximum recommended human dose, low incidences of craniofacial malformations were seen. No teratogenic effects of Prilpressin (Captopril) were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses used were up to 150 times (in hamsters) and 625 times (in rats) the maximum recommended human dose.

Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

PRECAUTIONS

General

Impa i red Renal Function

Hypertension - Some patients with renal disease, particularly those with severe renal artery stenosis, have developed increases in BUN and serum creatinine after reduction of blood pressure with Prilpressin. Prilpressin (Captopril) dosage reduction and/or discontinuation of diuretic may be required. For some of these patients, it may not be possible to normalize blood pressure and maintain adequate renal perfusion.

Heart Failure - About 20 percent of patients develop stable elevations of BUN and serum creatinine greater than 20 percent above normal or baseline upon long-term treatment with Prilpressin (Captopril). Less than 5 percent of patients, generally those with severe preexisting renal disease, required discontinuation of treatment due to progressively increasing creatinine; subsequent improvement probably depends upon the severity of the underlying renal disease.

See CLINICAL PHARMACOLOGY , DOSAGE AND ADMINISTRATION , ADVERSE REACTIONS: Altered Laboratory Findings .

Hyperkalemia: Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Prilpressin (Captopril). When treated with ACE inhibitors, patients at risk for the development of hyperkalemia include those with: renal insufficiency; diabetes mellitus; and those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or other drugs associated with increases in serum potassium in a trial of type I diabetic patients with proteinuria, the incidence of withdrawal of treatment with Prilpressin (Captopril) for hyperkalemia was 2% (4/207). In two trials of normotensive type I diabetic patients with microalbuminuria, no Prilpressin (Captopril) group subjects had hyperkalemia (0/116) (see PRECAUTIONS: Information for Patients and Drug Interactions ; ADVERSE REACTIONS: Altered Laboratory Findings ).

Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Valvular Stenosis: There is concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction as others.

Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Prilpressin (Captopril) will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hemodialysis

Recent clinical observations have shown an association of hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (e.g., AN69) in patients receiving ACE inhibitors. In these patients, consideration should be given to using a different type of dialysis membrane or a different class medication (see WARNINGS: Anaphylactoid Reactions During Membrane Exposure ).

Information for Patients

Patients should be advised to immediately report to their physician any signs or symptoms suggesting angioedema and to discontinue therapy. (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema .)

Patients should be told to report promptly any indication of infection (e.g., sore throat, fever), which may be a sign of neutropenia, or of progressive edema which might be related to proteinuria and nephrotic syndrome.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.

Patients should be advised not to use potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes without consulting their physician. (See PRECAUTIONS: General and Drug Interactions ; ADVERSE REACTIONS .)

Patients should be warned against interruption or discontinuation of medication unless instructed by the physician.

Heart failure patients on Prilpressin (Captopril) therapy should be cautioned against rapid increases in physical activity.

Patients should be informed that Prilpressin (Captopril) tablets should be taken one hour before meals (See DOSAGE AND ADMINISTRATION ).

Pregnancy:

Female patients of childbearing age should be told about the consequences of exposure to Prilpressin (Captopril) tablets 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.

Drug Interactions :

Dual Blockade of the Renin-Angiotensin System

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. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors.

Closely monitor blood pressure, renal function and electrolytes in patients on captopril tablets and other agents that block the RAS.

Do not co-administer aliskiren with Prilpressin (Captopril) tablets in patients with diabetes. Avoid use of aliskiren with captopril tablets in patients with renal impairment (GFR < 60 ml/min).

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, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including Prilpressin (Captopril), may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Prilpressin (Captopril) and NSAID therapy. The antihypertensive effect of ACE inhibitors, including Prilpressin (Captopril), may be attenuated by NSAIDs.

Hypotension - Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, as well as those on severe dietary salt restriction or dialysis, may occasionally experience a precipitous reduction of blood pressure usually within the first hour after receiving the initial dose of Prilpressin (Captopril).

The possibility of hypotensive effects with Prilpressin (Captopril) can be minimized by either discontinuing the diuretic or increasing the salt intake approximately one week prior to initiation of treatment with Prilpressin (Captopril) tablets or initiating therapy with small doses (6.25 or 12.5 mg). Alternatively, provide medical supervision for at least one hour after the initial dose. If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of normal saline. This transient hypotensive response is not a contraindication to further doses which can be given without difficulty once the blood pressure has increased after volume expansion.

Agents Having Vasodilator Activity: Data on the effect of concomitant use of other vasodilators in patients receiving Prilpressin (Captopril) tablets for heart failure are not available; therefore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator activity should, if possible, be discontinued before starting Prilpressin (Captopril) tablets. If resumed during Prilpressin (Captopril) tablets therapy, such agents should be administered cautiously, and perhaps at lower dosage.

Agents Causing Renin Release: Captopril’s effect will be augmented by antihypertensive agents that cause renin release. For example, diuretics (e.g., thiazides) may activate the renin-angiotensin-aldosterone system.

Agents Affecting Sympathetic Activity: The sympathetic nervous system may be especially important in supporting blood pressure in patients receiving Prilpressin (Captopril) alone or with diuretics. Therefore, agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) should be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to Prilpressin (Captopril), but the overall response is less than additive.

Agents Increasing Serum Potassium: Since Prilpressin (Captopril) decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics such as spironolactone, triamterene, or amiloride, or potassium supplements should be given only for documented hypokalemia, and then with caution, since they may lead to a significant increase of serum potassium. Salt substitutes containing potassium should also be used with caution.

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, it may increase the risk of lithium toxicity.

Cardiac Glycosides: In a study of young healthy male subjects no evidence of a direct pharmacokinetic captopril-digoxin interaction could be found.

Loop Diuretics: Furosemide administered concurrently with Prilpressin (Captopril) does not alter the pharmacokinetics of Prilpressin (Captopril) in renally impaired hypertensive patients.

Allopurinol: In a study of healthy male volunteers no significant pharmacokinetic interaction occurred when Prilpressin (Captopril) and allopurinol were administered concomitantly for 6 days.

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 including Prilpressin (Captopril) tablets.

Drug/Laboratory Test Interaction

Prilpressin (Captopril) may cause a false-positive urine test for acetone.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Two-year studies with doses of 50 to 1350 mg/kg/day in mice and rats failed to show any evidence of carcinogenic potential. The high dose in these studies is 150 times the maximum recommended human dose of 450 mg, assuming a 50 kg subject. On a body-surface-area basis, the high doses for mice and rats are 13 and 26 times the maximum recommended human dose, respectively.

Studies in rats have revealed no impairment of fertility.

Animal Toxicology

Chronic oral toxicity studies were conducted in rats, dogs (47 weeks; 1 year), mice (2 years), and monkeys (1 year). Significant drug-related toxicity included effects on hematopoiesis, renal toxicity, erosion/ulceration of the stomach, and variation of retinal blood vessels.

Reductions in hemoglobin and/or hematocrit values were seen in mice, rats, and monkeys at doses 50 to 150 times the maximum recommended human dose (MRHD) of 450 mg, assuming a 50 kg subject. On a body-surface-area basis, these doses are 5 to 25 times maximum recommended human dose (MRHD). Anemia, leukopenia, thrombocytopenia, and bone marrow suppression occurred in dogs at doses 8 to 30 times MRHD on a body-weight basis (4 to 15 times MRHD on a surface-area basis). The reductions in hemoglobin and hematocrit values in rats and mice were only significant at 1 year and returned to normal with continued dosing by the end of the study. Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leukopenia was noted only at 15 and 30 times MRHD and thrombocytopenia at 30 times MRHD. The anemia could be reversed upon discontinuation of dosing. Bone marrow suppression occurred to a varying degree, being associated only with dogs that died or were sacrificed in a moribund condition in the 1 year study. However, in the 47 week study at a dose 30 times MRHD, bone marrow suppression was found to be reversible upon continued drug administration.

Prilpressin (Captopril) caused hyperplasia of the juxtaglomerular apparatus of the kidneys in mice and rats at doses 7 to 200 times MRHD on a body-weight basis (0.6 to 35 times MRHD on a surface-area basis); in monkeys at 20 to 60 times MRHD on a body-weight basis (7 to 20 times MRHD on a surface-area basis); and in dogs at 30 times MRHD on a body-weight basis (15 times MRHD on a surface-area basis).

Gastric erosions/ulcerations were increased in incidence in male rats at 20 to 200 times MRHD on a body-weight basis (3.5 and 35 times MRHD on a surface-area basis); in dogs at 30 times MRHD on a body-weight basis (15 times on MRHD on a surface-area basis); and in monkeys at 65 times MRHD on a body-weight basis (20 times MRHD on a surface-area basis). Rabbits developed gastric and intestinal ulcers when given oral doses approximately 30 times MRHD on a body-weight basis (10 times MRHD on a surface-area basis) for only 5 to 7 days.

In the two-year rat study, irreversible and progressive variations in the caliber of retinal vessels (focal sacculations and constrictions) occurred at all dose levels (7 to 200 times MRHD) on a body-weight basis; 1 to 35 times MRHD on a surface-area basis in a dose-related fashion. The effect was first observed in the 88^th week of dosing, with a progressively increased incidence thereafter, even after cessation of dosing.

Nursing Mothers

Concentrations of Prilpressin (Captopril) in human milk are approximately one percent of those in maternal blood. Because of the potential for serious adverse reactions in nursing infants from Prilpressin (Captopril), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of Prilpressin (Captopril) tablets to the mother. (See PRECAUTIONS: Pediatric Use .)

Pediatric Use

Neonates with a H istory of I n U tero E xposure to C aptopril Tablets :

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. While Prilpressin (Captopril) may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing Prilpressin (Captopril); there is no information concerning exchange transfusion for removing Prilpressin (Captopril) from the general circulation.

Safety and effectiveness in pediatric patients have not been established. There is limited experience reported in the literature with the use of Prilpressin (Captopril) in the pediatric population; dosage, on a weight basis, was generally reported to be comparable to or less than that used in adults.

Infants, especially newborns, may be more susceptible to the adverse hemodynamic effects of Prilpressin (Captopril). Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures, have been reported.

Prilpressin (Captopril) tablets should be used in pediatric patients only if other measures for controlling blood pressure have not been effective.

ADVERSE REACTIONS

Reported incidences are based on clinical trials involving approximately 7,000 patients.

Renal: About one of 100 patients developed proteinuria.

Each of the following has been reported in approximately 1 to 2 of 1,000 patients and are of uncertain relationship to drug use: renal insufficiency, renal failure, nephrotic syndrome, polyuria, oliguria, and urinary frequency.

Hematologic: Neutropenia/agranulocytosis has occurred (see WARNINGS ). Cases of anemia, thrombocytopenia, and pancytopenia have been reported.

Dermatologic: Rash, often with pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 4 to 7 (depending on renal status and dose) of 100 patients, usually during the first four weeks of therapy. It is usually maculopapular, and rarely urticarial. The rash is usually mild and disappears within a few days of dosage reduction, short-term treatment with an antihistaminic agent, and/or discontinuing therapy; remission may occur even if Prilpressin (Captopril) is continued. Pruritus, without rash, occurs in about 2 of 100 patients. Between 7 and 10 percent of patients with skin rash have shown an eosinophilia and/or positive ANA titers. A reversible associated pemphigoid-like lesion, and photosensitivity, have also been reported.

Flushing or pallor has been reported in 2 to 5 of 1,000 patients.

Cardiovascular: Hypotension may occur; see WARNINGS and PRECAUTIONS [Drug Interactions] for discussion of hypotension with Prilpressin (Captopril) therapy.

Tachycardia, chest pain, and palpitations have each been observed in approximately 1 of 100 patients.

Angina pectoris, myocardial infarction, Raynaud’s syndrome, and congestive heart failure have each occurred in 2 to 3 of 1,000 patients.

Dysgeusia: Approximately 2 to 4 (depending on renal status and dose) of 100 patients developed a diminution or loss of taste perception. Taste impairment is reversible and usually self-limited (2 to 3 months) even with continued drug administration. Weight loss may be associated with the loss of taste.

Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in approximately one in 1,000 patients. Angioedema involving the upper airways has caused fatal airway obstruction (see WARNINGS: Head and Neck Angioedema , Intestinal Angioedema and PRECAUTIONS: Information for Patients ).

Cough: Cough has been reported in 0.5 to 2% of patients treated with Prilpressin (Captopril) in clinical trials (See PRECAUTIONS: General , Cough).

The following have been reported in about 0.5 to 2 percent of patients but did not appear at increased frequency compared to placebo or other treatments used in controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous ulcers, peptic ulcer, dizziness, headache, malaise, fatigue, insomnia, dry mouth, dyspnea, alopecia, paresthesias.

Other clinical adverse effects reported since the drug was marketed are listed below by body system. In this setting, an incidence or causal relationship cannot be accurately determined.

Body as a Whole: Anaphylactoid reactions (See WARNINGS: Anaphylactoid and Possible Related Reactions and PRECAUTIONS: Hemodialysis ).

General: Asthenia, gynecomastia.

Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope.

Dermatologic: Bullous pemphigus, erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis.

Gastrointestinal: Pancreatitis, glossitis, dyspepsia.

Hematologic: Anemia, including aplastic and hemolytic.

Hepatobi l i ary: Jaundice, hepatitis, including rare cases of necrosis, cholestasis.

Metabolic: Symptomatic hyponatremia.

Musculoskeletal: Myalgia, myasthenia.

Nervous/Psych i atric: Ataxia, confusion, depression, nervousness, somnolence.

Respiratory: Bronchospasm, eosinophilic pneumonitis, rhinitis.

Special Senses: Blurred vision.

Urogenital: Impotence.

As with other ACE inhibitors, a syndrome has been reported which may include: fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash or other dermatologic manifestations, eosinophilia and an elevated ESR.

Altered Laboratory Findings

Serum Electrolytes: Hyperkalemia: Small increases in serum potassium, especially in patients with renal impairment (see PRECAUTIONS ).

Hyponatremia: Particularly in patients receiving a low sodium diet or concomitant diuretics.

BUN/Serum Creatinine: Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine.

Hematologic: A positive ANA has been reported.

Liver Function Tests: Elevations of liver transaminases, alkaline phosphatase, and serum bilirubin have occurred.

To report SUSPECTED A DVERSE REACTIONS, contact West-W ard Pharmaceutical s Corp. at 1-877-233-2001, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

Correction of hypotension would be of primary concern. Volume expansion with an intravenous infusion of normal saline is the treatment of choice for restoration of blood pressure.

While Prilpressin (Captopril) may be removed from the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the circulation of neonates or children. Peritoneal dialysis is not effective for removing Prilpressin (Captopril); there is no information concerning exchange transfusion for removing Prilpressin (Captopril) from the general circulation.

DOSAGE AND ADMINISTRATION

Prilpressin (Captopril) tablets should be taken one hour before meals. Dosage must be individualized.

Hypertension : Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other clinical circumstances. If possible, discontinue the patient’s previous antihypertensive drug regimen for one week before starting Prilpressin (Captopril) tablets.

The initial dose of Prilpressin (Captopril) tablets is 25 mg b.i.d. or t.i.d. If satisfactory reduction of blood pressure has not been achieved after one or two weeks, the dose may be increased to 50 mg b.i.d. or t.i.d. Concomitant sodium restriction may be beneficial when Prilpressin (Captopril) tablets are used alone.

The dose of Prilpressin (Captopril) tablets in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily controlled after one to two weeks at this dose, (and the patient is not already receiving a diuretic), a modest dose of a thiazide-type diuretic (e.g., hydrochlorothiazide, 25 mg daily), should be added. The diuretic dose may be increased at one to two-week intervals until its highest usual antihypertensive dose is reached.

If Prilpressin (Captopril) tablets are being started in a patient already receiving a diuretic, Prilpressin (Captopril) tablets therapy should be initiated under close medical supervision (see WARNINGS and PRECAUTIONS: Drug Interactions regarding hypotension), with dosage and titration of Prilpressin (Captopril) tablets as noted above.

If further blood pressure reduction is required, the dose of Prilpressin (Captopril) tablets may be increased to 100 mg b.i.d. or t.i.d. and then, if necessary, to 150 mg b.i.d. or t.i.d. (while continuing the diuretic). The usual dose range is 25 to 150 mg b.i.d. or t.i.d. A maximum daily dose of 450 mg Prilpressin (Captopril) tablets should not be exceeded.

For patients with severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinuation of current antihypertensive therapy is not practical or desirable, or when prompt titration to more normotensive blood pressure levels is indicated, diuretic should be continued but other current antihypertensive medication stopped and Prilpressin (Captopril) tablets dosage promptly initiated at 25 mg b.i.d. or t.i.d., under close medical supervision.

When necessitated by the patient’s clinical condition, the daily dose of Prilpressin (Captopril) tablets may be increased every 24 hours or less under continuous medical supervision until a satisfactory blood pressure response is obtained or the maximum dose of Prilpressin (Captopril) tablets is reached. In this regimen, addition of a more potent diuretic, e.g., furosemide, may also be indicated.

Beta-blockers may also be used in conjunction with Prilpressin (Captopril) tablets therapy (see PRECAUTIONS: Drug Interactions ), but the effects of the two drugs are less than additive.

Heart Failure : Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. In patients with either normal or low blood pressure, who have been vigorously treated with diuretics and who may be hyponatremic and/or hypovolemic, a starting dose of 6.25 or 12.5 mg t.i.d. may minimize the magnitude or duration of the hypotensive effect (see WARNINGS: Hypotension ); for these patients, titration to the usual daily dosage can then occur within the next several days.

For most patients the usual initial daily dosage is 25 mg t.i.d. After a dose of 50 mg t.i.d. is reached, further increases in dosage should be delayed, where possible, for at least two weeks to determine if a satisfactory response occurs. Most patients studied have had a satisfactory clinical improvement at 50 or 100 mg t.i.d. A maximum daily dose of 450 mg of Prilpressin (Captopril) tablets should not be exceeded.

Prilpressin (Captopril) tablets should generally be used in conjunction with a diuretic and digitalis. Prilpressin (Captopril) tablets therapy must be initiated under very close medical supervision.

Left Ventricular Dysfunction After Myocardial Infarction: The recommended dose for long-term use in patients following a myocardial infarction is a target maintenance dose of 50 mg t.i.d.

Therapy may be initiated as early as three days following a myocardial infarction. After a single dose of 6.25 mg, Prilpressin (Captopril) tablets therapy should be initiated at 12.5 mg t.i.d. Prilpressin (Captopril) tablets should then be increased to 25 mg t.i.d. during the next several days and to a target dose of 50 mg t.i.d. over the next several weeks as tolerated (see CLINICAL PHARMACOLOGY ).

Prilpressin (Captopril) tablets may be used in patients treated with other post-myocardial infarction therapies, e.g., thrombolytics, aspirin, beta blockers.

Diabetic Nephropathy: The recommended dose of Prilpressin (Captopril) tablets for long term use to treat diabetic nephropathy is 25 mg t.i.d.

Other antihypertensives such as diuretics, beta blockers, centrally acting agents or vasodilators may be used in conjunction with Prilpressin (Captopril) tablets if additional therapy is required to further lower blood pressure.

Dosage Adjustment i n Renal Impairment : Because Prilpressin (Captopril) tablets are excreted primarily by the kidneys, excretion rates are reduced in patients with impaired renal function. These patients will take longer to reach steady-state Prilpressin (Captopril) levels and will reach higher steady-state levels for a given daily dose than patients with normal renal function. Therefore, these patients may respond to smaller or less frequent doses.

Accordingly, for patients with significant renal impairment, initial daily dosage of Prilpressin (Captopril) tablets should be reduced, and smaller increments utilized for titration, which should be quite slow (one- to two-week intervals). After the desired therapeutic effect has been achieved, the dose should be slowly back-titrated to determine the minimal effective dose. When concomitant diuretic therapy is required, a loop diuretic (e.g., furosemide), rather than a thiazide diuretic, is preferred in patients with severe renal impairment (see WARNINGS: Anaphylactoid Reactions During Membrane Exposure and PRECAUTIONS: Hemodialysis ).

HOW SUPPLIED

Prilpressin (Captopril) Tablets, USP are available as follows:

12.5 mg - White, Round Tablets; Debossed "W-7" on one side and Scored on the other side.

Bottles of 100 tablets.

Bottles of 1000 tablets.

25 mg - White, Round Tablets; Debossed "WW 172" on one side and Quadrisect Scored on the other side.

Bottles of 100 tablets.

Bottles of 1000 tablets.

50 mg - White, Oblong Tablets; Debossed "WW 173" on one side and Scored on the other side.

Bottles of 100 tablets.

Bottles of 1000 tablets.

100 mg - White, Oblong Tablets; Debossed "WW 174" on one side and Scored on the other side.

Bottles of 100 tablets.

All Prilpressin (Captopril) Tablets, USP are white and may exhibit a slight sulfurous odor.

Store at 20° to 25°C (68° to 77°F).

Keep bottles tightly closed (protect from moisture).

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

Manufactured by:

West-W ard Pharmaceutical s Corp.

Eatontown, NJ 07724

Revised March 2016