Adpace

Losartan Potassium:

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

INDICATIONS AND USAGE

Hypertension

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

Hypertensive Patients with Left Ventricular Hypertrophy

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

Nephropathy in Type 2 Diabetic Patients

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

CONTRAINDICATIONS

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

WARNINGS

Fetal/Neonatal Morbidity and Mortality

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

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

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

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

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

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

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

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

Hypotension - Volume-Depleted Patients

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

PRECAUTIONS

General

Hypersensitivity: Angioedema.

See ADVERSE REACTIONS , Post-Marketing Experience.

Impaired Hepatic Function

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

Impaired Renal Function

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

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

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

Electrolyte Imbalance

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

Information for Patients

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

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

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

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

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

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

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

Pregnancy

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

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

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

Race

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

ADVERSE REACTIONS

Hypertension

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Hypertensive Patients with Left Ventricular Hypertrophy

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

Nephropathy in Type 2 Diabetic Patients

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

Post-Marketing Experience

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

Digestive: Hepatitis (reported rarely).

General Disorders and Administration Site Conditions : Malaise.

Hemic: Thrombocytopenia (reported rarely).

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

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

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

Nervous system disorders: Dysgeusia

Respiratory: Dry cough.

Skin: Erythroderma

Laboratory Test Findings

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

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

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

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

OVERDOSAGE

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

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

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

DOSAGE AND ADMINISTRATION

Adult Hypertensive Patients

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

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

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

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

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

Pediatric Hypertensive Patients ≥ 6 years of age

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

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

Preparation of Suspension

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

Hypertensive Patients with Left Ventricular Hypertrophy

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

Nephropathy in Type 2 Diabetic Patients

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

HOW SUPPLIED

Adpace Tablets USP 25 mg

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

Bottles of 30 (NDC 60505-3160-3)

Bottles of 90 (NDC 60505-3160-9)

Bottles of 1000 (NDC 60505-3160-8)

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

Adpace (Losartan Potassium) Tablets USP 50 mg

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

Bottles of 30 (NDC 60505-3161-3)

Bottles of 90 (NDC 60505-3161-9)

Bottles of 1000 (NDC 60505-3161-8)

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

Adpace (Losartan Potassium) Tablets USP 100 mg

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

Bottles of 30 (NDC 60505-3162-3)

Bottles of 90 (NDC 60505-3162-9)

Bottles of 1000 (NDC 60505-3162-8)

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

Storage

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

** Trademark of Paddock Laboratories, Inc

APOTEX CORP.

Adpace (Losartan Potassium) TABLETS USP

25 mg, 50 mg and 100 mg

Revised: May 2012

PATIENT INFORMATION

Adpace Tablets USP

25 mg, 50 mg, 100 mg

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

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

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

What is Adpace Tablets?

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

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

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

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

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

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

Who should not take Adpace Tablets?

• 
  

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

What should I tell my doctor before taking Adpace Tablets?

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

• 
  

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

• 
  

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

• 
  

  are vomiting a lot or having a lot of diarrhea
  

• 
  

  have liver problems
  

• 
  

  have kidney problems
  

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

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

• 
  

  potassium supplements
  

• 
  

  salt substitutes containing potassium
  

• 
  

  water pills (diuretics)
  

• 
  

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

• other medicines to reduce blood pressure.

How should I take Adpace (Losartan Potassium) Tablets?

• 
  

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

• Adpace (Losartan Potassium) Tablets
  

  can be taken with or without food.
  

• 
  

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

• 
  

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

What are the possible side effects of Adpace Tablets?

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

• 
  

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

• 
  

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

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

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

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

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

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

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

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

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

How do I store Adpace Tablets?

• 
  

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

• 
  

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

• 
  

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

General information about Adpace Tablets

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

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

What are the ingredients in Adpace Tablets?

Active ingredients: Adpace (Losartan Potassium)

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

Rx only

APOTEX CORP.

Adpace (Losartan Potassium) TABLETS USP

25 mg, 50 mg and 100 mg

Revised: May 2012

Adpace (Losartan Potassium) 25mg Tablet

Perindopril:

• Warning: fetal toxicity
• 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
• Adpace (Perindopril) reviews

WARNING: FETAL TOXICITY

• When pregnancy is detected, discontinue Adpace (Perindopril) as soon as possible .
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus .

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

• When pregnancy is detected, discontinue Adpace (Perindopril) as soon as possible. (5.1)
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

1 INDICATIONS AND USAGE

Adpace (Perindopril) contains Adpace (Perindopril) arginine, an angiotensin converting enzyme inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, and is indicated for the treatment of hypertension, to lower blood pressure.

Adpace (Perindopril) may be used in patients whose blood pressure is not adequately controlled on monotherapy.

Adpace (Perindopril) may be used as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine and the ACE inhibitor class to which Adpace (Perindopril) principally belongs. There are no controlled trials demonstrating risk reduction with Adpace (Perindopril).

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

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

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

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. In a clinical trial of Adpace (Perindopril), treatment with Adpace (Perindopril) 14/10 mg did not provide additional antihypertensive effect beyond that achieved with use of amlodipine 10 mg in black and diabetic patients .

The choice of Adpace (Perindopril) as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of Adpace (Perindopril).

Patients with moderate-to-severe hypertension are at a relatively high risk of cardiovascular events (e.g., stroke, heart attack, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, target goal and the incremental likelihood of achieving the goal with a combination product, such as Adpace (Perindopril), versus a monotherapy product when deciding upon initial therapy. Individual blood pressure goals may vary based on the patient's risk.

Data from an 6-week, active-controlled trial provide estimates of the probability of reaching a target blood pressure with Adpace (Perindopril) compared with Adpace (Perindopril) erbumine or amlodipine monotherapy .

Figures 1.a-1.d provide estimates of the likelihood of achieving target clinic systolic and diastolic blood pressure control with Adpace (Perindopril) 14/10 mg tablets after 6 weeks, based on baseline systolic and diastolic blood pressure. The curve for each treatment group was estimated by logistic regression modeling and is less well defined in the tails.

Figure 1.a Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 6

Figure 1.b Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 6

Figure 1.c Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 6

Figure 1.d Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 6

For example, a patient with a baseline blood pressure of 170/105 mmHg has approximately a 26% likelihood of achieving a goal of <140 mmHg (systolic) and 31% likelihood of achieving <90 mmHg (diastolic) on Adpace (Perindopril) erbumine 16 mg. The likelihood of achieving these same goals on amlodipine 10 mg is approximately 40% (systolic) and 46% (diastolic). These likelihoods rise to 50% (systolic) and 65% (diastolic) with Adpace (Perindopril) 14/10 mg.

Adpace (Perindopril) is a combination of Adpace (Perindopril), an angiotensin converting enzyme inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, indicated for the treatment of hypertension to lower blood pressure:

• In patients not adequately controlled with monotherapy (1).
• As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals (1).

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1).

Figure 1a Figure 1b Figure 1c Figure 1d

2 DOSAGE AND ADMINISTRATION

• Initiate treatment at 3.5/2.5 mg, once daily. Adjust dose according to blood pressure goals waiting 1 to 2 weeks between titration steps.

2.1 General Considerations

The recommended starting dose of Adpace (Perindopril) is 3.5/2.5 mg once daily.

Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. The maximum recommended dose is 14/10 mg once daily .

Adpace (Perindopril) may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.

Consider use in patients unable to achieve adequate antihypertensive effect with amlodipine monotherapy because of dose-limiting peripheral edema caused by amlodipine .

Administered as monotherapy, Adpace (Perindopril) erbumine is an effective treatment for hypertension in once-daily doses ranging from 4 mg to 16 mg daily. Amlodipine is effective in once-daily doses of 5 mg and 10 mg. Adverse reactions related to Adpace (Perindopril) are generally uncommon and independent of dose, while those related to amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter .

2.2 Dosage Adjustment in Renal Impairment

Adpace is not recommended in patients with creatinine clearances <30 mL/min. For patients with creatinine clearance between 30 and 80 mL/min (mild or moderate renal impairment), do not exceed 7/5 mg .

2.3 Monitoring in Elderly Patients (Over 65 Years of Age)

Monitor blood pressure for up to two weeks following titrations at dosages above 7/5 mg in patients over 65 years of age .

3 DOSAGE FORMS AND STRENGTHS

Adpace (Perindopril) is available as fixed dose combination tablets of Adpace (Perindopril) arginine and amlodipine:

• 3.5/2.5 mg tablets: white, uncoated tablets debossed with 3.5 on one side and 2.5 on the other side.
• 7/5 mg tablets: white, uncoated tablets debossed with 7/5 on one side and blank on the other side.
• 14/10 mg tablets: white, uncoated tablets debossed with 14/10 on one side and blank on the other side.

• Tablets (perindopril arginine/amlodipine): 3.5/2.5 mg, 7/5 mg and 14/10 mg (3).

4 CONTRAINDICATIONS

Adpace (Perindopril) tablets are contraindicated in patients with hereditary or idiopathic angioedema, with or without previous ACE inhibitor treatment, and in patients who are hypersensitive to Adpace (Perindopril), to any other ACE inhibitor, or to amlodipine.

Do not co-administer aliskiren with ACE inhibitors, including Adpace (Perindopril), in patients with diabetes.

Adpace (Perindopril) is contraindicated in combination with neprilysin inhibitor (e.g., sacubitril). Do not administer Adpace (Perindopril) within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor .

• History of angioedema, or hypersensitivity to any ACE-inhibitor or to amlodipine (4).
• Do not use aliskiren with Adpace (Perindopril) in patients with diabetes (4).
• Do not take a neprilysin inhibitor with Adpace (Perindopril) (4).
• Do not administer Adpace (Perindopril) within 36 hours of switching to or from sacubitril/valsartan (4).

5 WARNINGS AND PRECAUTIONS

• Anaphylactoid reactions, including angioedema (5.2).
• Myocardial infarction: Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Adpace (Perindopril), particularly in patients with severe obstructive coronary artery disease (5.3).
• Assess for hypotension and hyperkalemia (5.4, 5.5).
• Monitor renal function during therapy (5.7).

5.1 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 Adpace (Perindopril) as soon as possible .

5.2 Anaphylactoid and Possibly Related Reactions

Angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin. Patients taking ACE inhibitors ) may, therefore, be subject to a variety of bradykinin- or prostaglandin-mediated adverse reactions, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared with non-blacks.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors (0.1% of patients treated with Adpace (Perindopril) in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue Adpace (Perindopril) treatment immediately and observe until the swelling disappears. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), promptly.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy or a neprilysin inhibitor 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 (with or without nausea or vomiting), and the angioedema was diagnosed by imaging studies such as abdominal CT or ultrasound, or at surgery. In some cases there was no prior history of facial angioedema, and C-1 esterase levels were normal. 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.

5.3 Increased Angina and/or Myocardial Infarction

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

5.4 Hypotension

Adpace can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume- or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

In patients at risk of excessive hypotension, start Adpace (Perindopril) therapy under close medical supervision. Follow patients closely for the first 2 weeks of treatment and whenever the dose of Adpace (Perindopril) is increased or a diuretic is added or its dose increased.

If excessive hypotension occurs, immediately place patient in a supine position and, if necessary, treat patient with an intravenous infusion of physiological saline. Adpace (Perindopril) treatment can usually be continued following restoration of volume and blood pressure.

Patients with severe aortic stenosis may be more likely to experience symptomatic hypotension. Because of the gradual onset of action, acute hypotension is unlikely.

Surgery/Anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Adpace (Perindopril) may 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.

5.5 Hyperkalemia

Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including Adpace (Perindopril). Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes .

Monitor serum potassium periodically in patients receiving Adpace (Perindopril).

5.6 Cough

Presumably because of 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.

5.7 Impaired Renal Function

Monitor renal function periodically in patients receiving Adpace. Drugs that affect the renin-angiotensin system can cause reductions in renal function, including acute renal failure. 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 non-steroidal anti-inflammatory agents (NSAIDS) or angiotensin receptor blockers-may be at particular risk of developing acute renal failure on Adpace (Perindopril). Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Adpace (Perindopril).

5.8 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.

6 ADVERSE REACTIONS

The most common adverse reactions were edema, cough (3.2%), headache (2.5%), and dizziness (2.5%) (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact SYMPLMED LLC at 1-866-561-3088 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.

In an active-controlled 6-week trial, the safety of the maximum dose of Adpace (Perindopril) (14/10 mg) was evaluated in 279 patients with hypertension and compared with Adpace (Perindopril) erbumine 16 mg and amlodipine 10 mg. Adverse reactions were generally mild and transient in nature.

Discontinuations because of adverse events occurred in 3.6% of patients treated with Adpace (Perindopril) 14/10 mg compared to 4.3% of patients treated with Adpace (Perindopril) erbumine 16 mg and 4.6% of patients treated with amlodipine 10 mg. The most common reason for discontinuation of therapy with Adpace (Perindopril) was peripheral edema (1.8%).

Common adverse events that occurred in at least 2% of patients treated with Adpace (Perindopril) in the 6-week trial are presented in Table 1.

The overall frequency of adverse reactions was similar between men and women, and black and non-black patients. In black patients, the incidence of peripheral edema was similar in the Adpace (Perindopril) 14/10 mg and amlodipine 10 mg arms (3%).

Other adverse reactions in the controlled clinical trial with some plausible relationship to Adpace (Perindopril) are listed below.

Dermatologic: Rash

Digestive: Nausea, diarrhea

The safety of the lowest dose of Adpace (Perindopril) (3.5/2.5 mg) was evaluated in 249 patients with hypertension and compared with placebo and Adpace (Perindopril) and amlodipine administered as monotherapies in an 8-week trial. The only emergent adverse event observed in at least 2% of patients treated with Adpace (Perindopril) was hyperkalemia (2.4%). Peripheral edema was reported in 1.6% of patients receiving Adpace (Perindopril) 3.5/2.5 mg.

Monotherapy with Adpace (Perindopril) or amlodipine has been evaluated for safety in clinical trials in over 3,000 and 11,000 patients, respectively, as summarized below.

Adpace (Perindopril)

Adpace (Perindopril) erbumine has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented here are based on results from the 1,417 perindopril-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with Adpace (Perindopril) for at least one year.

In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with Adpace (Perindopril) erbumine and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia, and dizziness.

Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with Adpace (Perindopril) erbumine and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on Adpace (Perindopril) erbumine was at least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).

Dizziness was not reported more frequently in the Adpace (Perindopril) group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with Adpace (Perindopril).

Amlodipine

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In controlled clinical trials comparing amlodipine (N=1730) in doses up to 10 mg with placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in about 1.5% of amlodipine-treated patients and about 1% of placebo-treated patients. The most common side effects were edema, dizziness, flushing, and palpitations.

The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,¹ back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,¹ myalgia.

Psychiatric: sexual dysfunction (male¹ and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System: dyspnea,¹ epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus,¹ rash,¹ rash erythematous, rash maculopapular.

Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary System: micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System: dry mouth, sweating increased.

Metabolic and Nutritional: hyperglycemia, thirst.

Hematopoietic: leukopenia, purpura, thrombocytopenia.

¹ These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

Clinical Laboratory Findings

Adpace (Perindopril)

Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with Adpace (Perindopril), but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials.

Liver Function Tests: Elevations in alanine transaminase (ALT; 1.6% Adpace (Perindopril) erbumine vs. 0.9% placebo) and aspartate transaminase (AST; 0.5% Adpace (Perindopril) erbumine vs. 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of the individual components of Adpace (Perindopril). 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.

Adpace (Perindopril): Voluntary reports of adverse events in patients taking Adpace (Perindopril) that have been received since market introduction and are of unknown causal relationship to Adpace (Perindopril) include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis, and a syndrome that may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive antinuclear antibody (ANA), leukocytosis, eosinophilia, or an elevated erythrocyte sedimentation rate (ESR).

Amlodipine: The following postmarketing event has been reported infrequently where a causal relationship is uncertain: palpitations, gynecomastia, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), some requiring hospitalization.

7 DRUG INTERACTIONS

• Potassium supplements and potassium-sparing diuretics: risk of hyperkalemia (7).
• Lithium: increased serum lithium levels; toxicity symptoms (7).
• Injectable gold: flushing, nausea, vomiting, or hypotension (7).
• Dual inhibition of the renin-angiotensin system: increased risk of renal impairment, hypotension, and hyperkalemia (7).
• Do not exceed doses greater than 20 mg daily of simvastatin (7).
• NSAIDs: risk of renal impairment and loss of antihypertensive effect (7).
• Diuretics: increased risk of hypotension, consider dose reduction (7).
• CYP3A inhibitors: risk of hypotension and edema (7).
• Neprilysin Inhibitor: risk of angioedema (7).

Adpace (Perindopril)

The pharmacokinetics of Adpace (Perindopril) and amlodipine are not altered when the drugs are co-administered.

No drug interaction studies have been conducted with Adpace (Perindopril), although studies have been conducted with Adpace (Perindopril) and amlodipine.

mTOR Inhibitors: Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.

Neprilysin Inhibitor: Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema.

Adpace (Perindopril)

Diuretics:Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Adpace (Perindopril). Provide close medical supervision with the first dose of Adpace (Perindopril), for at least two hours and until blood pressure has stabilized for another hour. Adpace (Perindopril) can attenuate potassium loss caused by thiazide diuretics.

Potassium Supplements and Potassium-Sparing Diuretics:Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements, or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) 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 co-administering Adpace (Perindopril) and lithium, frequent monitoring of serum lithium levels is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

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 (NSAIDS) 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 Adpace (Perindopril), may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Adpace (Perindopril) and NSAID therapy.

The antihypertensive effects of ACE inhibitors, including Adpace (Perindopril), may be attenuated by NSAIDS, including selective COX-2 inhibitors.

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. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Adpace (Perindopril) and other agents that affect the RAS.

Do not co-administer aliskiren with Adpace (Perindopril) in patients with diabetes. Avoid use of aliskiren with Adpace (Perindopril) in patients with renal impairment (GFR <60 mL/min).

Amlodipine

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin administered alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Cyclosporine: A prospective study in renal transplant patients showed an average 40% increase in trough cyclosporin levels during concomitant treatment with amlodipine. Frequent monitoring of trough blood levels of cyclosporine is recommended.

CYP3A Inhibitors: Co-administration of the moderate CYP3A inhibitor diltiazem increases the exposure to amlodipine by 60%. Co-administered erythromycin, also a moderate CYP3A inhibitor, does not impact the exposure to amlodipine. Strong CYP3A inhibitors (e.g., itraconazole) may increase the plasma concentrations of the CYP3A substrate amlodipine to a greater extent. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with moderate or strong CYP3A inhibitors to determine the need for dose adjustment.

CYP3A Inducers: No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be monitored when amlodipine is co-administered with CYP3A inducers.

8 USE IN SPECIFIC POPULATIONS

• Nursing Mothers: Discontinue nursing or Adpace (8.3)
• Geriatrics: Monitor blood pressure for up to two weeks following titrations at doses above 7/5 mg in patients >65 years old.( 8.5).
• Renal Impairment: Not recommended in patients with creatinine clearances <30 mL/min. For patients with mild or moderate impairment, do not exceed 7/5 mg (2.3, 5.7, 8.6).

8.1 Pregnancy

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 Adpace (Perindopril) 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 therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultra-sound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Adpace (Perindopril), 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 Adpace (Perindopril) for hypotension, oliguria, and hyperkalemia .

Radioactivity was detectable in fetuses after administration of ¹⁴C-perindopril to pregnant rats.

8.3 Nursing Mothers

It is not known whether Adpace or amlodipine is excreted in human milk, but radioactivity was detected in the milk of lactating rats following administration of ¹⁴C-perindopril. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue Adpace (Perindopril).

8.4 Pediatric Use

Neonates with a history of in utero exposure to Adpace (Perindopril):

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.

The safety and effectiveness of Adpace (Perindopril) in pediatric patients have not been established.

8.5 Geriatric Use

The mean blood pressure effect of Adpace was somewhat smaller in patients over 60 years of age than in younger patients, although the difference was not significant. Plasma concentrations of both Adpace (Perindopril) and perindoprilat in elderly patients (>65 years) are approximately twice those observed in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and rash.

Amlodipine is extensively metabolized in the liver. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life, and AUC.

Experience with Adpace (Perindopril) is limited in the elderly at doses exceeding 7/5 mg. If doses above 7/5 mg are required, monitor blood pressure up to two weeks following up titration .

8.6 Renal Impairment

Pharmacokinetic data indicate that perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when creatinine clearance drops below 30 mL/min. Adpace (Perindopril) is not recommended in patients with creatinine clearances <30 mL/min. For patients with creatinine clearance between 30 and 80 mL/min (mild or moderate renal impairment), do not exceed 7/5 mg .

10 OVERDOSAGE

Adpace (Perindopril)

In animals, doses of Adpace (Perindopril) up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal. Past experiences were scant but suggested that overdosage with other ACE inhibitors was also fairly well tolerated by humans. The most likely manifestation is hypotension, and treatment should be symptomatic and supportive. Therapy with the ACE inhibitor should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.

Among the reported cases of Adpace (Perindopril) overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of Adpace (Perindopril). The intervention for Adpace (Perindopril) overdose may require vigorous support.

Laboratory determinations of serum levels of Adpace (Perindopril) and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Adpace (Perindopril) overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Adpace (Perindopril) and its metabolites.

Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of Adpace (Perindopril) overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Adpace (Perindopril) is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Adpace (Perindopril) overdose by infusion of normal saline solution.

Amlodipine

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m² basis) caused a marked peripheral vasodilation and hypotension.

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

11 DESCRIPTION

Adpace (Perindopril) is a combination of Adpace (Perindopril) arginine and amlodipine besylate.

Adpace (Perindopril) arginine is the L-arginine salt of Adpace (Perindopril), the ethyl ester of a non-sulfhydryl angiotensin converting enzyme inhibitor. Adpace (Perindopril) arginine is chemically described as L-arginine (2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl] octahydro-1H-indole-2-carboxylate. Its empirical formula is C₁₉H₃₂N₂O₅-C₆H₁₄N₄O₂ and its structural formula is:

Adpace (Perindopril) arginine is a white, crystalline powder with a molecular weight 542.7. The free acid has the molecular weight of 368.5. It is readily soluble in purified water, slightly soluble in 95% ethanol, and practically insoluble in chloroform.

Adpace (Perindopril) is the free-acid form of Adpace (Perindopril) arginine. Adpace (Perindopril) is a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.

Amlodipine besylate is the benzene sulphonic acid salt of amlodipine, a long-acting dihydropyridine calcium channel blocker. Amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate monobenzenesulphonate. Its empirical formula is C₂₀H₂₅ClN₂O₅-C₆H₆O₃S and its structural formula is:

Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. The content of the tablets is expressed as amlodipine (free base) which has a molecular weight of 409.1.

Adpace (Perindopril) tablets are formulated in three different strengths for oral administration. Tablets contain Adpace (Perindopril) arginine 3.5 mg, 7 mg, or 14 mg and amlodipine 2.5 mg, 5 mg, or 10 mg for the following available Adpace (Perindopril) arginine/amlodipine combinations: 3.5/2.5 mg, 7/5 mg, and 14/10 mg.

Inactive ingredients are lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

Structural Formula Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Adpace

Adpace (Perindopril), a pro-drug, is hydrolyzed to perindoprilat, which inhibits ACE in humans and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with an increase in serum potassium .

ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Adpace (Perindopril) remains to be elucidated.

While the principal mechanism of Adpace (Perindopril) in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Adpace (Perindopril) has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to Adpace (Perindopril) was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses.

Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pK_a=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.

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

12.2 Pharmacodynamics

Adpace (Perindopril)

After administration of Adpace (Perindopril), ACE is inhibited in a dose and blood concentration-related fashion. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID₅₀ increases). The pressor response to an angiotensin I infusion is reduced by Adpace (Perindopril), but this is not as persistent as the effect on ACE.

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral 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 amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than did patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).

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

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with β-blockers to humans. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

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

12.3 Pharmacokinetics

Adpace (Perindopril)

Following administration of Adpace (Perindopril), peak plasma concentration of Adpace (Perindopril), perindoprilat and amlodipine occur at approximately 1 hour, 4 hours and 6-12 hours, respectively. The mean half-life of Adpace (Perindopril) is approximately 1.3 hours. The decline in the plasma concentration of perindoprilat is multiphasic and shows a terminal elimination half-life of approximately 100 hours, resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours.

When Adpace (Perindopril) is administered with food, the exposure to Adpace (Perindopril), perindoprilat and amlodipine is not impacted.

Adpace (Perindopril)

Following administration of Adpace (Perindopril), Adpace (Perindopril) is rapidly absorbed, with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of Adpace (Perindopril) is approximately 75%. Following absorption, approximately 30% to 50% of systemically available Adpace (Perindopril) is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of approximately 25%. Peak plasma concentrations of perindoprilat are attained approximately 4 hours after Adpace (Perindopril) administration. Food had no effect on the extent of absorption of Adpace (Perindopril) or perindoprilat, but slightly reduced the rate of absorption of Adpace (Perindopril) and perindoprilat by 18% and 14%, respectively.

The C_max and AUC of Adpace (Perindopril) and perindoprilat increase in a linear and dose proportional manner following both single oral dosing and at steady state during an once-a-day multiple dosing regimen. Adpace (Perindopril) exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of Adpace (Perindopril) associated with most of its elimination is approximately 0.8 to 1 hours.

Adpace (Perindopril) is extensively metabolized following oral administration, with only 4% to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation, and cyclization via dehydration have been identified. These include the active ACE inhibitor perindoprilat (hydrolyzed Adpace (Perindopril)), Adpace (Perindopril), and perindoprilat glucuronides, dehydrated Adpace (Perindopril), and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of Adpace (Perindopril).

The active metabolite, perindoprilat, also exhibits multiexponential pharmacokinetics following the oral administration of Adpace (Perindopril). Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows a prolonged terminal elimination half-life of 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once-daily dosing with Adpace (Perindopril), perindoprilat accumulates about 1.5- to 2-fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.

Approximately 60% of circulating Adpace (Perindopril) is bound to plasma proteins, and only 10% to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.

Amlodipine

Absolute bioavailability of amlodipine has been estimated between 64% and 90%. Ex vivo studies indicate that approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. 10% of unchanged drug and 60% of amlodipine metabolites are excreted in urine.

Drug Interactions:

Adpace (Perindopril): Co-administered Adpace (Perindopril) does not impact the exposure to amlodipine or digoxin.

Amlodipine: Co-administered cimetidine, magnesium- and aluminum hydroxide antacids, sildenalfil, and grapefruit juice have no impact on the exposure to amlodipine. Co-administered amlodipine does not affect the exposure to Adpace (Perindopril), perindoprilat, atorvastatin, ethanol and the warfarin prothrombin response time.

Specific Populations

Elderly:

Adpace (Perindopril): Plasma concentrations of both Adpace (Perindopril) and perindoprilat in elderly patients (>65 years) are approximately twice those observed in younger patients, reflecting both increased conversion of Adpace (Perindopril) to perindoprilat and decreased renal excretion of perindoprilat .

Amlodipine: Clearance of amlodipine is decreased in elderly patients, resulting in an increased area under the plasma concentration curve (AUC) of approximately 40% to 60% .

Renal Impairment:

Adpace (Perindopril): Perindoprilat elimination is decreased in renally impaired patients. At creatinine clearances of 30 mL/min to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly .

During dialysis, Adpace (Perindopril) is removed with the same clearance as in patients with normal renal function. In a limited number of patients studied, Adpace (Perindopril) clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min .

Amlodipine: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment .

Hepatic Impairment:

Adpace (Perindopril): The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function .

Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%.

Heart Failure:

Adpace (Perindopril): Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.

Amlodipine: Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of Adpace and amlodipine. However, these studies have been conducted for Adpace (Perindopril) and amlodipine alone.

Adpace (Perindopril)

Carcinogenicity: No evidence of carcinogenicity was observed in studies in rats and mice when Adpace (Perindopril) was administered at dosages up to 5 times (mg/m²) the maximum recommended human dose (MRHD) of 14 mg/day for 104 weeks.

Mutagenesis: No genotoxic potential was detected for Adpace (Perindopril), perindoprilat, and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, thymidine kinase ± mouse lymphoma assay, mouse and rat micronucleus tests, the in vivo micronucleus and chromosomal aberration tests, and Chinese hamster bone marrow assay.

Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in rats given up to 7 times (mg/m²) the MRHD during the period of spermatogenesis in males or oogenesis and gestation in females.

Amlodipine

Carcinogenicity: Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily amlodipine dosage levels of 0.5, 1.25, and 2.5 mg/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 amlodipine MRHD of 10 mg/day. For the rat, the highest dose was, on a body surface area basis, approximately 2.5 times the MRHD, assuming a patient weight of 60 kg.

Mutagenesis: Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

Impairment of Fertility: There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at amlodipine doses of up to 10 mg/kg/day, about 10 times the MRHD of 10 mg/day on a body surface area basis.

13.3 Reproductive Toxicity

Reproductive toxicity studies have not been conducted with this combination. However, these studies have been conducted for amlodipine alone.

Amlodipine

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at amlodipine doses of up to 10 mg/kg/day (respectively, about 8 and 23 times the maximum recommended human dose of 10 mg on a mg/m² basis, assuming a patient weight of 50 kg) during their periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at an amlodipine dose equivalent to 10 mg/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

14 CLINICAL STUDIES

The antihypertensive effects of Adpace (Perindopril) have been demonstrated in two randomized controlled trials.

The highest strength of Adpace (Perindopril) (14/10 mg) was studied in a double-blind, active controlled study in hypertensive patients. A total of 837 patients with seated diastolic pressure 95 to 115 mmHg (mean baseline systolic/diastolic blood pressure was 158/101 mmHg) received treatments of Adpace (Perindopril) 14/10 mg, Adpace (Perindopril) erbumine 16 mg, or amlodipine 10 mg once daily for 6 weeks. The mean age of the population was 51 years, 51% of patients were male, and 34% were black. Overall, 20% of the population had type 2 diabetes.

At Week 6, Adpace (Perindopril) 14/10 mg produced statistically significantly greater reductions in blood pressure than each of the monotherapies. The reductions in systolic/diastolic blood pressure with Adpace (Perindopril) 14/10 mg were 10.1/6.3 mmHg greater than with Adpace (Perindopril) erbumine 16 mg and 3.9/2.5 mmHg greater than with amlodipine 10 mg. In black patients and in diabetic patients, treatment with Adpace (Perindopril) 14/10 mg did not provide additional antihypertensive effect beyond that achieved with use of amlodipine 10 mg.

The lowest strength of Adpace (Perindopril) arginine/amlodipine (3.5/2.5 mg) was studied in 246 hypertensive patients. A total of 1581 patients with supine diastolic pressure 95-110 mmHg (mean baseline systolic/diastolic blood pressure was 161/101 mmHg) received treatment with Adpace (Perindopril) arginine/amlodipine 3.5/2.5 mg, Adpace (Perindopril) arginine 3.5 mg, Adpace (Perindopril) arginine 5 mg, amlodipine 2.5 mg, amlodipine 5 mg, or placebo. The mean age of the population was 52 years, 47% were male, and 1% were black. No included patients had a history of diabetes.

At Week 8, Adpace (Perindopril) 3.5/2.5 mg produced statistically significantly greater reductions in blood pressure than Adpace (Perindopril) arginine 3.5 mg and amlodipine 2.5 mg. The reduction in systolic/diastolic blood pressure with Adpace (Perindopril) arginine/amlodipine 3.5/2.5 mg was 7.2/4.1 mmHg greater than with placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Adpace (Perindopril) is available as white, uncoated tablets containing Adpace (Perindopril) arginine 3.5 mg, 7 mg, or 14 mg and amlodipine 2.5 mg, 5 mg, or 10 mg for the following three combinations of Adpace (Perindopril) arginine/amlodipine: 3.5/2.5 mg, 7/5 mg, and 14/10 mg. All three strengths are packaged in bottles of 90 tablets. Each tablet is debossed with the tablet strength.

Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. Dispense in tight container (USP).

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Tell female patients of childbearing age that use of drugs like Adpace (Perindopril) that act on the renin-angiotensin system can cause serious problems in the fetus and infant, including low blood pressure, poor development of skull bones, kidney failure, and death. Discuss other treatment options with female patients planning to become pregnant. Tell women using Adpace (Perindopril) who become pregnant to notify their physician as soon as possible.

In case of a missed dose, have patients resume the usual dose at the next scheduled time.

Patient Information

Adpace (Perindopril) ^® (pres-ta-li-a)

(perindopril arginine and amlodipine)

tablets

Read this Patient Information before you start taking Adpace (Perindopril) and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information I should know about Adpace (Perindopril)?

• Adpace (Perindopril) can cause harm or death to your unborn baby.
• Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.
• If you become pregnant while taking Adpace (Perindopril), tell your doctor right away. Your doctor may switch you to a different medicine to treat your high blood pressure.

What is Adpace (Perindopril)?

Adpace (Perindopril) is a prescription medicine that contains Adpace (Perindopril) arginine, an angiotensin converting enzyme inhibitor (ACE inhibitor), and amlodipine, a calcium channel blocker.

Adpace (Perindopril) is used to treat high blood pressure (hypertension):

• when one medicine to lower your high blood pressure is not enough
• as the first medicine to lower your high blood pressure if your doctor decides you are likely to need more than one medicine

It is not known if Adpace (Perindopril) is safe and effective in children.

Who should not take Adpace (Perindopril)?

Do not take Adpace (Perindopril) if you:

• have a history of angioedema. Symptoms of angioedema may include swelling of your face, tongue or throat, trouble breathing, itching, hives or skin rash, and stomach (abdominal) pain.
• are allergic to Adpace (Perindopril), or any other ACE inhibitor medicine
• are allergic to amlodipine
• have diabetes and take a medicine that contains aliskiren

What should I tell my doctor before taking Adpace (Perindopril)?

Before you take Adpace (Perindopril), tell your doctor about all of your medical conditions, including if you:

• have heart, liver or kidney problems
• have diabetes
• have been told that you have abnormal potassium levels in your blood
• are vomiting or have diarrhea
• plan to have a surgical procedure
• are pregnant or plan to become pregnant. See “What is the most important information I should know about Adpace (Perindopril)?”
• are breastfeeding or plan to breastfeed. It is not known if Adpace (Perindopril) passes into your breast milk. You and your doctor should decide if you will take Adpace (Perindopril) or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking Adpace (Perindopril) with other medicines can cause serious side effects.

Especially tell your doctor if you take:

• medicines for high blood pressure or heart problems
• water pills
• salt substitute
• potassium-containing medicines, potassium supplements, or salt substitutes containing potassium

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Adpace (Perindopril)?

• Take Adpace (Perindopril) exactly as your doctor tells you.
• Take Adpace (Perindopril) 1 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.
• If you take too much Adpace (Perindopril), call your doctor or go to the nearest emergency room right away.

What are the possible side effects of Adpace (Perindopril)?

Adpace (Perindopril) can cause serious side effects, including:

See “What is the most important information I should know about Adpace (Perindopril)?”

• Serious allergic reactions that can be life threatening. Stop taking Adpace (Perindopril) and get emergency medical help right away if you get any of these symptoms of a serious allergic reaction:
  • swelling of your face, lips, tongue, throat, arms, hands, legs, or feet
  • trouble swallowing
  • trouble breathing
  • stomach (abdomen) pain with or without nausea or vomiting
  
  

  People who are black and take Adpace (Perindopril) have a greater risk of having a serious allergic reaction than people who are not black and take Adpace (Perindopril).

• Worsening of chest pain (angina) or a heart attack (myocardial infarction) can happen after you start taking or increase your dose of Adpace (Perindopril). Get emergency help if you get worse chest pain or chest pain that does not go away.
• Low blood pressure (hypotension) is most likely to happen if you also:
  • take water pills (diuretics)
  • are on a low salt diet
  • are on kidney dialysis
  • have heart problems
  • have vomiting or diarrhea
  
  

  If you feel faint or dizzy, lie down and call your doctor right away.

• Increased amount of potassium in the blood. Your doctor will check your potassium blood level during your treatment with Adpace (Perindopril).
• Cough.
• Kidney problems. Some people with certain conditions may develop kidney problems and may need to stop treatment with Adpace (Perindopril). Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain.

The most common side effects of Adpace (Perindopril) include:

• swelling of the feet, ankles, and hands
• cough
• headache
• dizziness

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Adpace (Perindopril). For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Adpace (Perindopril)?

• Store Adpace (Perindopril) at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep Adpace (Perindopril) in a tightly closed container and in a dry place.

Keep Adpace (Perindopril) and all medicines out of the reach of children.

General information about Adpace (Perindopril)

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Adpace (Perindopril) for a condition for which it was not prescribed. Do not give Adpace (Perindopril) to other people, even if they have the same symptoms that you have. It may harm them.

For more information, go to www.symplmed.com or call 1-888-552-9769.

What is high blood pressure (hypertension)?

Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too great.

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

What are the ingredients in Adpace (Perindopril)?

Active ingredients: Adpace (Perindopril) arginine and amlodipine besylate

Inactive ingredients: lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate

This Patient Information has been approved by the U.S. Food and Drug Administration.

Marketed by:

SYMPLMED PHARMACEUTICALS, LLC

Cincinnati OH 45227

symplmed pharmaceuticals ^®

THE PRESCRIPTION FOR BETTER CARE

Issued: Month Year

Adpace (Perindopril)^® is a registered trademark of Biofarma used by Symplmed Pharmaceutics, LLC under license from Biofarma. SYMPLMED and the SYMPLMED logo are trademarks of Symplmed Pharmaceutics, LLC. ACEON^® is a registered trademark of Biofarma used by Symplmed Pharmaceutics, LLC under license from Biofarma and NORVASC^® is a trademark of Pfizer.

PRINCIPAL DISPLAY PANEL – 3.5 mg/2.5 mg, 90 Tablet Bottle Label

90 Tablets

NDC 61894-010-02

Adpace (Perindopril) ^®

(perindopril arginine and

amlodipine) Tablets

3.5 mg/2.5 mg

Rx ONLY

Keep out of reach of children

symplmed^TM

PRINCIPAL DISPLAY PANEL – 7 mg/5 mg, 90 Tablet Bottle Label

90 Tablets

NDC 61894-011-02

Adpace (Perindopril) ^®

(perindopril arginine and

amlodipine) Tablets

7 mg/5 mg

Rx ONLY

Keep out of reach of children

symplmed^TM

PRINCIPAL DISPLAY PANEL – 14 mg/10 mg, 90 Tablet Bottle Label

90 Tablets

NDC 61894-012-02

Adpace (Perindopril) ^®

(perindopril arginine and

amlodipine) Tablets

14 mg/10 mg

Rx ONLY

Keep out of reach of children

symplmed^TM