Perigard DF

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Perigard DF uses

Perigard DF consists of Indapamide, Perindopril.

Indapamide:



40-9191

Revised - November 2015

Rx Only

DESCRIPTION

Perigard DF (Indapamide) is an oral antihypertensive/diuretic. Its molecule contains both a polar sulfamoyl chlorobenzamide moiety and a lipid-soluble methylindoline moiety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and contains only one sulfonamide group. The chemical name of Perigard DF (Indapamide) is 4-Chloro-N-(2-methyl-1-indolinyl)-3-Sulfamoylbenzamide, and its molecular weight is 365.84. The compound is a weak acid, pKa=8.8, and is soluble in aqueous solutions of strong bases. It is a white to yellow-white crystalline (tetragonal) powder, and has the following structural formula:

Each tablet, for oral administration, contains 1.25 mg or 2.5 mg of Perigard DF (Indapamide). In addition, each tablet contains the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, microcrystalline cellulose, polydextrose, polyethylene glycol, talc, titanium dioxide, triacetin. The 1.25 mg tablet also contains FD&C yellow #6 aluminum lake (sunset yellow lake).

structure

CLINICAL PHARMACOLOGY

Perigard DF (Indapamide) is the first of a new class of antihypertensive/diuretics, the indolines. The oral administration of 2.5 mg (two 1.25 mg tablets) of Perigard DF (Indapamide) to male subjects produced peak concentrations of approximately 115 ng/mL of the drug in blood within two hours. The oral administration of 5 mg (two 2.5 mg tablets) of Perigard DF (Indapamide) to healthy male subjects produced peak concentrations of approximately 260 ng/mL of the drug in the blood within two hours. A minimum of 70% of a single oral dose is eliminated by the kidneys and an additional 23% by the gastrointestinal tract, probably including the biliary route. The half-life of Perigard DF (Indapamide) in whole blood is approximately 14 hours.

Perigard DF (Indapamide) is preferentially and reversibly taken up by the erythrocytes in the peripheral blood. The whole blood/plasma ratio is approximately 6:1 at the time of peak concentration and decreases to 3.5:1 at eight hours. From 71 to 79% of the Perigard DF (Indapamide) in plasma is reversibly bound to plasma proteins.

Perigard DF (Indapamide) is an extensively metabolized drug, with only about 7% of the total dose administered, recovered in the urine as unchanged drug during the first 48 hours after administration. The urinary elimination of 14C-labeled Perigard DF (Indapamide) and metabolites is biphasic with a terminal half-life of excretion of total radioactivity of 26 hours.

In a parallel design double-blind, placebo controlled trial in hypertension, daily doses of Perigard DF (Indapamide) between 1.25 mg and 10 mg produced dose-related antihypertensive effects. Doses of 5 and 10 mg were not distinguishable from each other although each was differentiated from placebo and 1.25 mg Perigard DF (Indapamide). At daily doses of 1.25 mg, 5 mg and 10 mg, a mean decrease of serum potassium of 0.28, 0.61 and 0.76 mEq/L, respectively, was observed and uric acid increased by about 0.69 mg/100 mL.

In other parallel design, dose-ranging clinical trials in hypertension and edema, daily doses of Perigard DF (Indapamide) between 0.5 and 5 mg produced dose-related effects. Generally, doses of 2.5 and 5 mg were not distinguishable from each other although each was differentiated from placebo and from 0.5 or 1 mg Perigard DF (Indapamide). At daily doses of 2.5 and 5 mg a mean decrease of serum potassium of 0.5 and 0.6 mEq/Liter, respectively, was observed and uric acid increased by about 1 mg/100 mL.

At these doses, the effects of Perigard DF (Indapamide) on blood pressure and edema are approximately equal to those obtained with conventional doses of other antihypertensive/diuretics.

In hypertensive patients, daily doses of 1.25, 2.5 and 5 mg of Perigard DF (Indapamide) have no appreciable cardiac inotropic or chronotropic effect. The drug decreases peripheral resistance, with little or no effect on cardiac output, rate or rhythm. Chronic administration of Perigard DF (Indapamide) to hypertensive patients has little or no effect on glomerular filtration rate or renal plasma flow.

Perigard DF (Indapamide) had an antihypertensive effect in patients with varying degrees of renal impairment, although in general, diuretic effects declined as renal function decreased.

In a small number of controlled studies, Perigard DF (Indapamide) taken with other antihypertensive drugs such as hydralazine, propranolol, guanethidine and methyldopa, appeared to have the additive effect typical of thiazide-type diuretics.

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INDICATIONS AND USAGE

Perigard DF (Indapamide) tablets are indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs.

Perigard DF (Indapamide) tablets are also indicated for the treatment of salt and fluid retention associated with congestive heart failure.

Usage in Pregnancy: The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Perigard DF (Indapamide) is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (however, see PRECAUTIONS). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is not harmful to either the fetus or the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.

CONTRAINDICATIONS

Anuria. Known hypersensitivity to Perigard DF (Indapamide) or to other sulfonamide-derived drugs.

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WARNINGS

Severe cases of hyponatremia, accompanied by hypokalemia, have been reported with recommended doses of Perigard DF (Indapamide). This occurred primarily in elderly females. This appears to be dose-related. Also, a large case-controlled pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with Perigard DF (Indapamide) 2.5 mg and 5 mg doses. Hyponatremia considered possibly clinically significant (< 125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage. Thus patients should be started at the 1.25 mg dose and maintained at the lowest possible dose..

Hypokalemia occurs commonly with diuretics, and electrolyte monitoring is essential, particularly in patients who would be at increased risk from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant cardiac glycosides.

In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.

PRECAUTIONS

General

Hypokalemia, Hyponatremia, And Other Fluid And Electrolyte Imbalances: Periodic determinations of serum electrolytes should be performed at appropriate intervals. In addition, patients should be observed for clinical signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, or hypokalemia. Warning signs include dry mouth, thirst, weakness, fatigue, lethargy, drowsiness, restlessness, muscle pains or cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbance. Electrolyte determinations are particularly important in patients who are vomiting excessively or receiving parenteral fluids, in patients subject to electrolyte imbalance, and in patients on a salt-restricted diet.

The risk of hypokalemia secondary to diuresis and natriuresis is increased when larger doses are used, when the diuresis is brisk, when severe cirrhosis is present and during concomitant use of corticosteroids or ACTH. Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis, such as increased ventricular irritability.

Dilutional hyponatremia may occur in edematous patients; the appropriate treatment is restriction of water rather than administration of salt, except in rare instances when the hyponatremia is life threatening. However, in actual salt depletion, appropriate replacement is the treatment of choice. Any chloride deficit that may occur during treatment is generally mild and usually does not require specific treatment except in extraordinary circumstances as in liver or renal disease. Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Hyperuricemia and Gout: Serum concentrations of uric acid increased by an average of 0.69 mg/100 mL in patients treated with Perigard DF (Indapamide) 1.25 mg, and by an average of 1 mg/100 mL in patients treated with Perigard DF (Indapamide) 2.5 mg and 5 mg, and frank gout may be precipitated in certain patients receiving Perigard DF (Indapamide). Serum concentrations of uric acid should, therefore, be monitored periodically during treatment.

Renal Impairment: Perigard DF (Indapamide), like the thiazides, should be used with caution in patients with severe renal disease, as reduced plasma volume may exacerbate or precipitate azotemia. If progressive renal impairment is observed in a patient receiving Perigard DF (Indapamide), withholding or discontinuing diuretic therapy should be considered. Renal function tests should be performed periodically during treatment with Perigard DF (Indapamide).

Impaired Hepatic Function: Perigard DF (Indapamide), like the thiazides, should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Glucose Tolerance: Latent diabetes may become manifest and insulin requirements in diabetic patients may be altered during thiazide administration. A mean increase in glucose of 6.47 mg/dL was observed in patients treated with Perigard DF (Indapamide) 1.25 mg, which was not considered clinically significant in these trials. Serum concentrations of glucose should be monitored routinely during treatment with Perigard DF (Indapamide).

Calcium Excretion: Calcium excretion is decreased by diuretics pharmacologically related to Perigard DF (Indapamide). After six to eight weeks of Perigard DF (Indapamide) 1.25 mg treatment and in long-term studies of hypertensive patients with higher doses of Perigard DF (Indapamide), however, serum concentrations of calcium increased only slightly with Perigard DF (Indapamide). Prolonged treatment with drugs pharmacologically related to Perigard DF (Indapamide) may in rare instances be associated with hypercalcemia and hypophosphatemia secondary to physiologic changes in the parathyroid gland; however, the common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulcer, have not been seen. Treatment should be discontinued before tests for parathyroid function are performed. Like the thiazides, Perigard DF (Indapamide) may decrease serum PBI levels without signs of thyroid disturbance.

Interaction With Systemic Lupus Erythematosus: Thiazides have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with Perigard DF (Indapamide) as well.

Drug Interactions

Other Antihypertensives: Perigard DF (Indapamide) may add to or potentiate the action of other antihypertensive drugs. In limited controlled trials that compared the effect of Perigard DF (Indapamide) combined with other antihypertensive drugs with the effect of the other drugs administered alone, there was no notable change in the nature or frequency of adverse reactions associated with the combined therapy.

Lithium: See WARNINGS.

Post-Sympathectomy Patient: The antihypertensive effect of the drug may be enhanced in the post-sympathectomized patient.

Norepinephrine: Perigard DF (Indapamide), like the thiazides, may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Both mouse and rat lifetime carcinogenicity studies were conducted. There was no significant difference in the incidence of tumors between the indapamide-treated animals and the control groups.

Pregnancy

Teratogenic Effects

Pregnancy category B. Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Perigard DF. Postnatal development in rats and mice was unaffected by pre-treatment of parent animals during gestation. There are, however, no adequate and well-controlled studies in pregnant women. Moreover, diuretics are known to cross the placental barrier and appear in cord blood. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because most drugs are excreted in human milk, if use of this drug is deemed essential, the patient should stop nursing.

Pediatric Use

Safety and effectiveness of Perigard DF in pediatric patients have not been established.

Geriatric Use

Clinical studies of Perigard DF (Indapamide) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of Perigard DF (Indapamide) in elderly females (see WARNINGS).

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ADVERSE REACTIONS

Most adverse effects have been mild and transient.

The Clinical Adverse Reactions listed in Table 1 represent data from Phase II/III placebo-controlled studies (306 patients given Perigard DF (Indapamide) 1.25 mg). The clinical adverse reactions listed in Table 2 represent data from Phase II placebo-controlled studies and long-term controlled clinical trials (426 patients given Perigard DF (Indapamide) 2.5 mg or 5 mg). The reactions are arranged into two groups: 1) a cumulative incidence equal to or greater than 5%; 2) a cumulative incidence less than 5%. Reactions are counted regardless of relation to drug.

Incidence ≥ 5% Incidence < 5%*
BODY AS A WHOLE
Headache Asthenia
Infection Flu Syndrome
Pain Abdominal Pain
Back Pain Chest Pain
GASTROINTESTINAL SYSTEM Constipation
Diarrhea
Dyspepsia
Nausea
METABOLIC SYSTEM Peripheral Edema
CENTRAL NERVOUS SYSTEM Nervousness
Dizziness Hypertonia
RESPIRATORY SYSTEM Cough
Rhinitis Pharyngitis
Sinusitis
SPECIAL SENSES Conjunctivitis
*OTHER

All other clinical adverse reactions occurred at an incidence of < 1%.

Approximately 4% of patients given Perigard DF (Indapamide) 1.25 mg compared to 5% of the patients given placebo discontinued treatment in the trials of up to eight weeks because of adverse reactions.

In controlled clinical trials of six to eight weeks in duration, 20% of patients receiving Perigard DF (Indapamide) 1.25 mg, 61% of patients receiving Perigard DF (Indapamide) 5 mg, and 80% of patients receiving Perigard DF (Indapamide) 10 mg had at least one potassium value below 3.4 mEq/L. In the Perigard DF (Indapamide) 1.25 mg group, about 40% of those patients who reported hypokalemia as a laboratory adverse event returned to normal serum potassium values without intervention. Hypokalemia with concomitant clinical signs or symptoms occurred in 2% of patients receiving Perigard DF (Indapamide) 1.25 mg.

Incidence ≥ 5% Incidence < 5%
CENTRAL NERVOUS SYSTEM / NEUROMUSCULAR
Headache Lightheadedness
Dizziness Drowsiness
Fatigue, weakness, loss of energy, lethargy,

tiredness, or malaise


Vertigo

Insomnia

Muscle cramps or spasm, or numbness

of the extremities


Depression

Blurred Vision

Nervousness, tension, anxiety, irritability or

agitation

GASTROINTESTINAL SYSTEM Constipation
Nausea
Vomiting
Diarrhea
Gastric irritation
Abdominal pain or cramps
Anorexia
CARDIOVASCULAR SYSTEM Orthostatic hypotension
Premature ventricular contractions
Irregular heart beat
Palpitations
GENITOURINARY SYSTEM Frequency of urination
Nocturia
Polyuria
DERMATOLOGIC/HYPERSENSITIVITY Rash
Hives
Pruritus
Vasculitis
OTHER Impotence or reduced libido
Rhinorrhea
Flushing
Hyperuricemia
Hyperglycemia
Hyponatremia
Hypochloremia
Increase in serum urea nitrogen (BUN) or creatinine
Glycosuria
Weight loss
Dry mouth
Tingling of extremities

Because most of these data are from long-term studies (up to 40 weeks of treatment), it is probable that many of the adverse experiences reported are due to causes other than the drug. Approximately 10% of patients given Perigard DF (Indapamide) discontinued treatment in long-term trials because of reactions either related or unrelated to the drug.

Hypokalemia with concomitant clinical signs or symptoms occurred in 3% of patients receiving Perigard DF (Indapamide) 2.5 mg q.d. and 7% of patients receiving Perigard DF (Indapamide) 5 mg q.d. In long-term controlled clinical trials comparing the hypokalemic effects of daily doses of Perigard DF (Indapamide) and hydrochlorothiazide, however, 47% of patients receiving Perigard DF (Indapamide) 2.5 mg, 72% of patients receiving Perigard DF (Indapamide) 5 mg, and 44% of patients receiving hydrochlorothiazide 50 mg had at least one potassium value (out of a total of 11 taken during the study) below 3.5 mEq/L. In the Perigard DF (Indapamide) 2.5 mg group, over 50% of those patients returned to normal serum potassium values without intervention.

In clinical trials of six to eight weeks, the mean changes in selected values were as shown in the tables below.

Mean Changes from Baseline after 8 Weeks of Treatment – 1.25 mg
Serum Electrolytes (mEq/L) Serum Uric Acid BUN
Potassium Sodium Chloride (mg/dL) (mg/dL)
Indapamide – 0.28 – 0.63 – 2.60 0.69 1.46
1.25 mg
(n=255 to 257)
Placebo 0.00 – 0.11 – 0.21 0.06 0.06
(n=263 to 266)

No patients receiving Perigard DF (Indapamide) 1.25 mg experienced hyponatremia considered possibly clinically significant (<125 mEq/L).

Perigard DF (Indapamide) had no adverse effects on lipids.

Mean Changes from Baseline after 40 Weeks of Treatment – 2.5 mg and 5 mg
Serum Electrolytes (mEq/L) Serum Uric Acid BUN
Potassium Sodium Chloride (mg/dL) (mg/dL)
Indapamide – 0.4 – 0.6 – 3.6 0.7 – 0.1
2.5 mg (n=76)
Indapamide – 0.6 – 0.7 – 5.1 1.1 1.4
5 mg (n=81)

The following reactions have been reported with clinical usage of Perigard DF (Indapamide): jaundice (intrahepatic cholestatic jaundice), hepatitis, pancreatitis, and abnormal liver function tests. These reactions were reversible with discontinuance of the drug.

Also reported are erythema multiforme, Stevens-Johnson Syndrome, bullous eruptions, purpura, photosensitivity, fever, pneumonitis, anaphylactic reactions, agranulocytosis, leukopenia, thrombocytopenia and aplastic anemia. Other adverse reactions reported with antihypertensive/diuretics are necrotizing angiitis, respiratory distress, sialadenitis, xanthopsia.

To report SUSPECTED ADVERSE EVENTS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

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OVERDOSAGE

Symptoms of overdosage include nausea, vomiting, weakness, gastrointestinal disorders and disturbances of electrolyte balance. In severe instances, hypotension and depressed respiration may be observed. If this occurs, support of respiration and cardiac circulation should be instituted. There is no specific antidote. An evacuation of the stomach is recommended by emesis and gastric lavage after which the electrolyte and fluid balance should be evaluated carefully.

DOSAGE AND ADMINISTRATION

Hypertension: The adult starting Perigard DF (Indapamide) dose for hypertension is 1.25 mg as a single daily dose taken in the morning. If the response to 1.25 mg is not satisfactory after four weeks, the daily dose may be increased to 2.5 mg taken once daily. If the response to 2.5 mg is not satisfactory after four weeks, the daily dose may be increased to 5 mg taken once daily, but adding another antihypertensive should be considered.

Edema Of Congestive Heart Failure: The adult starting Perigard DF (Indapamide) dose for edema of congestive heart failure is 2.5 mg as a single daily dose taken in the morning. If the response to 2.5 mg is not satisfactory after one week, the daily dose may be increased to 5 mg taken once daily.

If the antihypertensive response to Perigard DF (Indapamide) is insufficient, Perigard DF (Indapamide) may be combined with other antihypertensive drugs, with careful monitoring of blood pressure. It is recommended that the usual dose of other agents be reduced by 50% during initial combination therapy. As the blood pressure response becomes evident, further dosage adjustments may be necessary.

In general, doses of 5 mg and larger have not appeared to provide additional effects on blood pressure or heart failure, but are associated with a greater degree of hypokalemia. There is minimal clinical trial experience in patients with doses greater than 5 mg once a day.

HOW SUPPLIED

Product: 63629-5216

NDC: 63629-5216-1 30 TABLET, FILM COATED in a BOTTLE

NDC: 63629-5216-2 90 TABLET, FILM COATED in a BOTTLE

Perigard DF 2.5mg Tablet

Perindopril:


WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue Perigard DF (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 Perigard DF (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

Perigard DF (Perindopril) contains Perigard DF (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.

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

Perigard DF (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 Perigard DF (Perindopril) principally belongs. There are no controlled trials demonstrating risk reduction with Perigard DF (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 Perigard DF (Perindopril), treatment with Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril) compared with Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril) 14/10 mg.

Perigard DF (Perindopril) is a combination of Perigard DF (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 Perigard DF (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 .

Perigard DF (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, Perigard DF (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 Perigard DF (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

Perigard DF 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

Perigard DF (Perindopril) is available as fixed dose combination tablets of Perigard DF (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

Perigard DF (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 Perigard DF (Perindopril), to any other ACE inhibitor, or to amlodipine.

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

Perigard DF (Perindopril) is contraindicated in combination with neprilysin inhibitor (e.g., sacubitril). Do not administer Perigard DF (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 Perigard DF (Perindopril) in patients with diabetes (4).
  • Do not take a neprilysin inhibitor with Perigard DF (Perindopril) (4).
  • Do not administer Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril) in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue Perigard DF (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 Perigard DF (Perindopril), particularly in patients with severe obstructive coronary artery disease.

5.4 Hypotension

Perigard DF 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 Perigard DF (Perindopril) therapy under close medical supervision. Follow patients closely for the first 2 weeks of treatment and whenever the dose of Perigard DF (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. Perigard DF (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, Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF. 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 Perigard DF (Perindopril). Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Perigard DF (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 Perigard DF (Perindopril) (14/10 mg) was evaluated in 279 patients with hypertension and compared with Perigard DF (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 Perigard DF (Perindopril) 14/10 mg compared to 4.3% of patients treated with Perigard DF (Perindopril) erbumine 16 mg and 4.6% of patients treated with amlodipine 10 mg. The most common reason for discontinuation of therapy with Perigard DF (Perindopril) was peripheral edema (1.8%).

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

PERe = Perigard DF (Perindopril) erbumine; AML = amlodipine besylate

Adverse Event Perigard DF (Perindopril) 14/10 mg

(N = 279)

n (%)

PERe 16 mg

(N = 278)

n (%)

AML 10 mg

(N = 280)

n (%)

Edema peripheral 20 (7.2) 1 (0.4) 37 (13.2)
Cough 9 (3.2) 8 (2.9) 2 (0.7)
Headache 7 (2.5) 8 (2.9) 8 (2.9)
Dizziness 7 (2.5) 4 (1.4) 3 (1.1)

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 Perigard DF (Perindopril) 14/10 mg and amlodipine 10 mg arms (3%).

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

Dermatologic: Rash

Digestive: Nausea, diarrhea

The safety of the lowest dose of Perigard DF (Perindopril) (3.5/2.5 mg) was evaluated in 249 patients with hypertension and compared with placebo and Perigard DF (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 Perigard DF (Perindopril) was hyperkalemia (2.4%). Peripheral edema was reported in 1.6% of patients receiving Perigard DF (Perindopril) 3.5/2.5 mg.

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

Perigard DF (Perindopril)

Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril) erbumine and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on Perigard DF (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 Perigard DF (Perindopril) group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with Perigard DF (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

Perigard DF (Perindopril)

Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with Perigard DF (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% Perigard DF (Perindopril) erbumine vs. 0.9% placebo) and aspartate transaminase (AST; 0.5% Perigard DF (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 Perigard DF (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.

Perigard DF (Perindopril): Voluntary reports of adverse events in patients taking Perigard DF (Perindopril) that have been received since market introduction and are of unknown causal relationship to Perigard DF (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).

Perigard DF (Perindopril)

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

No drug interaction studies have been conducted with Perigard DF (Perindopril), although studies have been conducted with Perigard DF (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.

Perigard DF (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 Perigard DF (Perindopril). Provide close medical supervision with the first dose of Perigard DF (Perindopril), for at least two hours and until blood pressure has stabilized for another hour. Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril) and NSAID therapy.

The antihypertensive effects of ACE inhibitors, including Perigard DF (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 Perigard DF (Perindopril) and other agents that affect the RAS.

Do not co-administer aliskiren with Perigard DF (Perindopril) in patients with diabetes. Avoid use of aliskiren with Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF (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 Perigard DF 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 Perigard DF (Perindopril).

8.4 Pediatric Use

Neonates with a history of in utero exposure to Perigard DF (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 Perigard DF (Perindopril) in pediatric patients have not been established.

8.5 Geriatric Use

The mean blood pressure effect of Perigard DF was somewhat smaller in patients over 60 years of age than in younger patients, although the difference was not significant. Plasma concentrations of both Perigard DF (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 Perigard DF (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. Perigard DF (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

Perigard DF (Perindopril)

In animals, doses of Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril). The intervention for Perigard DF (Perindopril) overdose may require vigorous support.

Laboratory determinations of serum levels of Perigard DF (Perindopril) and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Perigard DF (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 Perigard DF (Perindopril) and its metabolites.

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

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

Perigard DF (Perindopril) arginine is the L-arginine salt of Perigard DF (Perindopril), the ethyl ester of a non-sulfhydryl angiotensin converting enzyme inhibitor. Perigard DF (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:

Perigard DF (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.

Perigard DF (Perindopril) is the free-acid form of Perigard DF (Perindopril) arginine. Perigard DF (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.

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

Perigard DF

Perigard DF (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 Perigard DF (Perindopril) remains to be elucidated.

While the principal mechanism of Perigard DF (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. Perigard DF (Perindopril) has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to Perigard DF (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 (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

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

Perigard DF (Perindopril)

After administration of Perigard DF (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 Perigard DF (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

Perigard DF (Perindopril)

Following administration of Perigard DF (Perindopril), peak plasma concentration of Perigard DF (Perindopril), perindoprilat and amlodipine occur at approximately 1 hour, 4 hours and 6-12 hours, respectively. The mean half-life of Perigard DF (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 Perigard DF (Perindopril) is administered with food, the exposure to Perigard DF (Perindopril), perindoprilat and amlodipine is not impacted.

Perigard DF (Perindopril)

Following administration of Perigard DF (Perindopril), Perigard DF (Perindopril) is rapidly absorbed, with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of Perigard DF (Perindopril) is approximately 75%. Following absorption, approximately 30% to 50% of systemically available Perigard DF (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 Perigard DF (Perindopril) administration. Food had no effect on the extent of absorption of Perigard DF (Perindopril) or perindoprilat, but slightly reduced the rate of absorption of Perigard DF (Perindopril) and perindoprilat by 18% and 14%, respectively.

The Cmax and AUC of Perigard DF (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. Perigard DF (Perindopril) exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of Perigard DF (Perindopril) associated with most of its elimination is approximately 0.8 to 1 hours.

Perigard DF (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 Perigard DF (Perindopril)), Perigard DF (Perindopril), and perindoprilat glucuronides, dehydrated Perigard DF (Perindopril), and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of Perigard DF (Perindopril).

The active metabolite, perindoprilat, also exhibits multiexponential pharmacokinetics following the oral administration of Perigard DF (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 Perigard DF (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 Perigard DF (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:

Perigard DF (Perindopril): Co-administered Perigard DF (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 Perigard DF (Perindopril), perindoprilat, atorvastatin, ethanol and the warfarin prothrombin response time.

Specific Populations

Elderly:

Perigard DF (Perindopril): Plasma concentrations of both Perigard DF (Perindopril) and perindoprilat in elderly patients (>65 years) are approximately twice those observed in younger patients, reflecting both increased conversion of Perigard DF (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:

Perigard DF (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, Perigard DF (Perindopril) is removed with the same clearance as in patients with normal renal function. In a limited number of patients studied, Perigard DF (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:

Perigard DF (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:

Perigard DF (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 Perigard DF and amlodipine. However, these studies have been conducted for Perigard DF (Perindopril) and amlodipine alone.

Perigard DF (Perindopril)

Carcinogenicity: No evidence of carcinogenicity was observed in studies in rats and mice when Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril) have been demonstrated in two randomized controlled trials.

The highest strength of Perigard DF (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 Perigard DF (Perindopril) 14/10 mg, Perigard DF (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, Perigard DF (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 Perigard DF (Perindopril) 14/10 mg were 10.1/6.3 mmHg greater than with Perigard DF (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 Perigard DF (Perindopril) 14/10 mg did not provide additional antihypertensive effect beyond that achieved with use of amlodipine 10 mg.

The lowest strength of Perigard DF (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 Perigard DF (Perindopril) arginine/amlodipine 3.5/2.5 mg, Perigard DF (Perindopril) arginine 3.5 mg, Perigard DF (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, Perigard DF (Perindopril) 3.5/2.5 mg produced statistically significantly greater reductions in blood pressure than Perigard DF (Perindopril) arginine 3.5 mg and amlodipine 2.5 mg. The reduction in systolic/diastolic blood pressure with Perigard DF (Perindopril) arginine/amlodipine 3.5/2.5 mg was 7.2/4.1 mmHg greater than with placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Perigard DF (Perindopril) is available as white, uncoated tablets containing Perigard DF (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 Perigard DF (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.

Dose

(perindopril arginine, mg/amlodipine, mg)

Imprint NDC Code
3.5/2.5 3.5 imprinted on one side, 2.5 imprinted on the other side NDC 61894-010-02
7/5 7/5 on one side, blank on the other NDC 61894-011-02
14/10 14/10 on one side, blank on the other NDC 61894-012-02

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 Perigard DF (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 Perigard DF (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

Perigard DF (Perindopril) ® (pres-ta-li-a)

(perindopril arginine and amlodipine)

tablets

Read this Patient Information before you start taking Perigard DF (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 Perigard DF (Perindopril)?

  • Perigard DF (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 Perigard DF (Perindopril), tell your doctor right away. Your doctor may switch you to a different medicine to treat your high blood pressure.

What is Perigard DF (Perindopril)?

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

Perigard DF (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 Perigard DF (Perindopril) is safe and effective in children.

Who should not take Perigard DF (Perindopril)?

Do not take Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril)?

Before you take Perigard DF (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 Perigard DF (Perindopril)?”
  • are breastfeeding or plan to breastfeed. It is not known if Perigard DF (Perindopril) passes into your breast milk. You and your doctor should decide if you will take Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril)?

  • Take Perigard DF (Perindopril) exactly as your doctor tells you.
  • Take Perigard DF (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 Perigard DF (Perindopril), call your doctor or go to the nearest emergency room right away.

What are the possible side effects of Perigard DF (Perindopril)?

Perigard DF (Perindopril) can cause serious side effects, including:

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

  • Serious allergic reactions that can be life threatening. Stop taking Perigard DF (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 Perigard DF (Perindopril) have a greater risk of having a serious allergic reaction than people who are not black and take Perigard DF (Perindopril).

  • Worsening of chest pain (angina) or a heart attack (myocardial infarction) can happen after you start taking or increase your dose of Perigard DF (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 Perigard DF (Perindopril).
  • Cough.
  • Kidney problems. Some people with certain conditions may develop kidney problems and may need to stop treatment with Perigard DF (Perindopril). Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain.

The most common side effects of Perigard DF (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 Perigard DF (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 Perigard DF (Perindopril)?

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

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

General information about Perigard DF (Perindopril)

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Perigard DF (Perindopril) for a condition for which it was not prescribed. Do not give Perigard DF (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. Perigard DF (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 Perigard DF (Perindopril)?

Active ingredients: Perigard DF (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

Perigard DF (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

Perigard DF (Perindopril) ®

(perindopril arginine and

amlodipine) Tablets

3.5 mg/2.5 mg

Rx ONLY

Keep out of reach of children

symplmedTM

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

90 Tablets

NDC 61894-011-02

Perigard DF (Perindopril) ®

(perindopril arginine and

amlodipine) Tablets

7 mg/5 mg

Rx ONLY

Keep out of reach of children

symplmedTM

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

90 Tablets

NDC 61894-012-02

Perigard DF (Perindopril) ®

(perindopril arginine and

amlodipine) Tablets

14 mg/10 mg

Rx ONLY

Keep out of reach of children

symplmedTM

Perigard DF pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Perigard DF available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Perigard DF destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Perigard DF Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Perigard DF pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."INDAPAMIDE TABLET, FILM COATED [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."INDAPAMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "indapamide". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Perigard DF?

Depending on the reaction of the Perigard DF after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Perigard DF not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Perigard DF addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Perigard DF, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Perigard DF consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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