Coversum Combi

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Coversum Combi uses

Coversum Combi consists of Indapamide, Perindopril Erbumine.

Indapamide:



40-9191

Revised - November 2015

Rx Only

DESCRIPTION

Coversum Combi (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 Coversum Combi (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 Coversum Combi (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

Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (Indapamide) in whole blood is approximately 14 hours.

Coversum Combi (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 Coversum Combi (Indapamide) in plasma is reversibly bound to plasma proteins.

Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (Indapamide) to hypertensive patients has little or no effect on glomerular filtration rate or renal plasma flow.

Coversum Combi (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, Coversum Combi (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

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

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

Renal Impairment: Coversum Combi (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 Coversum Combi (Indapamide), withholding or discontinuing diuretic therapy should be considered. Renal function tests should be performed periodically during treatment with Coversum Combi (Indapamide).

Impaired Hepatic Function: Coversum Combi (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 Coversum Combi (Indapamide) 1.25 mg, which was not considered clinically significant in these trials. Serum concentrations of glucose should be monitored routinely during treatment with Coversum Combi (Indapamide).

Calcium Excretion: Calcium excretion is decreased by diuretics pharmacologically related to Coversum Combi (Indapamide). After six to eight weeks of Coversum Combi (Indapamide) 1.25 mg treatment and in long-term studies of hypertensive patients with higher doses of Coversum Combi (Indapamide), however, serum concentrations of calcium increased only slightly with Coversum Combi (Indapamide). Prolonged treatment with drugs pharmacologically related to Coversum Combi (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, Coversum Combi (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 Coversum Combi (Indapamide) as well.

Drug Interactions

Other Antihypertensives: Coversum Combi (Indapamide) may add to or potentiate the action of other antihypertensive drugs. In limited controlled trials that compared the effect of Coversum Combi (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: Coversum Combi (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 Coversum Combi. 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 Coversum Combi in pediatric patients have not been established.

Geriatric Use

Clinical studies of Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (Indapamide) 1.25 mg, 61% of patients receiving Coversum Combi (Indapamide) 5 mg, and 80% of patients receiving Coversum Combi (Indapamide) 10 mg had at least one potassium value below 3.4 mEq/L. In the Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (Indapamide) 2.5 mg q.d. and 7% of patients receiving Coversum Combi (Indapamide) 5 mg q.d. In long-term controlled clinical trials comparing the hypokalemic effects of daily doses of Coversum Combi (Indapamide) and hydrochlorothiazide, however, 47% of patients receiving Coversum Combi (Indapamide) 2.5 mg, 72% of patients receiving Coversum Combi (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 Coversum Combi (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 Coversum Combi (Indapamide) 1.25 mg experienced hyponatremia considered possibly clinically significant (<125 mEq/L).

Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (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 Coversum Combi (Indapamide) is insufficient, Coversum Combi (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

Coversum Combi 2.5mg Tablet

Perindopril Erbumine:


WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue Coversum Combi (Perindopril Erbumine) as soon as possible [see Warnings and Precautions (5.4) ].
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.4) ].

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

  • When pregnancy is detected, discontinue Coversum Combi (Perindopril Erbumine) as soon as possible [see Warnings and Precautions (5.4)].
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [ see Warnings and Precautions (5.4) ].

1 INDICATIONS AND USAGE

  • Coversum Combi tablets are indicated for the treatment of patients with essential hypertension. (1.1)
  • Coversum Combi (Perindopril Erbumine) tablets are indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction. (1.2)

1.1 Hypertension

Coversum Combi (Perindopril Erbumine) tablets are indicated for the treatment of patients with essential hypertension. Coversum Combi (Perindopril Erbumine) tablets may be used alone or given with other classes of antihypertensives, especially thiazide diuretics.

1.2 Stable Coronary Artery Disease

Coversum Combi (Perindopril Erbumine) tablets are indicated for treatment of patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction. Coversum Combi (Perindopril Erbumine) tablets can be used with conventional treatment for management of coronary artery disease, such as antiplatelet, antihypertensive or lipid-lowering therapy.

2 DOSAGE AND ADMINISTRATION

Hypertension

  • The recommended initial dose is 4 mg once a day. The dosage may be titrated upward until blood pressure, when measured just before the next dose, is controlled or to a maximum of 16 mg per day.

Stable Coronary Artery Disease

  • Coversum Combi (Perindopril Erbumine) tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased, as tolerated, to a maintenance dose of 8 mg once daily. (2.2)

2.1 Hypertension

Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dose may be titrated, as needed to a maximum of 16 mg per day. The usual maintenance dose range is 4 mg to 8 mg administered as a single daily dose or in two divided doses.

Use in Elderly Patients: The recommended initial daily dosage of Coversum Combi (Perindopril Erbumine) tablets for the elderly is 4 mg daily, given in one or two divided doses. Experience with Coversum Combi (Perindopril Erbumine) tablets is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with careful blood pressure monitoring and dose titration .


Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of Coversum Combi (Perindopril Erbumine) tablets. Consider reducing the dose of diuretic prior to starting Coversum Combi (Perindopril Erbumine) tablets .

2.2 Stable Coronary Artery Disease

In patients with stable coronary artery disease, Coversum Combi tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (greater than 70 years), Coversum Combi (Perindopril Erbumine) tablets should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated.

2.3 Dose Adjustment in Renal Impairment and Dialysis

Perindoprilat elimination is decreased in renally impaired patients. Coversum Combi (Perindopril Erbumine) tablets are not recommended in patients with creatinine clearance <30 mL/min. For patients with lesser degrees of impairment, the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.

3 DOSAGE FORMS AND STRENGTHS

2 mg tablet is white to off-white colored round biconvex, uncoated tablets, with debossing “D” on one side and “5” & “7” on either side of the breakline on another side.

4 mg tablet is white to off-white colored capsule shaped uncoated tablets, with debossing “D” on one side and “5” & “8” on either side of the breakline on another side.

8 mg tablet is white to off-white colored round biconvex uncoated tablets, with debossing “D” on one side and “5” & “9” on either side of breakline on another side.

Tablets: 2 mg, 4 mg and 8 mg (3)

4 CONTRAINDICATIONS

Coversum Combi (Perindopril Erbumine) tablets are contraindicated in patients known to be hypersensitive (including angioedema) to this product or to any other ACE inhibitor. Coversum Combi (Perindopril Erbumine) tablets are also contraindicated in patients with hereditary or idiopathic angioedema.

Do not co-administer aliskiren with Coversum Combi (Perindopril Erbumine) tablets in patients with diabetes.

  • Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema. (4, 5.1)
  • Do not co-administer aliskiren with Coversum Combi (Perindopril Erbumine) tablets in patients with diabetes (4, 7.8)

5 WARNINGS AND PRECAUTIONS

  • Watch for anaphylactoid reactions, including angioedema.
  • Monitor renal function during therapy. (5.5)
  • Assess for hypotension and hyperkalemia. (5.2, 5.6)

5.1 Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Coversum Combi (Perindopril Erbumine)) may be subject to a variety of adverse events, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, or larynx has been reported in patients treated with ACE inhibitors, including Coversum Combi (Perindopril Erbumine) (0.1% of patients treated with Coversum Combi (Perindopril Erbumine) in U.S. clinical trials). Angioedema associated with involvement of the tongue, glottis or larynx may be fatal. In such cases, discontinue Coversum Combi (Perindopril Erbumine) 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.


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

5.2 Hypotension

Coversum Combi can cause symptomatic hypotension. Coversum Combi (Perindopril Erbumine) has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.

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 .

ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

In patients at risk of excessive hypotension, Coversum Combi (Perindopril Erbumine) therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of Coversum Combi (Perindopril Erbumine) and/or diuretic is increased.

If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. Coversum Combi (Perindopril Erbumine) treatment can usually be continued following restoration of volume and blood pressure.

5.3 Neutropenia/Agranulocytosis

ACE inhibitors have been associated with agranulocytosis and bone marrow depression, most frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma.

5.4 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 Coversum Combi as soon as possible [see Use in Specific Populations (8.1) ].

5.5 Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. Renal function should be monitored periodically in patients receiving Coversum Combi (Perindopril Erbumine) ,.

In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Coversum Combi (Perindopril Erbumine), may be associated with oliguria, progressive azotemia, and, rarely, acute renal failure and death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur; usually reversible upon discontinuation of the ACE inhibitor. In such patients, renal function should be monitored during the first few weeks of therapy.

Some perindopril erbumine-treated patients have developed minor and transient increases in blood urea nitrogen and serum creatinine especially in those concomitantly treated with a diuretic.

5.6 Hyperkalemia

Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including Coversum Combi. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. 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 .

Serum potassium should be monitored periodically in patients receiving Coversum Combi (Perindopril Erbumine).

5.7 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.

5.8 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.

5.9 Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, Coversum Combi (Perindopril Erbumine) may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse event 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.

  • Hypertension: Most common adverse events are cough, dizziness and back pain. (6.1)
  • Stable Coronary Artery Disease: Most common adverse events leading to discontinuation were cough, drug intolerance, and hypotension. (6.1)


To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

The following adverse reactions are discussed elsewhere in labeling:

  • Anaphylactoid reactions, including angioedema
  • Hypotension
  • Neutropenia and agranulocytosis
  • Impaired renal function
  • Hyperkalemia
  • Cough

Hypertension

Coversum Combi (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 erbumine-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with Coversum Combi (Perindopril Erbumine) 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 Coversum Combi (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 Coversum Combi (Perindopril Erbumine) and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on Coversum Combi (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 perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with perindopril.


Stable Coronary Artery Disease


Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension.

6.2 Postmarketing Experience

Voluntary reports of adverse events in patients taking Coversum Combi that have been received since market introduction and are of unknown causal relationship to Coversum Combi (Perindopril Erbumine) 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 which 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).

6.3 Clinical Laboratory Test Findings

Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with Coversum Combi (Perindopril Erbumine), 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 ALT (1.6% Coversum Combi (Perindopril Erbumine) versus 0.9% placebo) and AST (0.5% Coversum Combi (Perindopril Erbumine) versus 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.

7 DRUG INTERACTIONS

  • Diuretics: Excessive drop in blood pressure.
  • Potassium-Sparing Diuretics/Potassium Supplements: Hyperkalemia. (7.2)
  • Lithium: Increase serum lithium levels, symptoms of lithium toxicity. (7.3)
  • Injectable Gold: Nitritoid reactions (facial flushing, nausea, vomiting, and hypotension). (7.4)
  • NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect. (7.7)
  • Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. (7.8)

7.1 Diuretics

Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of Coversum Combi (Perindopril Erbumine) therapy. The possibility of hypotensive effects can be minimized by either decreasing the dose of or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretic therapy cannot be altered, provide close medical supervision with the first dose of Coversum Combi (Perindopril Erbumine), for at least two hours and until blood pressure has stabilized for another hour .

The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition.

7.2 Potassium Supplements and Potassium-Sparing Diuretics

Coversum Combi may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently.

7.3 Lithium

Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity.

7.4 Gold

Nitritoid reactions have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including Coversum Combi (Perindopril Erbumine).

7.5 Digoxin

A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with Coversum Combi (Perindopril Erbumine), but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded.

7.6 Gentamicin

Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies.

7.7 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-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 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 perindopril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including perindopril, may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.8 Dual Blockade of the Renin-Angiotensin System

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Coversum Combi (Perindopril Erbumine) and other agents that affect the RAS.

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

8 USE IN SPECIFIC POPULATIONS

  • Geriatrics: Start at low daily dose and titrate slowly as needed. Experience with doses exceeding 8 mg is limited. (8.5)
  • Dosage adjustment may be necessary in renally impaired patients. (8.6)

8.1 Pregnancy

Teratogenic Effects


Pregnancy Category D .

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Coversum Combi (Perindopril Erbumine) as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Coversum Combi (Perindopril Erbumine), 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 Coversum Combi (Perindopril Erbumine) for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4) ].

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

8.3 Nursing Mothers

Milk of lactating rats contained radioactivity following administration of 14C-perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when Coversum Combi is given to nursing mothers.

8.4 Pediatric Use

Neonates With a History of in utero Exposure to Coversum Combi (Perindopril Erbumine):

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. Perindopril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.

Safety and effectiveness of Coversum Combi (Perindopril Erbumine) in pediatric patients have not been established.

8.5 Geriatric Use

The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 than in younger patients, although the difference was not significant. Plasma concentrations of both perindopril and perindoprilat were increased in elderly patients compared to concentrations in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and possibly rash.

Start at a low dose and titrate slowly as needed. Monitor for dizziness because of potential for falls.

Experience with Coversum Combi in elderly patients at daily doses exceeding 8 mg is limited.

8.6 Renal Impairment

Dosage adjustment may be necessary in renally impaired patients .

8.7 Hepatic Impairment

The bioavailability of perindoprilat is increased in patients with impaired hepatic function .

10 OVERDOSAGE

In animals, doses of 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 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 perindopril. The intervention for perindopril overdose may require vigorous support.

Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of 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 perindopril and its metabolites. Perindopril can be removed by hemodialysis, with clearance of 52 mL/min for perindopril and 67 mL/min for perindoprilat.

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

11 DESCRIPTION

Coversum Combi (Perindopril Erbumine) tablets contain the tert-butylamine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Coversum Combi (Perindopril Erbumine) is chemically described as (2S,3αS,7αS)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1). Its molecular formula is C19H32N2O5C4H11N. Its structural formula is:

Perindopril erbumine is a white or almost white, crystalline powder, slightly hygroscopic with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform.

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

Coversum Combi (Perindopril Erbumine) tablets are available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to Coversum Combi (Perindopril Erbumine), each tablet contains the following inactive ingredients: anhydrous lactose, silica hydrophobic colloidal anhydrous, microcrystalline cellulose, and magnesium stearate.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Coversum Combi is a pro-drug for perindoprilat, which inhibits ACE in human subjects and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, 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 a small increase of 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 Coversum Combi (Perindopril Erbumine) remains to be elucidated.

While the principal mechanism of 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. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.

12.2 Pharmacodynamics

After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion, with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. 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 perindopril, but this effect is not as persistent as the effect on ACE; there is about 35% inhibition at 24 hours after a 12 mg dose.

12.3 Pharmacokinetics

Absorption: Oral administration of Coversum Combi (Perindopril Erbumine) results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after perindopril administration. Oral administration of Coversum Combi (Perindopril Erbumine) with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state.

With 4 mg, 8 mg and 16 mg doses of Coversum Combi (Perindopril Erbumine), Cmax and AUC of perindopril and perindoprilat increase in a dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen.

Distribution: Approximately 60% of circulating 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.

Metabolism and Elimination: Following oral administration perindopril exhibits multicompartment pharmacokinetics including a deep tissue compartment (ACE binding sites). The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1 hours.

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

The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following the oral administration of Coversum Combi (Perindopril Erbumine). Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once daily dosing with 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.

Elderly: Plasma concentrations of both perindopril and perindoprilat in elderly patients (greater than 70 years) are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat .

Heart Failure: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.

Renal Impairment: With perindopril doses of 2 mg to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 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.

In a limited number of patients studied, perindopril clearance by dialysis ranged from about 40 to 80 mL/min. Perindoprilat clearance by dialysis ranged from about 40 to 90 mL/min .


Hepatic Impairment: 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity: No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks.

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


Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of Coversum Combi (Perindopril Erbumine) during the period of spermatogenesis in males or oogenesis and gestation in females.

14 CLINICAL STUDIES

14.1 Hypertension

In placebo-controlled studies of perindopril monotherapy in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 mg to 16 mg lowered blood pressure. The 8 mg and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. In these studies, doses of 8 mg and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once daily and twice daily dosing were compared, the twice daily dosing regimen was generally slightly superior, but by not more than about 0.5 mm Hg to 1 mm Hg. After 2 mg to 16 mg doses of perindopril, the trough mean systolic and diastolic blood pressure effects were about 75 to 100% of peak effects.

Perindopril’s effects on blood pressure were similar when given alone or on a background of 25 mg hydrochlorothiazide. In general, the effect of perindopril occurred promptly, with effects increasing slightly over several weeks.

Formal interaction studies of Coversum Combi (Perindopril Erbumine) have not been carried out with antihypertensive agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering Coversum Combi (Perindopril Erbumine) with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system.

In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these patients.

The effectiveness of Coversum Combi (Perindopril Erbumine) was not influenced by sex and it was less effective in black patients than in nonblack patients. In elderly patients (greater than or equal to 60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the difference was not significant.

14.2 Stable Coronary Artery Disease

The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108). The mean follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease.

The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of perindopril on the primary outcome was evident after about one year of treatment (Figure 1). The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).

Perindopril

(N = 6,110)

Placebo

(N = 6,108)

RRR

(95% CI)

P
CI=confidence interval; RRR: relative risk reduction; MI: myocardial infarction

Combined Endpoint





Cardiovascular mortality, nonfatal MI or cardiac arrest

488 (8%)

603 (9.9%)

20% (9 to 29)

0.0003

Component Endpoint





Cardiovascular mortality

215 (3.5%)

249 (4.1%)

14% (-3 to 28)

0.107

Nonfatal MI

295 (4.8%)

378 (6.2%)

22% (10 to 33)

0.001

Cardiac arrest

6 (0.1%)

11 (0.2%)

46% (-47 to 80)

0.22



Size of squares proportional to the number of patients in that group. Dashed line indicates overall relative risk.

Figure 1. Time to First Occurrence of Primary Endpoint Figure 2. Beneficial Effect of Perindopril Treatment on Primary Endpoint in Predefined Subgroups

16 HOW SUPPLIED/STORAGE AND HANDLING

Coversum Combi (Perindopril Erbumine) T ablets, 2 mg are white to off-white colored round biconvex, uncoated tablets, with debossing “D” on one side and “5” & “7” on either side of the breakline on another side.

Bottles of 100 NDC 65862-286-01

Coversum Combi (Perindopril Erbumine) T ablets, 4 mg are white to off-white colored capsule shaped uncoated tablets, with debossing “D” on one side and “5” & “8” on either side of the breakline on another side.

Bottles of 100 NDC 65862-287-01

Coversum Combi (Perindopril Erbumine) T ablets, 8 mg are white to off-white colored round biconvex uncoated tablets, with debossing “D” on one side and “5” & “9” on either side of breakline on another side.

Bottles of 100 NDC 65862-288-01

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from moisture.

Keep out of the reach of children.


For further information, please call Aurobindo Pharma USA, Inc. at 1-866-850-2876.

17 PATIENT COUNSELING INFORMATION

Female patients of childbearing age should be told about the consequences of exposure to Coversum Combi (Perindopril Erbumine) during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Tell patients to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.

Distributed by:

Aurobindo Pharma USA, Inc.

2400 Route 130 North

Dayton, NJ 08810

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 038, India

Revised: 07/2017

NDC 65862-286-01

Rx only

Perindopril

Erbumine Tablets

2 mg

AUROBINDO 100 Tablets



NDC 65862-287-01

Rx only

Perindopril

Erbumine Tablets

4 mg

AUROBINDO 100 Tablets


NDC 65862-288-01

Rx only

Perindopril

Erbumine Tablets

8 mg

AUROBINDO 100 Tablets


Coversum Combi 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.


Coversum Combi 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.


Coversum Combi 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.


Coversum Combi 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.


Coversum Combi 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."PERINDOPRIL ERBUMINE TABLET [AUROBINDO PHARMA LIMITED]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."INDAPAMIDE TABLET, FILM COATED [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. 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).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Coversum Combi?

Depending on the reaction of the Coversum Combi after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Coversum Combi 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 Coversum Combi 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 Coversum Combi, 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 Coversum Combi 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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One visitor reported administration

The drugs are administered in various routes, like oral or injection form. They are administered before food or after food. How are you taking Coversum Combi drug, before food or after food?
Click here to find out how other users of our website are taking it. For any doubts or queries on how and when the medicine is administered, contact your health care provider immediately.
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Empty stomach1
100.0%

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

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