Perindopril

Perindopril is the generic form of the brand-name medicine Aceon, which is used to treat high blood pressure.

Lowering your blood pressure can reduce your risk of having a heart attack, a stroke, or another cardiovascular complication.

Perindopril is also used to reduce the risk of heart attack or death in certain people with coronary artery disease.

This prescription medicine belongs to a class of drugs called angiotensin-converting enzyme (ACE) inhibitors. It works by helping to relax blood vessels.

The U.S. Food and Drug Administration (FDA) approved perindopril in 1993.

Perindopril Warnings

Before taking perindopril, tell your doctor if you have, or have ever had:

• Heart disease, heart attack, or another heart problem
• Liver disease
• Kidney disease or a kidney transplant
• Stroke
• Lupus (an autoimmune disease characterized by inflammation and a variety of symptoms)
• Diabetes
• Scleroderma (a skin condition)
• Rheumatoid arthritis
• An electrolyte imbalance
• Angioedema (swelling of the face, lips, tongue, throat, arms, or legs)
• Allergies to medications (especially ACE inhibitors)

Also let your doctor know if you have diabetes and are taking the medicine Tekturna or Amturnide (aliskiren).

Perindopril may affect your blood sugar levels if you have diabetes. Be sure to monitor your condition carefully.

Your doctor may recommend a diet and exercise plan to follow while using perindopril. You may also be told to drink more fluids. Follow these instructions carefully.

Don't take potassium or salt substitutes while using perindopril unless your healthcare provider tells you to do so.

Excessive sweating, vomiting, diarrhea, or dehydration can raise your risk of developing low blood pressure. Tell your doctor if you experience any of these conditions.

Use caution when exercising or when outside in hot weather.

Keep all appointments with your doctor and laboratory while taking this medicine. You'll need to undergo frequent tests, including blood pressure checks.

This medicine may be less effective in African-Americans, and it may also increase the risk of angioedema in this group. Talk to your doctor if this is a concern.

Let your healthcare provider know you're taking this medicine before having any type of surgery, including a dental procedure.

Pregnancy and Perindopril

Perindopril contains a black box warning because it may cause injury or death to a fetus if taken during pregnancy.

Tell your doctor immediately if you become pregnant while using this medicine.

Use an effective form of birth control to prevent pregnancy while taking perindopril.

It's not known whether perindopril passes into breastmilk or could hurt a breastfeeding baby. Don't breastfeed a baby while using this medicine.

Black Box Warnings

Discontinue as soon as possible when pregnancy is detected; affects renin-angiotensin system causing oligohydramnios, which may result in fetal injury and/or death

Contraindications

Hypersensitivity to perindopril/other ACE inhibitors

History of hereditary or angioedema associated with previous ACE inhibitor treatment

Coadministration of neprilysin inhibitors (eg, sacubitril) with ACE inhibitors may increase angioedema risk; do not administer ACE inhibitors within 36 hr of switching to or from sacubitril/valsartan

Bilateral renal artery stenosis

Do not coadminister with aliskiren in patients with diabetes mellitus or with renal impairment (ie, GFR <60 mL/min/1.73 m²)

Cautions

Apheresis (LDL) with dextran sulfate, hypertrophic cardiomyopathy, collagen vascular disease, excessive hypotension - volume depletion, hemodialysis with high flux membrane, aortic stenosis

ACE inhibition also causes increased bradykinin levels which putatively mediates angioedema

Coadministration with mTOR inhibitors (eg, temsirolimus) may increased risk for angioedema

Dual blockade of the renin angiotensin system with ARBs, ACE inhibitors, or aliskiren associated with increased risk for hypotension, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy

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 with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident; If excessive hypotension occurs, place patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline; perinopril treatment can usually be continued following restoration of volume and blood pressure

Discontinue immediately if pregnant (see Contrainidications and Black Box Warnings)

Less effective in blacks

Renal impairment may occur

Neutropenia/agranulocytosis reported

Cough may occur within the first few months

Cholestatic jaundice may occur

Renal impairment

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

• potassium-sparing diuretics such as:
  • spironolactone (Aldactone)
  • triamterene (Dyrenium)
  • amiloride (Midamor)
• other diuretics such as:
  • furosemide (Lasix)
  • hydrochlorothiazide
  • torsemide (Demadex)
• aliskiren (Tekturna)
• angiotensin receptor blockers such as candesartan (Atacand), losartan (Cozaar), and telmisartan (Micardis, Twynsta)
• aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) such as:
  • celecoxib (Celebrex)
  • diclofenac (Cambia, Cataflam, Flector, Voltaren, Zipsor and others)
  • etodolac (Lodine)
  • ibuprofen (Advil, Motrin, Nuprin)
  • indomethacin (Indocin, Indocin SR)
  • ketoprofen (Orudis, Actron, Oruvail)
  • ketorolac (Toradol)
  • meloxicam (Mobic)
  • nabumetone (Relafen)
  • naproxen (Naprosyn)
  • naproxen sodium (Aleve, Anaprox, Naprelan)
  • oxaprozin (Daypro)
  • piroxicam (Feldene)
• gentamicin (Garamycin)
• lithium (Eskalith, Lithobid)
• potassium supplements
• injectable gold (sodium aurothiomalate)

This is not a complete list of perindopril drug interactions. Ask your doctor or pharmacist for more information.

Before taking perindopril, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• have a history of angioedema (swelling under the skin)
• have diabetes (high blood sugar) and you are taking aliskiren (Tekturna; also in Amturnide, Tekamlo, Tekturna HCT). Your doctor will probably tell you not to take perindopril if you have diabetes and you are also taking aliskiren.
• have or have ever had heart or kidney disease or diabetes
• have liver disease
• are having surgery, including dental surgery. Inform the doctor or dentist that you are taking perindopril.
• are using salt substitutes containing potassium. If your doctor prescribes a low-salt or low-sodium diet, follow these instructions carefully.
• are pregnant or breastfeeding

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

If you take too much perindopril call your healthcare provider or poison control center, or seek emergency medical attention right away.

Perindopril is used alone or together with other medicines to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. Lowering blood pressure can reduce the risk of strokes and heart attacks.

Perindopril works by blocking a substance in the body that causes the blood vessels to tighten. As a result, perindopril relaxes the blood vessels. This lowers blood pressure and increases the supply of blood and oxygen to the heart.

Perindopril is also used in patients with coronary artery disease to prevent heart attacks.

perindopril is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Body aches or pain
• chills
• cough
• difficulty breathing
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat
• unusual tiredness or weakness

• Abdominal or stomach pain
• bladder pain
• bloody or cloudy urine
• change in hearing
• chest pain
• cold or flu-like symptoms
• congestion
• difficult, burning, or painful urination
• dryness of the throat
• earache or pain in the ear
• ear drainage
• frequent urge to urinate
• hoarseness
• lower back or side pain
• swelling
• tender, swollen glands in the neck
• trouble with swallowing
• voice changes
• vomiting

• Blurred vision
• confusion
• decreased urination
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• irregular heartbeat
• muscle cramps or pain
• numbness, tingling, pain, or weakness in the hands or feet
• rapid breathing
• seizures
• sunken eyes
• sweating
• thirst
• trembling
• weakness and heaviness of the legs

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• lack or loss of strength
• pain or tenderness around the eyes and cheekbones
• tightness of the chest

• Belching
• bloated
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• diarrhea
• difficulty moving
• discouragement
• excess air or gas in the stomach or intestines
• feeling sad or empty
• full feeling
• hearing loss
• injury
• irritability
• lack of appetite
• leg pain
• loss of interest or pleasure
• muscle aching, stiffness, tension, or tightness
• nausea
• neck pain
• nervousness
• pain, swelling, or redness in the joints
• passing gas
• rash
• sleepiness or unusual drowsiness
• stomach discomfort or upset
• swollen joints
• trouble concentrating
• trouble sleeping

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take perindopril or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to perindopril. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Diuretics

Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of 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 Perindopril erbumine, for at least two hours and until blood pressure has stabilized for another hour [see Warnings and Precautions (5.2)].

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.

Potassium Supplements and Potassium-Sparing Diuretics

Perindopril erbumine 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.

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.

Gold

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

Digoxin

A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with Perindopril erbumine, but an effect of digoxin on the plasma concentration of Perindopril/Perindoprilat has not been excluded.

Gentamicin

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

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including 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.

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. 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 Perindopril erbumine and other agents that affect the RAS.

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

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.

Female patients of childbearing age should be told about the consequences of exposure to 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 65862-287-01
Rx only
Perindopril
Erbumine Tablets
4 mg
AUROBINDO           100 Tablets

Peak effect: 1-2 hours

Time to Peak

Chronic therapy: Perindopril: 1 hour; Perindoprilat: 3-7 hours (maximum perindoprilat serum levels are 2-3 times higher and Tmax is shorter following chronic therapy); CHF: Perindoprilat: 6 hours

Half-Life Elimination

Parent drug: 1.5-3 hours; Metabolite: Effective: 3-10 hours, Terminal: 30-120 hours

Protein Binding

Perindopril: 60%; Perindoprilat: 10% to 20%

Bioavailability of perindoprilat is increased, and plasma concentrations are approximately 50% higher.

Oral: Administer prior to a meal.

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

May lead to false-negative aldosterone/renin ratio (ARR) (Funder 2016)

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Drugs that act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Their use in pregnancy is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. Teratogenic effects may occur following maternal use of an ACE inhibitor during the first trimester, although this finding may be confounded by maternal disease. Because adverse fetal events are well documented with exposure later in pregnancy, ACE inhibitor use in pregnant women is not recommended (Seely 2014; Weber 2014). Infants exposed to an ACE inhibitor in utero should be monitored for hyperkalemia, hypotension, and oliguria. Oligohydramnios may not appear until after irreversible fetal injury has occurred. Exchange transfusions or dialysis may be required to reverse hypotension or improve renal function, although data related to the effectiveness in neonates is limited.

Chronic maternal hypertension itself is also associated with adverse events in the fetus/infant and mother. ACE inhibitors are not recommended for the treatment of uncomplicated hypertension in pregnancy (ACOG 2013) and they are specifically contraindicated for the treatment of hypertension and chronic heart failure during pregnancy by some guidelines (Regitz-Zagrosek 2011). In addition, ACE inhibitors should generally be avoided in women of reproductive age (ACOG, 2013). If treatment for hypertension or chronic heart failure in pregnancy is needed, other agents should be used (ACOG 2013; Regitz-Zagrosek 2011).

Applies to perindopril: oral tablet

Along with its needed effects, perindopril may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking perindopril:

• Body aches or pain
• chills
• cough
• difficulty breathing
• ear congestion
• fever
• headache
• loss of voice
• nasal congestion
• runny nose
• sneezing
• sore throat
• unusual tiredness or weakness

• Abdominal or stomach pain
• bladder pain
• bloody or cloudy urine
• change in hearing
• chest pain
• cold or flu-like symptoms
• congestion
• difficult, burning, or painful urination
• dryness of the throat
• earache or pain in the ear
• ear drainage
• frequent urge to urinate
• hoarseness
• lower back or side pain
• swelling
• tender, swollen glands in the neck
• trouble with swallowing
• voice changes
• vomiting

• Blurred vision
• confusion
• decreased urination
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry mouth
• irregular heartbeat
• muscle cramps or pain
• numbness, tingling, pain, or weakness in the hands or feet
• rapid breathing
• seizures
• sunken eyes
• sweating
• thirst
• trembling
• weakness and heaviness of the legs

Some side effects of perindopril may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• lack or loss of strength
• pain or tenderness around the eyes and cheekbones
• tightness of the chest

• Belching
• bloated
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• diarrhea
• difficulty moving
• discouragement
• excess air or gas in the stomach or intestines
• feeling sad or empty
• full feeling
• hearing loss
• injury
• irritability
• lack of appetite
• leg pain
• loss of interest or pleasure
• muscle aching, stiffness, tension, or tightness
• nausea
• neck pain
• nervousness
• pain, swelling, or redness in the joints
• passing gas
• rash
• sleepiness or unusual drowsiness
• stomach discomfort or upset
• swollen joints
• trouble concentrating
• trouble sleeping