Prestalia (perindopril arginine and amlodipine)

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

Prestalia is used to treat high blood pressure (hypertension):

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

It is not known if Prestalia is safe and effective in children.

WARNING

FETAL TOXICITY

• When pregnancy is detected, discontinue Prestalia as soon as possible.
• Drugs that act directly on the renin-angiotens in system can cause injury and death to the developing fetus

Prestalia can cause serious side effects, including:

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

People who are black and take Prestalia have a greater risk of having a serious allergic reaction than people who are not black and take Prestalia.

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

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

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

The most common side effects of Prestalia include:

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

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

These are not all the possible side effects of Prestalia. For more information, ask your doctor or pharmacist.

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

General Considerations

• The recommended starting dose of Prestalia is 3.5/2.5 mg once daily.
• Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps.
• The maximum recommended dose is 14/10 mg once daily.
• Prestalia may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.
• Consider use in patients unable to achieve adequate antihypertensive effect with amlodipine monotherapy because of dose-limiting peripheral edema caused by amlodipine.
• Administered as monotherapy, perindopril erbumine is an effective treatment for hypertension in oncedaily doses ranging from 4 mg to 16 mg daily.
• Amlodipine is effective in once-daily doses of 5 mg and 10 mg.
• Adverse reactions related to perindopril are generally uncommon and independent of dose, while those related to amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter.

Dosage Adjustment In Renal Impairment

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

Monitoring In Elderly Patients (Over 65 Years Of Age)

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

Prestalia

• The pharmacokinetics of perindopril and amlodipine are not altered when the drugs are co-administered.
• No drug interaction studies have been conducted with Prestalia, although studies have been conducted with perindopril and amlodipine.

mTOR Inhibitors

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

Neprilysin Inhibitor

• Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema.

Perindopril

Diuretics

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

Potassium Supplements And Potassium-Sparing Diuretics

• Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements, or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia.
• If concomitant use of such agents is indicated, the patient's serum potassium should be monitored frequently.

Lithium

• Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium.
• When co-administering Prestalia and lithium, frequent monitoring of serum lithium levels is recommended.
• Use of a diuretic may further increase the risk of lithium toxicity.

Gold

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

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

• In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDS, including selective COX-2 inhibitors, with ACE inhibitors, including 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 effects 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.
• In most patients no benefit has been associated with using two RAS inhibitors concomitantly.
• In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Prestalia and other agents that affect the RAS.
• Do not co-administer aliskiren with Prestalia in patients with diabetes. Avoid use of aliskiren with Prestalia in patients with renal impairment (GFR <60 mL/min).

Amlodipine

Simvastatin

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

Cyclosporine

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

CYP3A Inhibitors

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

CYP3A Inducers

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

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