perindopril/amlodipine (Rx)

Brand and Other Names:Prestalia
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

perindopril arginine/amlodipine

tablet

  • 3.5mg/2.5mg
  • 7mg/5mg
  • 14mg/10mg

Hypertension

Indicated for the treatment of hypertension in patients whose blood pressure is not adequately controlled on monotherapy or as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals

Initial: 3.5 mg/2.5 mg PO qDay with or without food

Adjust dose according to blood pressure goals; wait 7-14 days between titration steps

Not to exceed 14 mg/10 mg qDay

Dosage Modifications

Renal Impairment

  • CrCl <30 mL/min: Not recommended
  • CrCl 30-80 mL/min (mild or moderate renal impairment): Do not exceed 7/5 mg

Hepatic impairment: There are no data to guide dosing recommendations

Heart failure: There are no data to guide dosing recommendations

Dosing Considerations

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

Safety and efficacy not established

Neonates with a history of in utero exposure: 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

Not recommended: There are no data to guide dosing recommendations in patients aged >65 years

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%

A similar increase in AUC was observed in patients with moderate -o-severe heart failure

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Interactions

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            Adverse Effects

            1-10%

            Peripheral edema (7.2%)

            Cough (3.2%)

            Headache (2.5%)

            Dizziness (2.5%)

            Frequency Not Defined

            Dermatologic: Rash

            Digestive: Nausea, diarrhea

            Postmarketing Reports

            Perindopril

            • Cardiac arrest
            • Eosinophilic pneumonitis
            • Acute renal failure, nephritis
            • Falls
            • Hepatic failure, jaundice (hepatocellular or cholestatic), acute pancreatitis
            • Symptomatic bullous pemphigoid, pemphigus
            • Exfoliative dermatitis, psoriasis, and a syndrome that may include arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations
            • Positive antinuclear antibody (ANA), symptomatic hyponatremia, thrombocytopenia, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), leukocytosis, eosinophilia, or an elevated erythrocyte sedimentation rate (ESR)

            Amlodipine

            • Palpitations
            • Gynecomastia
            • Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), some requiring hospitalization
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            Warnings

            Black Box Warnings

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

            Contraindications

            History of hereditary or acquired 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

            Coadministration with aliskiren in patients with diabetes mellitus or with renal impairment (ie, GFR <60 mL/min/1.73 m²)

            Cautions

            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 (see Pregnancy)

            Worsening angina and acute MI can develop after starting or increasing the dose, particularly in patients with severe obstructive CAD

            Hyperkalemia reported; monitor serum potassium levels

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

            Persistent cough reported with all ACE inhibitors, presumably because of the inhibition of the degradation of endogenous bradykinin; generally resolves after discontinuing

            Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death; patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up

            Hypotension

            • May cause symptomatic hypotension; 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
            • Patients with severe aortic stenosis may be more likely to experience symptomatic hypotension
            • Correct hypotension in patients undergoing major surgery or during anesthesia with agents that produce hypotension with volume expansion
            • In patients at risk of excessive hypotension, monitor closely for the first 2 weeks of treatment and whenever the therapeutic dose is increased or a diuretic is added or its dose increased
            • If excessive hypotension occurs, immediately place patient in a supine position and, if necessary, treat patient with IV infusion of physiological saline; therapy can usually be continued following restoration of volume and blood pressure

            Renal impairment

            • Monitor renal function periodically
            • Perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when creatinine clearance < 30 mL/min
            • Drugs that affect renin-angiotensin system can cause reductions in renal function, including acute renal failure; patients whose renal function may depend in part on activity of renin-angiotensin system—(e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or who are on non-steroidal anti-inflammatory agents (NSAIDS) or angiotensin receptor blockers, may be at particular risk of developing acute renal failure

            Anaphylactoid reactions

            • ACE inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin; therefore, patients taking ACE inhibitors may be subject to a variety of bradykinin- or prostaglandin-mediated adverse reactions, some of them serious
            • Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema
            • Black patients receiving ACE inhibitors have a higher incidence of angioedema compared with nonblacks
            • Intestinal angioedema
              • Presents as abdominal pain (with or without nausea or vomiting)
              • Diagnosed by imaging studies (eg, abdominal CT or ultrasound) or at surgery
            • Angioedema of the face, extremities, lips, tongue, glottis, and larynx
              • Discontinue perindopril treatment immediately and observe until the swelling disappears
              • When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, administer appropriate therapy promptly (eg, SC epinephrine solution 1:1000 [0.3-0.5 mL])
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            Pregnancy & Lactation

            Pregnancy Category: D

            Discontinue as soon as pregnancy detected; during the second and third trimesters of pregnancy, drugs that act directly on the renin-angiotensin have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death

            Lactation: Unknown if distributed in human breast milk; because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue the drug

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Perindopril: A prodrug that is hydrolyzed to perindoprilat; competitively inhibits angiotensin-converting enzyme (ACE) that initially results in decreased plasma angiotensin II concentrations, and, consequently, blood pressure may be reduced in part through decreased vasoconstriction, increased renin activity, and decreased aldosterone secretion

            Amlodipine: A dihydropyridine calcium antagonist; it inhibits transmembrane influx of extracellular calcium ions across membranes of myocardial cells and vascular smooth muscle cells without changing serum calcium concentrations; this inhibits cardiac and vascular smooth muscle contraction, thereby dilating main coronary and systemic arteries

            Absorption

            Bioavailability (amlodipine): 64-90%

            Peak plasma concentration

            • Perindopril: 1 hr
            • Perindoprilat: 4 hr
            • Amlodipine: 6-12 hr

            Distribution

            Protein bound (amlodipine): 93%

            Metabolism

            Perindopril: Extensively metabolized to 6 metabolites resulting from hydrolysis, glucuronidation, and cyclization via dehydration, including the active moiety, perindoprilat

            Amlodipine: Extensively (~90%) metabolized in the liver to inactive metabolites

            Elimination

            Excretion (amlodipine): Mostly in urine (60% as metabolites, 10% as unchanged drug)

            Half-life

            • Perindoprilat: ~100 hr
            • Amlodipine: ~30-50 hr
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            Administration

            Oral Administration

            May take with or without food

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.