^ 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 [see Clinical Pharmacology (12.3)].
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 [see Adverse Reactions (6)].
Administered as monotherapy, perindopril erbumine is an effective treatment for hypertension in once-daily doses ranging from 4 mg to 16 mg daily. Amlodipine is effective in once-daily doses of 5 mg and 10 mg. Adverse reactions related to 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 [see Adverse Reactions (6)].
^ Reproductive Toxicity
Reproductive toxicity studies have not been conducted with this combination. However, these studies have been conducted for amlodipine alone.
^ Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Tell female patients of childbearing age that use of drugs like perindopril that act on the renin-angiotensin system can cause serious problems in the fetus and infant, including low blood pressure, poor development of skull bones, kidney failure, and death. Discuss other treatment options with female patients planning to become pregnant. Tell women using PRESTALIA who become pregnant to notify their physician as soon as possible.
In case of a missed dose, have patients resume the usual dose at the next scheduled time.
^ Description
PRESTALIA is a combination of perindopril arginine and amlodipine besylate.
Perindopril arginine is the L-arginine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin converting enzyme inhibitor. Perindopril arginine is chemically described as L-arginine (2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl] octahydro-1H-indole-2-carboxylate. Its empirical formula is C19H32N2O5∙C6H14N4O2 and its structural formula is:
Perindopril arginine is a white, crystalline powder with a molecular weight 542.7. The free acid has the molecular weight of 368.5. It is readily soluble in purified water, slightly soluble in 95% ethanol, and practically insoluble in chloroform.
Perindopril is the free-acid form of perindopril arginine. Perindopril is a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.
Amlodipine besylate is the benzene sulphonic acid salt of amlodipine, a long-acting dihydropyridine calcium channel blocker. Amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate monobenzenesulphonate. Its empirical formula is C20H25ClN2O5∙C6H6O3S and its structural formula is:
Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. The content of the tablets is expressed as amlodipine (free base) which has a molecular weight of 409.1.
PRESTALIA tablets are formulated in three different strengths for oral administration. Tablets contain perindopril arginine 3.5 mg, 7 mg, or 14 mg and amlodipine 2.5 mg, 5 mg, or 10 mg for the following available perindopril arginine/amlodipine combinations: 3.5/2.5 mg, 7/5 mg, and 14/10 mg.
Inactive ingredients are lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
90 Tablets NDC 72931-012-02
Prestalia®
(perindopril arginine and amlodipine) Tablets
14 mg/10 mg
Rx ONLY Keep out of reach of children
adhera THERAPEUTICS
^ Increased Angina And/or Myocardial Infarction
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of PRESTALIA, particularly in patients with severe obstructive coronary artery disease.
^ Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In an active-controlled 6-week trial, the safety of the maximum dose of PRESTALIA (14/10 mg) was evaluated in 279 patients with hypertension and compared with perindopril erbumine 16 mg and amlodipine 10 mg. Adverse reactions were generally mild and transient in nature.
Discontinuations because of adverse events occurred in 3.6% of patients treated with PRESTALIA 14/10 mg compared to 4.3% of patients treated with perindopril erbumine 16 mg and 4.6% of patients treated with amlodipine 10 mg. The most common reason for discontinuation of therapy with PRESTALIA was peripheral edema (1.8%).
Common adverse events that occurred in at least 2% of patients treated with PRESTALIA in the 6-week trial are presented in Table 1.
The overall frequency of adverse reactions was similar between men and women, and black and non-black patients. In black patients, the incidence of peripheral edema was similar in the PRESTALIA 14/10 mg and amlodipine 10 mg arms (3%).
Other adverse reactions in the controlled clinical trial with some plausible relationship to PRESTALIA are listed below.
Dermatologic: Rash
Digestive: Nausea, diarrhea
The safety of the lowest dose of PRESTALIA (3.5/2.5 mg) was evaluated in 249 patients with hypertension and compared with placebo and perindopril and amlodipine administered as monotherapies in an 8-week trial. The only emergent adverse event observed in at least 2% of patients treated with PRESTALIA was hyperkalemia (2.4%). Peripheral edema was reported in 1.6% of patients receiving PRESTALIA 3.5/2.5 mg.
Monotherapy with perindopril or amlodipine has been evaluated for safety in clinical trials in over 3,000 and 11,000 patients, respectively, as summarized below.
^ Anaphylactoid And Possibly Related Reactions
Angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin. Patients taking ACE inhibitors (including the one in PRESTALIA) may, therefore, be subject to a variety of bradykinin- or prostaglandin-mediated adverse reactions, some of them serious. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared with non-blacks.
^ Monitoring In Elderly Patients (over 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 [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
^Principal Display Panel - 7 Mg/5 Mg Tablet Bottle Label
90 Tablets NDC 72931-011-02
Prestalia®
(perindopril arginine and amlodipine) Tablets
7 mg/5 mg
Rx ONLY Keep out of reach of children
adhera THERAPEUTICS
^Warning: Fetal Toxicity
^ Nursing Mothers
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.
^ Renal Impairment
Pharmacokinetic data indicate that perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when creatinine clearance drops below 30 mL/min. 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 [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ].
^3 Dosage Forms And Strengths
PRESTALIA is available as fixed dose combination tablets of perindopril arginine and amlodipine:
^ 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.
^ Hypotension
PRESTALIA can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume- or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.
In patients at risk of excessive hypotension, start PRESTALIA therapy under close medical supervision. Follow patients closely for the first 2 weeks of treatment and whenever the dose of PRESTALIA is increased or a diuretic is added or its dose increased.
If excessive hypotension occurs, immediately place patient in a supine position and, if necessary, treat patient with an intravenous infusion of physiological saline. PRESTALIA treatment can usually be continued following restoration of volume and blood pressure.
Patients with severe aortic stenosis may be more likely to experience symptomatic hypotension. Because of the gradual onset of action, acute hypotension is unlikely.
^4 Contraindications
PRESTALIA tablets are contraindicated in patients with hereditary or idiopathic angioedema, with or without previous ACE inhibitor treatment, and in patients who are hypersensitive to perindopril, to any other ACE inhibitor, or to amlodipine.
Do not co-administer aliskiren with ACE inhibitors, including PRESTALIA, in patients with diabetes.
Prestalia is contraindicated in combination with neprilysin inhibitor (e.g., sacubitril). Do not administer Prestalia within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Warnings and Precautions (5.2)].
^ Postmarketing Experience
The following adverse reactions have been identified during post-approval use of the individual components of PRESTALIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
^ How Supplied/storage And Handling
PRESTALIA is available as white, uncoated tablets containing perindopril arginine 3.5 mg, 7 mg, or 14 mg and amlodipine 2.5 mg, 5 mg, or 10 mg for the following three combinations of perindopril arginine/amlodipine: 3.5/2.5 mg, 7/5 mg, and 14/10 mg. All three strengths are packaged in bottles of 90 tablets. Each tablet is debossed with the tablet strength.
^ Geriatric Use
The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 years of age than in younger patients, although the difference was not significant. Plasma concentrations of both perindopril and perindoprilat in elderly patients (>65 years) are approximately twice those observed in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and rash.
Amlodipine is extensively metabolized in the liver. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life, and AUC.
Experience with PRESTALIA is limited in the elderly at doses exceeding 7/5 mg. If doses above 7/5 mg are required, monitor blood pressure up to two weeks following up titration [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
^ 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.
^Patient Information Prestalia® (pres-ta-li-a)(perindopril Arginine And Amlodipine)tablets
Read this Patient Information before you start taking PRESTALIA and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
What is the most important information I should know about PRESTALIA?
What is PRESTALIA?
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):
It is not known if PRESTALIA is safe and effective in children.
Who should not take PRESTALIA?
Do not take PRESTALIA if you:
What should I tell my doctor before taking PRESTALIA?
Before you take PRESTALIA, tell your doctor about all of your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking PRESTALIA with other medicines can cause serious side effects.
Especially tell your doctor if you take:
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take PRESTALIA?
What are the possible side effects of PRESTALIA?
PRESTALIA can cause serious side effects, including:
See "What is the most important information I should know about PRESTALIA?"
If you feel faint or dizzy, lie down and call your doctor right away.
The most common side effects of PRESTALIA include:
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.
How should I store PRESTALIA?
Keep PRESTALIA and all medicines out of the reach of children.
General information about PRESTALIA
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PRESTALIA for a condition for which it was not prescribed. Do not give PRESTALIA to other people, even if they have the same symptoms that you have. It may harm them.
For more information, go to www.prestalia-us.net, contact: info@adherathera.com or call 1-888-359-0394.
What is high blood pressure (hypertension)?
Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too great.
High blood pressure makes the heart work harder to pump blood through the body and causes damage to the blood vessels. PRESTALIA can help your blood vessels relax so your blood pressure is lower. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack.
What are the ingredients in PRESTALIA?
Active ingredients: perindopril arginine and amlodipine besylate Inactive ingredients: lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate
This Patient Information has been approved by the U.S. Food and Drug Administration.
Marketed by:Adhera Therapeutics, Inc.Durham, NC 27703
Issued: 08/2019
PRESTALIA® is a registered trademark of Biofarma used by Adhera Therapeutics, Inc. under license from Biofarma. Adhera Therapeutics and the Adhera Therapeutics logo are trademarks of Adhera Therapeutics, Inc.
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of perindopril and amlodipine. However, these studies have been conducted for perindopril and amlodipine alone.
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
90 Tablets NDC 72931-010-02
Prestalia®
(perindopril arginine and amlodipine) Tablets
3.5 mg/2.5 mg
Rx ONLY Keep out of reach of children
adhera THERAPEUTICS
^ Hyperkalemia
Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including PRESTALIA. 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 [see Drug Interactions (7)].
Monitor serum potassium periodically in patients receiving PRESTALIA.
^ Clinical Studies
The antihypertensive effects of PRESTALIA have been demonstrated in two randomized controlled trials.
The highest strength of PRESTALIA (14/10 mg) was studied in a double-blind, active controlled study in hypertensive patients. A total of 837 patients with seated diastolic pressure 95 to 115 mmHg (mean baseline systolic/diastolic blood pressure was 158/101 mmHg) received treatments of PRESTALIA 14/10 mg, perindopril erbumine 16 mg, or amlodipine 10 mg once daily for 6 weeks. The mean age of the population was 51 years, 51% of patients were male, and 34% were black. Overall, 20% of the population had type 2 diabetes.
At Week 6, PRESTALIA 14/10 mg produced statistically significantly greater reductions in blood pressure than each of the monotherapies. The reductions in systolic/diastolic blood pressure with PRESTALIA 14/10 mg were 10.1/6.3 mmHg greater than with perindopril erbumine 16 mg and 3.9/2.5 mmHg greater than with amlodipine 10 mg. In black patients and in diabetic patients, treatment with PRESTALIA 14/10 mg did not provide additional antihypertensive effect beyond that achieved with use of amlodipine 10 mg.
The lowest strength of perindopril arginine/amlodipine (3.5/2.5 mg) was studied in 246 hypertensive patients. A total of 1581 patients with supine diastolic pressure 95-110 mmHg (mean baseline systolic/diastolic blood pressure was 161/101 mmHg) received treatment with perindopril arginine/amlodipine 3.5/2.5 mg, perindopril arginine 3.5 mg, perindopril arginine 5 mg, amlodipine 2.5 mg, amlodipine 5 mg, or placebo. The mean age of the population was 52 years, 47% were male, and 1% were black. No included patients had a history of diabetes.
At Week 8, PRESTALIA 3.5/2.5 mg produced statistically significantly greater reductions in blood pressure than perindopril arginine 3.5 mg and amlodipine 2.5 mg. The reduction in systolic/diastolic blood pressure with perindopril arginine/amlodipine 3.5/2.5 mg was 7.2/4.1 mmHg greater than with placebo.
^1 Indications And Usage
PRESTALIA contains perindopril arginine, an angiotensin converting enzyme inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, and is indicated for the treatment of hypertension, to lower blood pressure.
PRESTALIA may be used in patients whose blood pressure is not adequately controlled on monotherapy.
PRESTALIA may be used as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including amlodipine and the ACE inhibitor class to which perindopril principally belongs. There are no controlled trials demonstrating risk reduction with PRESTALIA.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. In a clinical trial of PRESTALIA, treatment with PRESTALIA 14/10 mg did not provide additional antihypertensive effect beyond that achieved with use of amlodipine 10 mg in black and diabetic patients [see Clinical Studies (14)].
The choice of PRESTALIA as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of PRESTALIA.
Patients with moderate-to-severe hypertension are at a relatively high risk of cardiovascular events (e.g., stroke, heart attack, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, target goal and the incremental likelihood of achieving the goal with a combination product, such as PRESTALIA, versus a monotherapy product when deciding upon initial therapy. Individual blood pressure goals may vary based on the patient's risk.
Data from an 6-week, active-controlled trial provide estimates of the probability of reaching a target blood pressure with PRESTALIA compared with perindopril erbumine or amlodipine monotherapy [see Clinical Studies (14)].
Figures 1.a-1.d provide estimates of the likelihood of achieving target clinic systolic and diastolic blood pressure control with PRESTALIA 14/10 mg tablets after 6 weeks, based on baseline systolic and diastolic blood pressure. The curve for each treatment group was estimated by logistic regression modeling and is less well defined in the tails.
For example, a patient with a baseline blood pressure of 170/105 mmHg has approximately a 26% likelihood of achieving a goal of <140 mmHg (systolic) and 31% likelihood of achieving <90 mmHg (diastolic) on perindopril erbumine 16 mg. The likelihood of achieving these same goals on amlodipine 10 mg is approximately 40% (systolic) and 46% (diastolic). These likelihoods rise to 50% (systolic) and 65% (diastolic) with PRESTALIA 14/10 mg.
^ 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 [see Use in Specific Populations (8.6) and Warnings and Precautions (5.7)].
^ Impaired Renal Function
Monitor renal function periodically in patients receiving PRESTALIA. Drugs that affect the renin-angiotensin system can cause reductions in renal function, including acute renal failure. Patients whose renal function may depend in part on the activity of the renin-angiotensin system—(e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or who are on non-steroidal anti-inflammatory agents (NSAIDS) or angiotensin receptor blockers—may be at particular risk of developing acute renal failure on PRESTALIA. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on PRESTALIA.