Prestalia

Amlodipine is a calcium channel blocker. Amlodipine relaxes (widens) blood vessels and improves blood flow.

Perindopril is an ACE inhibitor. ACE stands for angiotensin converting enzyme. Perindopril also widens blood vessels and also prevents the body from retaining water.

Amlodipine and perindopril is a combination medicine used to treat high blood pressure (hypertension).

Amlodipine and perindopril may also be used for purposes not listed in this medication guide.

Do not use if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Amlodipine and perindopril can cause injury or death to the unborn baby.

You should not use this medicine if you have ever had angioedema (hives or severe swelling of deep skin tissues, sometimes caused by allergic reaction).

If you have diabetes, do not use amlodipine and perindopril together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo, Valturna).

You should not use this medicine if you are allergic to amlodipine, perindopril, or any ACE inhibitor (benazepril, captopril, enalapril, lisinopril, ramipril, and others), or if you have ever had angioedema (hives or severe swelling of deep skin tissues, sometimes caused by allergic reaction).

If you have diabetes, do not use amlodipine and perindopril together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo, Valturna).

You may also need to avoid taking amlodipine and perindopril with aliskiren if you have kidney disease.

To make sure amlodipine and perindopril is safe for you, tell your doctor if you have:

• heart disease or congestive heart failure;
• coronary artery disease (hardened arteries);
• kidney disease (or if you are on dialysis);
• liver disease;
• high levels of potassium in your blood; or
• if you are on a low-salt diet.

Do not use this medicine if you are pregnant. Stop using and tell your doctor right away if you become pregnant. Amlodipine and perindopril can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control.

Amlodipine and perindopril can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using this medicine.

Serious side effects have been reported with Prestalia. See the “Prestalia Precautions” section.

Common side effects of Prestalia include:

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

This is not a complete list of Prestalia side effects. Ask your doctor or pharmacist for more information.

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

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

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Prestalia falls into category D. It has been shown that use of Prestalia in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

Take the missed dose as soon as you remember. If you are more than 12 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

In addition to using this medicine, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.

Remember that this medicine will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You might have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, strokes, or kidney disease.

This medicine comes with a patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

You may take this medicine with or without food.

Dosing

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

• For oral dosage form (tablets):
  • For high blood pressure:
    • Adults—At first, one tablet containing perindopril 3.5 milligrams (mg) and amlodipine 2.5 mg once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than perindopril 14 mg and amlodipine 10 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

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.

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.

Figure 1.a Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 6

Figure 1.b Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 6

Figure 1.c Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 6

Figure 1.d Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 6

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.

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)].

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)].

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 [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

Prestalia is available as fixed dose combination tablets of perindopril arginine and amlodipine:

• 3.5/2.5 mg tablets: white, uncoated tablets debossed with 3.5 on one side and 2.5 on the other side.
• 7/5 mg tablets: white, uncoated tablets debossed with 7/5 on one side and blank on the other side.
• 14/10 mg tablets: white, uncoated tablets debossed with 14/10 on one side and blank on the other side.

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.

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.1)]

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.

In the unusual case that there is no appropriate alternative therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultra-sound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Prestalia, 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 Prestalia 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.

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.

Pediatric Use

Neonates with a history of in utero exposure to Prestalia:

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.

The safety and effectiveness of Prestalia in pediatric patients have not been established.

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)].

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)].

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.

Perindopril

Carcinogenicity: No evidence of carcinogenicity was observed in studies in rats and mice when perindopril was administered at dosages up to 5 times (mg/m2) the maximum recommended human dose (MRHD) of 14 mg/day for 104 weeks.

Mutagenesis: No genotoxic potential was detected for perindopril, perindoprilat, and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, thymidine kinase ± mouse lymphoma assay, mouse and rat micronucleus tests, the in vivo micronucleus and chromosomal aberration tests, and Chinese hamster bone marrow assay.

Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in rats given up to 7 times (mg/m2) the MRHD during the period of spermatogenesis in males or oogenesis and gestation in females.

Amlodipine

Carcinogenicity: Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily amlodipine dosage levels of 0.5, 1.25, and 2.5 mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a body surface area basis, similar to the amlodipine MRHD of 10 mg/day. For the rat, the highest dose was, on a body surface area basis, approximately 2.5 times the MRHD, assuming a patient weight of 60 kg.

Mutagenesis: Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

Impairment of Fertility: There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at amlodipine doses of up to 10 mg/kg/day, about 10 times the MRHD of 10 mg/day on a body surface area basis.

Reproductive Toxicity

Reproductive toxicity studies have not been conducted with this combination. However, these studies have been conducted for amlodipine alone.

Amlodipine

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at amlodipine doses of up to 10 mg/kg/day (respectively, about 8 and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, assuming a patient weight of 50 kg) during their periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at an amlodipine dose equivalent to 10 mg/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Drinking alcohol with this medicine can cause side effects.

This medicine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Do not use salt substitutes or potassium supplements while taking Prestalia, unless your doctor has told you to.