EXFORGE

Amlodipine besylate is the besylate salt of amlodipine, a long-acting 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

C 20 H 25 ClN 2 O 5 •C 6 H 6 O 3 S, 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.

Amlodipine besylate tablets

USP are formulated as tablets equivalent to 2.5 mg, 5 mg and 10 mg of amlodipine for oral administration.

In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: colloidal silicon dioxide, dicalcium phosphate anhydrous, FD & C red no. 40 aluminum lake (only for 2.5 mg strength), magnesium stearate, microcrystalline cellulose and povidone.

Amlodipine besylate tablets USP meet USP Dissolution Test 2.

Amlodipine besylate tablets are calcium channel blocker and may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of: •Hypertension о Amlodipine besylate tablets are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. •Coronary Artery Disease о Chronic Stable Angina о Vasospastic Angina (Prinzmetal's or Variant Angina) о Angiographically Documented Coronary Artery Disease in patients without heart failure or an ejection fraction < 40% 1.1 Hypertension Amlodipine besylate tablets are indicated for the treatment of hypertension, to lower blood pressure.

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 besylate.

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.

Amlodipine besylate tablets may be used alone or in combination with other antihypertensive agents. 1.2 Coronary Artery Disease (CAD) Chronic Stable Angina Amlodipine besylate tablets are indicated for the symptomatic treatment of chronic stable angina.

Amlodipine besylate tablets may be used alone or in combination with other antianginal agents.

Angina (Prinzmetal's or Variant Angina) Amlodipine besylate tablets are indicated for the treatment of confirmed or suspected vasospastic angina.

Amlodipine besylate tablets may be used as monotherapy or in combination with other antianginal agents.

Angiographically Documented CAD In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, amlodipine besylate tablets are indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

Metabolic acidosis Anesthesia History of angioedema

Hypertrophic cardiomyopathy Connectivite Cardiac decompensation Dehydration Diabetes Female likely to be pregnant Primary hyperaldosteronism Hyperstimulation of the renin-angiotensin system Hypertension Hypoaldosteronism Hypovolaemia Heart failure Coronary heart failure Renal impairment Major surgery Myocardial Ischemia Newborn exposed in utero to the medicine Obstruction of left ventricular ejection route Cerebrovascular pathology Hemodialysis patient Aortic rectification Mitral shrinkage Elderly Subject at risk of hypotension Subject under 18 Black subject Concomitant immunosuppressive therapy Treatment of desensitization in progress Treatment with hyperkaliemic medicine Renal transplant, recent history (de).

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle.

Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites.

The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.

Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.

Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses.

Serum calcium concentration is not affected by amlodipine.

Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following: Exertional Angina In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro.

This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina. 12.2 Pharmacodynamics Hemodynamics Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures.

These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours.

Plasma concentrations correlate with effect in both young and elderly patients.

The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure to 104 mmHg).

Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.

In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man.

Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man.

In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing.

Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers.

In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Drug interactions Sildenafil

When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect. 12.3 Pharmacokinetics After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between and 12 hours.

Absolute bioavailability has been estimated to be between and 90%.

The bioavailability of amlodipine is not altered by the presence of food.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients.

Elimination from the plasma is biphasic with a terminal elimination half-life of about to 50 hours.

Steady-state plasma levels of amlodipine are reached after to 8 days of consecutive daily dosing.

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.

Patients with renal failure may therefore receive the usual initial dose.

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately to 60%, and a lower initial dose may be required.

A similar increase in

AUC was observed in patients with moderate to severe heart failure.

Drug interactions

In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Impact of other drugs on amlodipine

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure.

Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure.

However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent.

Impact of amlodipine on other drugs

Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

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 alone.

A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine.

Tacrolimus A prospective study in healthy

Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5-to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone.

This finding was not observed in

CYP3A5 non-expressers (N= 6).

However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported.

Irrespective of the

CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs. 12.4 Pediatric Patients Sixty-two hypertensive patients aged to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Mechanism of action

Perindopril is an enzyme inhibitor that converts angiotensin l to angiotensin II (angiotensin-enzyme-ECA).

This converting enzyme, or kinase, is an exopeptidase that allows the conversion of angiotensin l to angiotensin II vasoconstrictive causing the degradation of bradykinin vasodilatatrice into an inactive heptapeptide.

Inhibition of ECA induces a decrease in angiotensin II in plasma, leading to an increase in plasma renin activity (by inhibition of negative back control of renin release) and a decrease in the secretion of aldosterone.

As ECA inactive bradykinin, inhibition of ECA also leads to an increase in the activity of local and circulating kallikrein-kinin systems (and consequently also to activation of the prostaglandin-mediated system).

• Eosinophilia (Uncommon)
• Uremia (increase) (Uncommon)
• Hyperkalaemia (Uncommon)
• Hyponatremia (Uncommon)
• Blood creatinine (increase) (Uncommon)
• Hypoglycaemia (Uncommon)
• Liver enzymes (increase) (Rare)
• Bilirubinaemia (increase) (Rare)
• Blood globinaemia (decrease) (Very rare)
• Hyperbilirubinaemia (Rare)
• Neutropenia (Very rare)
• Hematocrite (decrease) (Very rare)
• Urticaria (Uncommon)
• Hypersudation (Uncommon)
• Photosensitivity (Uncommon)
• Hyperhidrosis (Uncommon)
• Pruritus (Common)
• Pemphigoid (Uncommon)
• Rash (Common)
• Polymorphic Erythema (Very rare)
• Psoriasis (aggravation) (Rare)
• Fall (Uncommon)
• Face edema (Uncommon)
• Chest pain (Uncommon)
• Peripheral edema (Uncommon)
• Mucous edema (Uncommon)
• Fever (Uncommon)
• Asthenia (Common)
• Inappropriate antidiuretic hormone secretion syndrome (IADH) (Rare)
• Agranulocytosis (Very rare)
• Thrombocytopenia (Very rare)
• Pancytopenia (Very rare)
• Haemolytic anaemia (Very rare)
• Leucopenia (Very rare)
• Cytolytic hepatitis (Very rare)
• Cholestatic hepatitis (Very rare)
• Oedema of Quincke Angioedema Vision disorder (Common)
• Vertigo (Common)
• Dysgueusia (Common)
• Oral dryness (Uncommon)
• Labial edema (Uncommon)
• Feeling dizzy (Common)
• Laryngeal edema (Uncommon)
• Tinnitus (Common)
• Rhinite (Very rare)
• Depression (Uncommon)
• Mood disorder (Uncommon)
• Sleep disorder (Uncommon)
• Mental confusion (Very rare)
• Vasculitis (Uncommon)
• Tachycardia (Uncommon)
• Hypotension (Common)
• Palpitation (Uncommon)
• Syncope (Uncommon)
• Malaise (Uncommon)
• Congestive puff (Rare)
• Arrhythmia (Very rare)
• Angor (Very rare)
• Myocardial infarction (Very rare)
• Raynaud's syndrome Cardiac arrest
• Abdominal pain (Common)
• Nausea (Common)
• Constipation (Common)
• Vomiting (Common)
• Dyspepsia (Common)
• Language edema (Uncommon)
• Diarrhoea (Common)
• Pancreatitis (Very rare)
• Cramp (Common)
• Joint pain (Uncommon)
• Muscle pain (Uncommon)
• Headache (Common)
• Somnolence (Uncommon)
• Balance disorder (Uncommon)
• Paraesthesia (Common)
• Stroke (Very rare)
• Dyspnoea (Common)
• Bronchospasm (Uncommon)
• Cough (Common)
• Eosinophilic pneumonia (Very rare)
• Renal impairment (Uncommon)
• Impower (Uncommon)
• Erection disorder (Uncommon)
• Acute renal impairment (Rare)
• Oliguria (Rare)
• Anuria (Rare).

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia.

In humans, experience with intentional overdosage of amlodipine is limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths.

Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension.

If massive overdose should occur, initiate active cardiac and respiratory monitoring.

Frequent blood pressure measurements are essential.

Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids.

If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output.

As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Known sensitivity to amlodipine

Amlodipine besylate tablets are contraindicated in patients with known sensitivity to amlodipine.

•Adult recommended starting dose: 5 mg once daily with maximum dose 10 mg once daily. о Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily. •Pediatric starting dose: 2.5 mg to 5 mg once daily.

Doses in excess of 5 mg daily have not been studied in pediatric patients. 2.1 Adults The usual initial antihypertensive oral dose of amlodipine besylate tablet is 5 mg once daily and the maximum dose is 10 mg once daily.

Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine besylate tablet to other antihypertensive therapy.

Adjust dosage according to blood pressure goals.

In general, wait to 14 days between titration steps.

Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

The recommended dose for chronic stable or vasospastic angina is to 10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency.

Most patients will require 10 mg for adequate effect.

Coronary artery disease

The recommended dose range for patients with coronary artery disease is to 10 mg once daily.

In clinical studies, the majority of patients required 10 mg. 2.2 Children The effective antihypertensive oral dose in pediatric patients ages to 17 years is 2.5 mg to 5 mg once daily.

Doses in excess of 5 mg daily have not been studied in pediatric patients.

mg Tablets Amlodipine Besylate Tablets USP, 2.5 mg – (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as Pink color mottled, round, flat-faced, beveled edged tablets debossed with "1" on one side and "U" on the other side and supplied as follows: NDC 68180-233-01 Bottles of 90 NDC 68180-233-02 Bottles of 1000 5 mg Tablets Amlodipine Besylate Tablets USP, 5 mg – (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are supplied as White to off white capsule shaped tablets debossed with "2" on one side and "U" on the other side and supplied as follows: NDC 68180-455-01 Bottles of 90 NDC 68180-455-02 Bottles of 1000 10 mg Tablets Amlodipine Besylate Tablets USP, 10 mg – (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are supplied as White to off white round, flat faced, beveled edged tablet debossed with "L" on one side and "32" on the other side and supplied as follows: NDC 68180-721-09 Bottles of 90 NDC 68180-721-03 Bottles of 1000 Storage Store at 20° to 25°C (68° to 77°F) and dispense in tight, light-resistant containers (USP).

Manufactured for

Naples, FL 34108 United States MADE IN INDIA.

December 2024.

The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.

There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy.

In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately and 20-times the maximum recommended human dose (MRHD), respectively.

However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold).

Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly.

Animal Data No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis.

However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold)in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/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.

Amlodipine besylate (2.5 to 5 mg daily) is effective in lowering blood pressure in patients to 17 years.

Effect of

Amlodipine besylate on blood pressure in patients less than 6 years of age is not known.

Clinical studies of amlodipine did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately to 60%, and a lower initial dose may be required.