AMLODIPINE BESYLATE
-
amlodipine besylate tablet
Lake Erie Medical DBA Quality Care Products LLC
Amlodipine Besylate 5 mg11 DESCRIPTION
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
20H
25ClN
2O
5•C
6H
6O
3S, 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 are formulated as white tablets equivalent to 2.5,
5, and 10 mg of amlodipine for oral administration. In addition to the active
ingredient, amlodipine besylate, each tablet contains the following inactive
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous,
sodium starch glycolate, colloidal silicon dioxide and magnesium stearate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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.
Vasospastic Angina: 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 105–114 mmHg)
had about a 50% greater response than patients with mild hypertension (diastolic
pressure 90–104 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.
Electrophysiologic 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.
12.3 Pharmacokinetics and Metabolism
After oral administration of therapeutic doses of amlodipine, absorption
produces peak plasma concentrations between 6 and 12 hours. Absolute
bioavailability has been estimated to be between 64 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 30– 50 hours. Steady-state plasma levels of
amlodipine are reached after 7 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
40–60%, and a lower initial dose may be required. A similar increase in AUC was
observed in patients with moderate to severe heart failure.
12.4 Pediatric Patients
Sixty-two hypertensive patients aged 6 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.
1.1 Hypertension
Amlodipine besylate tablets
are indicated for the treatment of hypertension. Amlodipine besylate tablets may
be used alone or in combination with other antihypertensive agents.1.2 Coronary Artery Disease (CAD)
Chronic Stable AnginaAmlodipine 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.
Vasospastic 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 CADIn patients with recently documented CAD by angiography and without heart
failure or an ejection fraction less than 40%, amlodipine besylate tablets are
indicated to reduce the risk of hospitalization due to angina and to reduce the
risk of a coronary revascularization procedure
4 CONTRAINDICATIONS
Amlodipine besylate
tablets are contraindicated in patients with known sensitivity to amlodipine.
6 ADVERSE REACTIONS6.1 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.
Amlodipine has been evaluated for safety in more
than 11,000 patients in U.S. and foreign clinical trials. In general, treatment
with amlodipine was well-tolerated at doses up to 10 mg daily. Most adverse
reactions reported during therapy with amlodipine were of mild or moderate
severity. In controlled clinical trials directly comparing amlodipine (N=1730)
at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to
adverse reactions was required in only about 1.5% of patients and was not
significantly different from placebo (about 1%). The most common side effects
are headache and edema.
10 OVERDOSAGE
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.
2.1 Adults
The usual initial antihypertensive
oral dose of amlodipine besylate tablets is 5 mg once daily with a maximum dose
of 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 tablets to other antihypertensive
therapy.
Adjust dosage according to each patient's need. In general,
titration should proceed over 7 to 14 days so that the physician can fully
assess the patient's response to each dose level. Titration may proceed more
rapidly, however, if clinically warranted, provided the patient is assessed
frequently.
The recommended dose for chronic stable or vasospastic angina
is 5–10 mg, with the lower dose suggested in the elderly and in patients with
hepatic insufficiency. Most patients will require 10 mg for adequate effect
[see Adverse Reactions (6)].The recommended dose range for patients with
coronary artery disease is 5–10 mg once daily. In clinical studies, the majority
of patients required 10 mg
[see Clinical Studies (14.4)].
2.2 Children
The effective antihypertensive
oral dose in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily.
Doses in excess of 5 mg daily have not been studied in pediatric patients
[see Clinical Pharmacology (12.4), Clinical Studies (14.1)].
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 2.5 mg Tablets
Amlodipine besylate
tablets 2.5 mg (amlodipine besylate equivalent to 2.5 mg of amlodipine per
tablet) are supplied as white to off white, round, flat-faced, beveled edge
tablets ‘211’ debossed on one side and plain on the other side and supplied as
follows:
NDC 51991-666-90 Bottle of 90
16.2 5 mg Tablets
Amlodipine besylate tablets
5 mg (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white
to off white, round, flat-faced, beveled edge tablets ‘210’ debossed on one side
and plain on the other side and supplied as follows:
NDC 51991-667-90 Bottle
of 90
16.3 10 mg Tablets
Amlodipine besylate
tablets 10 mg (amlodipine besylate equivalent to 10 mg of amlodipine per tablet)
are white to off white, round, flat-faced, beveled edge tablets ‘209’ debossed
on one side and plain on the other side and supplied as follows:
NDC
51991-668-90 Bottle of 90
PATIENT PACKAGE INSERT
AMLODIPINE BESYLATE TABLETS 2.5 mg, 5 mg, and
10 mgRead this information carefully before you start taking
amlodipine besylate tablets and each time you refill your prescription. There
may be new information. This information does not replace talking with your
doctor. If you have any questions about amlodipine besylate tablets, ask your
doctor. Your doctor will know if amlodipine besylate tablets is right for
you.
What is amlodipine besylate?Amlodipine besylate is
a type of medicine known as a calcium channel blocker (CCB). It is used to treat
high blood pressure (hypertension) and a type of chest pain called angina. It
can be used by itself or with other medicines to treat these conditions.
High Blood Pressure (hypertension)High blood
pressure comes from blood pushing too hard against your blood vessels.
Amlodipine besylate
relaxes your blood vessels, which
lets your blood flow more easily and helps lower your blood pressure. Drugs that
lower blood pressure lower your risk of having a stroke or heart attack.
AnginaAngina is a pain or discomfort that keeps
coming back when part of your heart does not get enough blood. Angina feels like
a pressing or squeezing pain, usually in your chest under the breastbone.
Sometimes you can feel it in your shoulders, arms, neck, jaws, or back.
Amlodipine besylate
can relieve this pain.
Who should not use amlodipine besylate?Do not use
amlodipine besylate if you are allergic to amlodipine (the active ingredient in
amlodipine besylate tablets), or to the inactive ingredients. Your doctor or
pharmacist can give you a list of these ingredients.
What should I tell my doctor before taking amlodipine besylate?
Tell your doctor about any prescription and non-prescription
medicines you are taking, including natural or herbal remedies.
Tell your
doctor if you:
- ever had heart disease
- ever had liver problems
- are pregnant, or plan to become pregnant. Your doctor will decide if
amlodipine besylate is the best treatment for you.
- are breast-feeding. Do not breast-feed while taking amlodipine besylate. You
can stop breast-feeding or take a different medicine.
How should I take amlodipine besylate?
- Take amlodipine besylate tablets once a day, with or without food. You can
take amlodipine besylate with most drinks, including grapefruit juice.
- It may be easier to take your dose if you do it at the same time every day,
such as with breakfast or dinner, or at bedtime. Do not take more than one dose
of amlodipine besylate at a time.
- If you miss a dose, take it as soon as you remember. Do not take amlodipine
besylate if it has been more than 12 hours since you missed your last dose. Wait
and take the next dose at your regular time.
-
Other medicines: You can use nitroglycerin and
amlodipine besylate together. If you take nitroglycerin for angina, don't stop
taking it while you are taking amlodipine besylate.
- While you are taking amlodipine besylate, do not stop taking your other
prescription medicines, including any other blood pressure medicines, without
talking to your doctor.
- If you took too much amlodipine besylate, call your doctor or Poison Control
Center, or go to the nearest hospital emergency room right away.
What should I avoid while taking amlodipine besylate?
-
Do not breast-feed. It is not known if amlodipine
besylate will pass through your milk.
-
Do not start any new prescription or
non-prescription medicines or supplements, unless you check with your doctor
first.
What are the possible side effects of amlodipine
besylate?Amlodipine besylate may cause the following side effects.
Most side effects are mild or moderate:
- headache
- swelling of your legs or ankles
- tiredness, extreme sleepiness
- stomach pain, nausea
- dizziness
- flushing (hot or warm feeling in your face)
- arrhythmia (irregular heartbeat)
- heart palpitations (very fast heartbeat)
It is rare, but when you first start taking amlodipine besylate or increase your
dose, you may have a heart attack or your angina may get worse. If that happens,
call your doctor right away or go directly to a hospital emergency room.
Tell your doctor if you are concerned about any side effects you experience.
These are not all the possible side effects of amlodipine besylate. For a
complete list, ask your doctor or pharmacist.
How do I store amlodipine besylate tablets?Keep
amlodipine besylate tablets away from children. Store amlodipine besylate
tablets at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59°
to 86°F) (see USP Controlled Room Temperature). Keep amlodipine besylate out of
the light. Do not store in the bathroom. Keep amlodipine besylate in a dry
place.
General advice about amlodipine besylateSometimes,
doctors will prescribe a medicine for a condition that is not written in the
patient information leaflets. Only use amlodipine besylate the way your doctor
told you to. Do not give amlodipine besylate to other people, even if they have
the same symptoms you have. It may harm them.
You can ask your pharmacist or doctor for information about amlodipine
besylate.
Image of label
AMLODIPINE BESYLATE
amlodipine besylate
tablet
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Revised: 11/2010Lake Erie Medical DBA Quality Care Products LLC