AMLODIPINE BESYLATE
DESCRIPTION:
AMLOPRESS is the besylate salt of amlodipine, a long-acting calcium channel
blocker.
AMLOPRESS is chemically described as (R.S.) 3-ethyl-5-methyl-2-(2-amino-
ethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro- 6-methyl-3,5-pyridinedicarboxylate
benzenesulphonate. Its empirical formula is C20H25CIN2O5.C6H6O3S.
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. AMLOPRESS
(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, and magnesium stearate.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION: AMLOPRESS 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 AMLOPRESS 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. AMLOPRESS 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 AMLOPRESS. Within the
physiologic pH range, AMLOPRESS 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.
AMLOPRESS 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 AMLOPRESS relieves angina have not been fully
delineated, but are thought to include the following:
Exertional Angina: In patients with exertional angina, AMLOPRESS 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: AMLOPRESS 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 AMLOPRESS in vasospastic
(Prinzmetal's or variant) angina.
PHARMACOKINETICS AND METABOLISM: After oral administration of therapeutic doses
of AMLOPRESS, absorption produces peak plasma concentrations between 6 and 12
hours. Absolute bioavailability has been estimated to be between 64 and 90%. The
bioavailability of AMLOPRESS is not altered by the presence of food.
AMLOPRESS 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 AMLOPRESS are reached after 7 to
8 days of consecutive daily dosing.
The pharmacokinetics of AMLOPRESS 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.
PHARMACODYNAMICS: Hemodynamics Following administration of therapeutic doses to
patients with hypertension, AMLOPRESS 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 administration of oral 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 AMLOPRESS 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
AMLOPRESS 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 AMLOPRESS 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, AMLOPRESS
has 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 normals
or well-compensated patients with heart failure with agents possessing
significant negative inotropic effects.
STUDIES IN PATIENTS WITH CONGESTIVE HEART FAILURE: AMLOPRESS has been compared to
placebo in four 8-12 week studies of patients with NYHA class II/III heart
failure, involving a total of 697 patients. In these studies, there was no
evidence of worsened heart failure based on measures of exercise tolerance, NYHA
classification, symptoms, or LVEF. In a long-term (follow-up at least 6 months,
mean 13.8 months) placebo-controlled mortality/morbidity study of AMLOPRESS 5-10
mg in 1153 patients with NYHA classes III (n=931) or IV (n=222) heart failure on
stable doses of diuretics, digoxin, and ACE inhibitors, AMLOPRESS had no effect on
the primary endpoint of the study which was the combined endpoint of all-cause
mortality and cardiac morbidity (as defined by life-threatening arrhythmia,
acute myocardial infarction, or hospitalization for worsened heart failure), or
on NYHA classification, or symptoms of heart failure. Total combined all-cause
mortality and cardiac morbidity events were 222/571 (39%) for patients on
AMLOPRESS and 246/583 (42%) for patients on placebo; the cardiac morbid events
represented about 25% of the endpoints in the study.
ELECTROPHYSIOLOGIC EFFECTS: AMLOPRESS 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 AMLOPRESS and concomitant beta
blockers. In clinical studies in which AMLOPRESS 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, AMLOPRESS therapy did not alter electrocardiographic
intervals or produce higher degrees of AV blocks.
EFFECTS IN HYPERTENSION: The antihypertensive efficacy of AMLOPRESS has been
demonstrated in a total of 15 double-blind, placebo-controlled, randomized
studies involving 800 patients on AMLOPRESS and 538 on placebo. Once daily
administration produced statistically significant placebo-corrected reductions
in supine and standing blood pressures at 24 hours postdose, averaging about
12/6 mmHg in the standing position and 13/7 mmHg in the supine position in
patients with mild to moderate hypertension. Maintenance of the blood pressure
effect over the 24-hour dosing interval was observed, with little difference in
peak and trough effect. Tolerance was not demonstrated in patients studied for
up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the
reduction in supine and standing blood pressures was dose- related within the
recommended dosing range. Effects on diastolic pressure were similar in young
and older patients. The effect on systolic pressure was greater in older
patients, perhaps because of greater baseline systolic pressure. Effects were
similar in black patients and in white patients.
EFFECTS IN CHRONIC STABLE ANGINA: The effectiveness of 5-10 mg/day of AMLOPRESS in
exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind
clinical trials of up to 6 weeks duration involving 1038 patients (684 AMLOPRESS,
354 placebo) with chronic stable angina. In 5 of the 8 studies significant
increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose.
Increases in symptom- limited exercise time averaged 12.8% (63 sec) for AMLOPRESS
10 mg, and averaged 7.9% (38 sec) for AMLOPRESS 5 mg. AMLOPRESS 10 mg also increased
time to 1 mm ST segment deviation in several studies and decreased angina attack
rate. The sustained efficacy of AMLOPRESS in angina patients has been demonstrated
over long-term dosing. In patients with angina there were no clinically
significant reductions in blood pressures (4/1 mmHg) or changes in heart rate
(+0.3 bpm).
EFFECTS IN VASOSPASTIC ANGINA: In a double-blind, placebo-controlled clinical
trial of 4 weeks duration in 50 patients, AMLOPRESS therapy decreased attacks by
approximately 4/week compared with a placebo decrease of approximately 1/week
(p<0.01). Two of 23 AMLOPRESS and 7 of 27 placebo patients discontinued from the
study due to lack of clinical improvement.
INDICATIONS AND USAGE:
1. Hypertension
AMLOPRESS is indicated for the treatment of hypertension. It may be used alone or
in combination with other antihypertensive agents.
2. Chronic Stable Angina
AMLOPRESS is indicated for the treatment of chronic stable angina. AMLOPRESS may be
used alone or in combination with other antianginal agents.
3. Vasospastic Angina (Prinzmetal's or Variant Angina)
AMLOPRESS is indicated for the treatment of confirmed or suspected vasospastic
angina. AMLOPRESS may be used as monotherapy or in combination with other
antianginal drugs.
CONTRAINDICATIONS:
AMLOPRESS is contraindicated in patients with known sensitivity to amlodipine.
WARNINGS:
INCREASED ANGINA AND/OR MYOCARDIAL INFARCTION: Rarely, patients, particularly
those with severe obstructive coronary artery disease, have developed documented
increased frequency, duration and/or severity of angina or acute myocardial
infarction on starting calcium channel blocker therapy or at the time of dosage
increase. The mechanism of this effect has not been elucidated.
PRECAUTIONS:
GENERAL: Since the vasodilation induced by AMLOPRESS is gradual in onset, acute
hypotension has rarely been reported after oral administration of AMLOPRESS.
Nonetheless, caution should be exercised when administering AMLOPRESS as with any
other peripheral vasodilator particularly in patients with severe aortic
stenosis.
USE IN PATIENTS WITH CONGESTIVE HEART FAILURE:
blockers should be used with caution in patients with heart failure. AMLOPRESS (5-
10 mg per day) has been studied in a placebo- controlled trial of 1153 patients
with NYHA Class III or IV heart failure (see CLINICAL PHARMACOLOGY) on stable
doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months,
with a mean of about 14 months. There was no overall adverse effect on survival
or cardiac morbidity (as defined by life-threatening arrhythmia, acute
myocardial infarction, or hospitalization for worsened heart failure). AMLOPRESS
has been compared to placebo in four 8-12 week studies of patients with NYHA
class II/III heart failure, involving a total of 697 patients. In these studies,
there was no evidence of worsened heart failure based on measures of exercise
tolerance, NYHA classification, symptoms, or LVEF.
BETA-BLOCKER WITHDRAWAL: AMLOPRESS is not a beta- blocker and therefore gives no
protection against the dangers of abrupt beta-blocker withdrawal; any such
withdrawal should be by gradual reduction of the dose of beta-blocker.
PATIENTS WITH HEPATIC FAILURE: Since AMLOPRESS is extensively metabolized by the
liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with
impaired hepatic function, caution should be exercised when administering
AMLOPRESS to patients with severe hepatic impairment.
DRUG INTERACTIONS: In Vitro data in human plasma indicate that AMLOPRESS has no
effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and
indomethacin). Special studies have indicated that the co-administration of
AMLOPRESS with digoxin did not change serum digoxin levels or digoxin renal
clearance in normal volunteers; that co-administration with cimetidine did not
alter the pharmacokinetics of amlodipine; and that co-administration with
warfarin did not change the warfarin prothrombin response time.
In clinical trials, AMLOPRESS has been safely administered with thiazide
diuretics, beta- blockers, angiotensin-converting enzyme inhibitors, long-acting
nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-
inflammatory drugs, antibiotics, and oral hypoglycemic drugs. DRUG/LABORATORY
TEST INTERACTIONS:
None known.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Rats and mice treated with
amlodipine in the diet for two years, at concentrations calculated to provide
daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of
carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the
maximum recommended clinical dose of 10 mg on a mg/M(squared) basis) was close
to the maximum tolerated dose for mice but not for rats.
*Based on patient weight of 50 kg.
Mutagenicity studies revealed no drug related effects at either the gene or
chromosome levels.
There was no effect on the fertility of rats treated with amlodipine (males for
64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8
times* the maximum recommended human dose of 10 mg on a mg/M(squared) basis).
*Based on patient weight of 50 kg.
PREGNANCY CATEGORY C: No evidence of teratogenicity or other embryo/fetal
toxicity was found when pregnant rats or rabbits were treated orally with up to
10 mg/kg amlodipine (respectively 8 times* and 23 times* the maximum recommended
human dose of 10 mg on a mg/M(squared) basis) during their respective 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) in rats administered 10 mg/kg amlodipine for 14 days before mating and
throughout mating and gestation. Amlodipine has been shown to prolong both the
gestation period and the duration of labor in rats at this dose. There are no
adequate and well-controlled studies in pregnant women. Amlodipine should be
used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
*Based on patient weight of 50 kg.
NURSING MOTHERS: It is not known whether amlodipine is excreted in human milk.
In the absence of this information, it is recommended that nursing be
discontinued while AMLOPRESS is administered.
PEDIATRIC USE: Safety and effectiveness of AMLOPRESS in children have not been
established.
DRUG INTERACTIONS:
In Vitro data in human plasma indicate that AMLOPRESS has no effect on the protein
binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin).
Special studies have indicated that the co-administration of AMLOPRESS with
digoxin did not change serum digoxin levels or digoxin renal clearance in normal
volunteers; that co-administration with cimetidine did not alter the
pharmacokinetics of amlodipine; and that co-administration with warfarin did not
change the warfarin prothrombin response time.
In clinical trials, AMLOPRESS has been safely administered with thiazide
diuretics, beta- blockers, angiotensin-converting enzyme inhibitors, long-acting
nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-
inflammatory drugs, antibiotics, and oral hypoglycemic drugs. DRUG/LABORATORY
TEST INTERACTIONS:
None known.
ADVERSE REACTIONS:
AMLOPRESS has been evaluated for safety in more than 11,000 patients in U.S. and
foreign clinical trials. In general, treatment with AMLOPRESS was well-tolerated
at doses up to 10 mg daily. Most adverse reactions reported during therapy with
AMLOPRESS were of mild or moderate severity. In controlled clinical trials
directly comparing AMLOPRESS (N=1730) in doses up to 10 mg to placebo (N=1250),
discontinuation of AMLOPRESS 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. The incidence (%) of side
effects which occurred in a dose related manner are as follows:
Adverse 2.5 mg 5.0 mg 10.0 mg Placebo
Event N=275 N=296 N=268 N=520
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Edema 1.8 3.0 10.8 0.6
Dizziness 1.1 3.4 3.4 1.5
Flushing 0.7 1.4 2.6 0.0
Palpitation 0.7 1.4 4.5 0.6
Other adverse experiences which were not clearly dose related but which were
reported with an incidence greater than 1.0% in placebo-controlled clinical
trials include the following:
PLACEBO-CONTROLLED STUDIES
AMLOPRESS (%) PLACEBO (%)
(N=1730) (N=1250)
Headache 7.3 7.8
Fatigue 4.5 2.8
Nausea 2.9 1.9
Abdominal Pain 1.6 0.3
Somnolence 1.4 0.6
For several adverse experiences that appear to be drug and dose related, there
was a greater incidence in women than men associated with amlodipine treatment
as shown in the following table:
AMLOPRESS PLACEBO
ADR M=% F=% M=% F=%
(N=1218) (N=512) (N=914) (N=336)
Edema 5.6 14.6 1.4 5.1
Flushing 1.5 4.5 0.3 0.9
Palpitations 1.4 3.3 0.9 0.9
Somnolence 1.3 1.6 0.8 0.3
The following events occurred in =1% but >0.1% of patients in controlled
clinical trials or under conditions of open trials or marketing experience where
a causal relationship is uncertain; they are listed to alert the physician to a
possible relationship:
CARDIOVASCULAR: arrhythmia (including ventricular tachycardia and atrial
fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia,
syncope, tachycardia, postural dizziness, postural hypotension.
CENTRAL AND PERIPHERAL NERVOUS SYSTEM: hypoesthesia, paresthesia, tremor,
vertigo.
GASTROINTESTINAL: anorexia, constipation, dyspepsia,** dysphagia, diarrhea,
flatulence, vomiting, gingival hyperplasia.
GENERAL: asthenia,** back pain, hot flushes, malaise, pain, rigors, weight gain.
MUSCULOSKELETAL SYSTEM: arthralgia, arthrosis, muscle cramps,** myalgia.
PSYCHIATRIC: sexual dysfunction (male** and female), insomnia, nervousness,
depression, abnormal dreams, anxiety, depersonalization.
RESPIRATORY SYSTEM: dyspnea,** epistaxis.
SKIN AND APPENDAGES: pruritus,** rash,** rash erythematous, rash maculopapular.
**These events occurred in less than 1% in placebo-controlled trials, but the
incidence of these side effects was between 1% and 2% in all multiple dose
studies.
SPECIAL SENSES: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
URINARY SYSTEM: micturition frequency, micturition disorder, nocturia.
AUTONOMIC NERVOUS SYSTEM: dry mouth, sweating increased.
METABOLIC AND NUTRITIONAL: thirst.
HEMOPOIETIC: purpura.
The following events occurred in =0.1% of patients: cardiac failure, pulse
irregularity, extrasystoles, skin discoloration, urticaria, skin dryness,
alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine,
cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite,
loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion,
abnormal visual accommodation, and xerophthalmia.
Other reactions occurred sporadically and cannot be distinguished from
medications or concurrent disease states such as myocardial infarction and
angina.
AMLOPRESS therapy has not been associated with clinically significant changes in
routine laboratory tests. No clinically relevant changes were noted in serum
potassium, serum glucose, total triglycerides, total cholesterol, HDL
cholesterol, uric acid, blood urea nitrogen, or creatinine.
The following postmarketing event has been reported infrequently where a causal
relationship is uncertain: gynecomastia. In postmarketing experience, jaundice
and hepatic enzyme elevations (mostly consistent with cholestasis) in some cases
severe enough to require hospitalization have been reported in association with
use of amlodipine.
AMLOPRESS has been used safely in patients with chronic obstructive pulmonary
disease, well- compensated congestive heart failure, peripheral vascular
disease, diabetes mellitus, and abnormal lipid profiles.
OVERDOSAGE:
Single oral doses of 40 mg/kg and 100 mg/kg in mice and rats, respectively,
caused deaths. A single oral dose of 4 mg/kg or higher in dogs caused a marked
peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with
marked hypotension and possibly a reflex tachycardia. In humans, experience with
intentional overdosage of AMLOPRESS is limited. Reports of intentional overdosage
include a patient who ingested 250 mg and was asymptomatic and was not
hospitalized; another (120 mg) was hospitalized, underwent gastric lavage and
remained normotensive; the third (105 mg) was hospitalized and had hypotension
(90/50 mmHg) which normalized following plasma expansion. A patient who took 70
mg amlodipine and an unknown quantity of benzodiazepine in a suicide attempt
developed shock which was refractory to treatment and died the following day
with abnormally high benzodiazepine plasma concentration. A case of accidental
drug overdose has been documented in a 19-month-old male who ingested 30 mg
amlodipine (about 2mg/kg). During the emergency room presentation, vital signs
were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac
was administered 3.5 hours after ingestion and on subsequent observation
(overnight) no sequelae were noted.
If massive overdose should occur, active cardiac and respiratory monitoring
should be instituted. Frequent blood pressure measurements are essential. Should
hypotension occur, cardiovascular support including elevation of the extremities
and the judicious administration of fluids should be initiated. If hypotension
remains unresponsive to these conservative measures, administration of
vasopressors (such as phenylephrine) should be considered with attention to
circulating volume and urine output. Intravenous calcium gluconate may help to
reverse the effects of calcium entry blockade. As AMLOPRESS is highly protein
bound, hemodialysis is not likely to be of benefit.
DOSAGE AND ADMINISTRATION:
The usual initial antihypertensive oral dose of AMLOPRESS is 5 mg once daily with
a maximum dose of 10 mg once daily. Small, fragile, or elderly individuals, or
patients with hepatic insufficiency may be started on 2.5 mg once daily and this
dose may be used when adding AMLOPRESS to other antihypertensive therapy.
Dosage should be adjusted 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 section for information related to dosage and side effects.
CO-ADMINISTRATION WITH OTHER ANTIHYPERTENSIVE AND/OR ANTIANGINAL DRUGS: AMLOPRESS
has been safely administered with thiazides, ACE inhibitors, betablockers, long-
acting nitrates, and/or sublingual nitroglycerin.
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