Amlodipine 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 molecular formula is C20H25CIN2O5•C6H 6O3S, 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 to off-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, corn starch, sodium
starch glycolate, and magnesium stearate.
Clinical Pharmacology
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. 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. 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. PharmacodynamicsHemodynamics: 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 coadministered
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. 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. Clinical StudiesEffects in HypertensionAdult Patients: The antihypertensive efficacy of amlodipine has been demonstrated
in a total of 15 double-blind, placebo-controlled, randomized studies involving
800 patients on amlodipine 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. Pediatric Patients: Two-hundred sixty-eight hypertensive patients aged 6 to 17 years
were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks and then
randomized again to the same dose or to placebo for another 4 weeks. Patients
receiving 5 mg at the end of 8 weeks had lower blood pressure than those
secondarily randomized to placebo. The magnitude of the treatment effect is
difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg
dose. Adverse events were similar to those seen in adults. Effects in Chronic Stable Angina: The effectiveness of 5 to 10 mg/day of amlodipine 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
amlodipine , 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 amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine
10 mg also increased time to 1 mm ST segment deviation in several studies and
decreased angina attack rate. The sustained efficacy of amlodipine 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, amlodipine therapy decreased attacks by approximately
4/week compared with a placebo decrease of approximately 1/week (p less than 0.01). Two
of 23 amlodipine and 7 of 27 placebo patients discontinued from the study due to
lack of clinical improvement. Effects in Documented Coronary Artery Disease: In PREVENT, 825 patients with angiographically documented
coronary artery disease were randomized to amlodipine (5 to 10 mg once daily) or
placebo and followed for 3 years. Although the study did not show significance
on the primary objective of change in coronary luminal diameter as assessed by
quantitative coronary angiography, the data suggested a favorable outcome with
respect to fewer hospitalizations for angina and revascularization procedures in
patients with CAD.
CAMELOT enrolled 1318 patients with CAD recently documented by angiography,
without left main coronary disease and without heart failure or an ejection
fraction less than 40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites,
89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44%
with a stent) were randomized to double-blind treatment with either amlodipine
(5 to 10 mg once daily) or placebo in addition to standard care that included
aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%),
anti-coagulants (40%), and diuretics (32%), but excluded other calcium channel
blockers. The mean duration of follow-up was 19 months. The primary endpoint was
the time to first occurrence of one of the following events: hospitalization for
angina pectoris, coronary revascularization, myocardial infarction,
cardiovascular death, resuscitated cardiac arrest, hospitalization for heart
failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and
151 (23.1%) first events occurred in the amlodipine and placebo groups
respectively for a hazard ratio of 0.691 (95% CI: 0.540-0.884, p= 0.003). The
primary endpoint is summarized in Figure 1 below. The outcome of this study was
largely derived from the prevention of hospitalizations for angina and the
prevention of revascularization procedures (see Table 1). Effects in
various subgroups are shown in Figure 2.
In an angiographic substudy (n=274) conducted within CAMELOT, there was no
significant difference between amlodipine and placebo on the change of atheroma
volume in the coronary artery as assessed by intravascular ultrasound.
Figure 1: Kaplan-Meier analysis of composite clinical outcomes for amlodipine
versus placebo
Figure 2 - Effects on primary endpoint of amlodipine versus placebo across
sub-groups
Table 1 below summarizes the significant clinical outcomes from the composites
of the primary endpoint. The other components of the primary endpoint including
cardiovascular death, resuscitated cardiac arrest, myocardial infarction,
hospitalization for heart failure, stroke/TIA, or peripheral vascular disease
did not demonstrate a significant difference between amlodipine and placebo.
Table 1. Incidence of Significant Clinical Outcomes for CAMELOT
Clinical Outcomes N (%)
Amlodipine (N=663)
Placebo (N=655)
Risk Reduction (p-value)
Composite CV Endpoint
110 (16.6)
151 (23.1)
31% (0.003)
Hospitalization for Angina*
51 (7.7)
84 (12.8)
42% (0.002)
Coronary revascularization*
78 (11.8)
103 (15.7)
27% (0.033)
*Â Â Total patients with these events
Studies in Patients with Congestive Heart
Failure: Amlodipinehas 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 left
ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean
13.8 months) placebo-controlled mortality/morbidity study of amlodipine 5 to10
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, amlodipine 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 amlodipine and 246/583 (42%) for patients on placebo; the cardiac
morbid events represented about 25% of the endpoints in the study.
Another study (PRAISE-2) randomized patients with NYHA class III (80%) or IV
(20%) heart failure without clinical symptoms or objective evidence of
underlying ischemic disease, on stable doses of ACE inhibitor (99%), digitalis
(99%) and diuretics (99%), to placebo (n=827) or amlodipine (n=827) and followed
them for a mean of 33 months. There was no statistically significant difference
between amlodipine and placebo in the primary endpoint of all cause mortality
(95% confidence limits from 8% reduction to 29% increase on amlodipine ). With
amlodipine there were more reports of pulmonary edema.
Indications And Usage
1. Hypertension Amlodipine is indicated for the treatment of hypertension. It may
be used alone or in combination with other antihypertensive agents. 2. Coronary Artery Disease (CAD)Chronic Stable Angina Amlodipine is indicated for the symptomatic treatment of chronic
stable angina. Amlodipine may be used alone or in combination with other
antianginal agents. Vasospastic Angina (Prinzmetal's or Variant
Angina) Amlodipine is indicated for the treatment of confirmed or
suspected vasospastic angina. Amlodipine may be used as monotherapy or in
combination with other antianginal drugs. Angiographically Documented CAD In patients with recently documented CAD by angiography and
without heart failure or an ejection fraction less than 40%, amlodipine is indicated
to reduce the risk of hospitalization due to angina and to reduce the risk of a
coronary revascularization procedure.
Contraindications
Amlodipine 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 amlodipine is gradual in onset,
acute hypotension has rarely been reported after oral administration.
Nonetheless, caution as with any other peripheral vasodilator, should be
exercised when administering amlodipine , particularly in patients with severe
aortic stenosis. Use in Patients with Congestive Heart Failure: In general, calcium channel blockers should be used with caution
in patients with heart failure. Amlodipine (5 to 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).
Amlodipine 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: Amlodipine 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 amlodipine 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 amlodipine to patients with severe hepatic impairment. Drug Interactions: In vitro data indicate that amlodipine
has no effect on the human plasma protein binding of digoxin, phenytoin,
warfarin, and indomethacin. Effect of other agents on amlodipine. CIMETIDINE: Coadministration of amlodipine with cimetidine did
not alter the pharmacokinetics of amlodipine.
GRAPEFRUIT JUICE: Coadministration of 240 mL of grapefruit juice with a
single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant
effect on the pharmacokinetics of amlodipine.
MAALOX®(antacid): Coadministration of the antacid
Maalox® with a single dose of amlodipine had no
significant effect on the pharmacokinetics of amlodipine.
SILDENAFIL: A single 100 mg dose of sildenafil (Viagra®) in subjects with essential hypertension had no effect on the
pharmacokinetic parameters of amlodipine . When amlodipine and sildenafil were
used in combination, each agent independently exerted its own blood pressure
lowering effect. Effect of amlodipine on other agents. ATORVASTATIN: Coadministration of multiple 10 mg doses of
amlodipine with 80 mg of atorvastatin resulted in no significant change in the
steady state pharmacokinetic parameters of atorvastatin.
DIGOXIN: Coadministration of amlodipine with digoxin did not change serum
digoxin levels or digoxin renal clearance in normal volunteers.
ETHANOL (alcohol): Single and multiple 10 mg doses of amlodipine had no
significant effect on the pharmacokinetics of ethanol.
WARFARIN: Coadministration of amlodipine with warfarin did not change the
warfarin prothrombin response time.
In clinical trials, amlodipine 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 maleate in the diet for up
to two years, at concentrations calculated to provide daily dosage levels of
0.5, 1.25, and 2.5 amlodipine mg/kg/day showed no evidence of a carcinogenic
effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg
amlodipine/day*). For the rat, the highest dose was, on a mg/m2basis, about twice the maximum recommended human dose*.
Mutagenicity studies conducted with amlodipine maleate revealed no drug
related effects at either the gene or chromosome level.
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 doses up
to 10 mg amlodipine/kg/day (8 times* the maximum recommended human dose of 10
mg/day on a mg/m2 basis). Pregnancy Category C: 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 (respectively 8 times* and 23 times* the
maximum recommended human dose of 10 mg on a mg/m2 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 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. 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 amlodipine is administered. Pediatric Use: The effect of amlodipine on blood pressure in patients less than
6 years of age is not known. Geriatric Use Clinical studies of amlodipine did not include sufficient numbers
of subjects aged 65 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 40-60%, and a lower initial dose may
be required (see DOSAGE
AND ADMINISTRATION ).
Adverse Reactions
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 mild or moderate severity. In
controlled clinical trials directly comparing amlodipine (N=1730) in doses up to
10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse
reactions was required in only about 1.5% of patinets 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 Event
2.5 mg N=275
5.0 mg N=296
10.0 mg N=268
Placebo N=520
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
Â
Amlodipine (%) (N=1730)
Placebo (%) (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:
Adverse Event
Amlodipine
Placebo
Â
Male=% (N=1218)
Female=% (N=512)
Male=% (N=914)
Female=% (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 less than 1% but greater than 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 uled to alert
the physician to a possible relationship:
**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.
The following events occurred in less than 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.
Amlodipine 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.
In the CAMELOT and PREVENT studies (see CLINICAL
PHARMACOLOGY: Clinical Studies: Studies in Patients with Coronary Artery
Disease:) the adverse event profile was similar to that reported
previously (see above), with the most common adverse event being peripheral
edema.
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 or
hepatitis) in some cases severe enough to require hospitalization have been
reported in association with use of amlodipine.
Amlodipine has been used safely in patients with chronic obstructive
pulmonary disease, well-compensated congestive heart failure, coronary artery
disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid
profiles.
Overdosage
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/m2basis) 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 amlodipine 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 case of
accidental drug overdose has been documented in a 19-month-old male who ingested
30 mg amlodipine (about 2 mg/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 amlodipine is highly protein
bound, hemodialysis is not likely to be of benefit.
Dosage And Administration
Adults: The usual initial antihypertensive oral dose of amlodipine 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 amlodipine 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 to10 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.
The recommended dose range for patients with coronary artery disease is 5 to
10 mg once daily. In clinical studies the majority of patients required 10 mg
(see CLINICAL
PHARMACOLOGY: Clinical Studies). 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.
Coadministration with Other Antihypertensive and/or
Antianginal Drugs: Amlodipine has been safely administered with thiazides, ACE
inhibitors, beta-blockers, long-acting nitrates, and/or sublingual
nitroglycerin.
How Supplied
Amlodipine besylate tablets 2.5 mg (amlodipine besylate
equivalent to 2.5 mg of amlodipine per tablet) are supplied as white to
off-white circular, beveled-edged, uncoated tablets with ‘G’ debossed on one
side and ‘58’ on the other side.
Bottles of 30
NDC 54868-5764-0
Bottles of 90
NDC 54868-5764-1
Bottles of 360
NDC 54868-5764-2
Amlodipine besylate tablets 5 mg (amlodipine besylate equivalent to 5 mg of
amlodipine per tablet) are supplied as white to off-white circular,
beveled-edged, uncoated tablets with ‘G58’ debossed on one side and ‘5’ on the
other side.
Bottles of 30
NDC 54868-5761-0
Bottles of 60
NDC 54868-5761-2
Bottles of 90
NDC 54868-5761-1
Bottles of 180
NDC 54868-5761-3
Amlodipine besylate tablets 10 mg (amlodipine besylate equivalent to 10 mg of
amlodipine per tablet) are supplied as white to off-white circular,
beveled-edged, uncoated tablets with ‘G58’ debossed on one side and ‘10’ on the
other side.
Bottles of 30
NDC 54868-5762-0
Bottles of 60
NDC 54868-5762-2
Bottles of 90
NDC 54868-5762-1
Store at 20° - 25°C (68°- 77°F) [See USP Controlled Room
Temperature]. Dispense in tight, light-resistant containers (USP).
Viagra® is a registered trademark of Pfizer.
Maalox® is a registered trademark of Novartis. Manufactured by:
Glenmark Generics
Ltd.
Colvale-Bardez, Goa 403 513, India
Manufactured for: Glenmark Generics Inc., USA
Mahwah, NJ 07430
Distributed and Repackaged by:
Physicians Total Care, Inc.Tulsa, OKÂ Â Â Â 74146
SUMMARY OF INFORMATION ABOUT Amlodipine Besylate
Tablets Read this information carefully before you start amlodipine 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, ask
your doctor. Your doctor will know if amlodipine is
right for you. What is amlodipine? Amlodipine 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 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. Angina Angina 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 can relieve this pain. Who should not use amlodipine? Do not use amlodipine 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 ul of these ingredients. What should I tell my doctor before taking
amlodipine? 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 is the best treatment for you.
are breastfeeding. Do not breast feed while taking amlodipine. You can stop breastfeeding or take a different
medicine.
How should I take amlodipine?
Take amlodipine once a day, with or without food.
You can take amlodipine 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, dinner, or at bedtime. Do not take more than one dose of
amlodipine at a time.
If you miss a dose, take it as soon as you remember. Do not take amlodipine 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 together. If you take nitroglycerin for angina,
don't stop taking it while you are taking amlodipine.
While you are taking amlodipine, 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, call your doctor or
Poison Control Center, or go to the nearest hospital emergency room right
away.
What should I avoid while taking amlodipine?
Do not breastfeed. It is not known if amlodipine 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? Amlodipine 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 amlodipine 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 side effects you experience.
These are not all the possible side effects of amlodipine. For a complete ul, ask your doctor or
pharmacist. How do I store amlodipine? Keep amlodipine away from children. Store
amlodipine at 20o to 25oC (68o to 77oF).
Keep amlodipine out of the light. Do not store in the
bathroom.Keep amlodipine in a dry place. General advice about amlodipine Sometimes, doctors will prescribe a medicine for a condition that
is not written in the patient information leaflets. Only use amlodipine the way your doctor told you to. Do not give amlodipine 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, or you can visit the Glenmark website at
www.glenmarkgenerics.com or call 1 (888)721-7115.
Call your doctor for medical advice about the side effects. You may report
side effects to FDA at 1-800-FDA-1088.
Manufactured by:
Glenmark Generics Ltd.
Colvale-Bardez, Goa 403 513, India
Manufactured for: Glenmark Generics Inc., USA
Mahwah, NJ 07430
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