Read all of this leaflet carefully before you start taking this
medicine because it contains important information for you.
* Keep this leaflet. You may need to read it again.
* If you have any further questions, ask your doctor or
pharmacist.
* This medicine has been prescribed for you only.
Do not pass it on to others. It may harm them, even if their
signs of illness are the same as yours.
* If you get any side effects talk to your doctor or pharmacist.
This includes any possible side effects not listed in this leaflet.
gradual association and dissociation with the receptor binding
site. Experimental data suggest that amlodipine binds to both
dihydropyridine and nondihydropyridine binding sites.
A. Hypertension: The mechanism by which amlodipine reduces
arterial blood pressure involves direct peripheral arterial
vasodilation and reduction in peripheral vascular resistance.
B. Angina: The precise mechanism by which amlodipine relieves
angina has not been fully delineated. Amlodipine is a dilator of
peripheral arteries and arterioles which reduces the total
peripheral resistance and, therefore, reduces the workload of the
heart (afterload). The unloading of the heart is thought to decrease
ischemia and relieve effort angina by reducing myocardial energy
oxygen consumption and oxygen requirements.
5-PHARMACOKINETICS
Absorption
Absorption After oral administration of therapeutic doses of
amlodipine, absorption occurs gradually with peak plasma
concentration reached 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.
Distribution
In vivo studies have shown that approximately 93% of the
circulating drug is bound to plasma proteins in hypertensive
patients.
Metabolism
Amlodipine is metabolized through the cytochrome P450 system,
mainly via CYP 3A4 isoenzyme. 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.
Excretion
Elimination from the plasma is biphasic with a terminal elimination
half-life of about 35 – 50 hours. Steady state plasma levels of
amlodipine are reached after 7 to 8 days of consecutive daily
dosing.
6-CONTRAINDICATIONS
AMLODIPRESS
®
is contraindicated in patients:
• Who are hypersensitive to this drug or to any ingredient in the
formulation, including any nonmedicinal ingredient.
• Who are hypersensitive to other dihydropyridines. Amlodipine
besylate is a dihydropyridine calcium channel blocker.
• Who are breast-feeding.
• With severe hypotension (less than 90 mmHg systolic).
• With shock including cardiogenic shock.
• With obstruction of the outflow tract of the left ventricle (e.g. high
grade aortic stenosis).
• With hemodynamically unstable heart failure after acute
myocardial infarction.
7-POSOLOGY
For both hypertension and angina, the recommended initial dose
of AMLODIPRESS
®
(amlodipine besylate) is 5 mg once daily. If
necessary, dose can be increased after 1 – 2 weeks to a maximum
dose of 10 mg once daily.
Use in the Elderly or in Patients with Impaired Renal Function
The recommended initial dose in patients over 65 years of age or
patients with impaired renal function is 5 mg once daily. If required,
increasing in the dose should be done gradually and with caution .
Use in Patients with Impaired Hepatic Function Dosage
requirements have not been established in patients with impaired
hepatic function. When AMLODIPRESS
®
is used in these patients,
the dosage should be carefully and gradually adjusted
depending on patient’s tolerance and response. A lower starting
dose of 2.5 mg once daily should be considered.
Use in Pediatric Patients (6 – 17 years of age) 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; dose should be determined based upon the
medical need of the patients.
8-WARNINGS and PRECAUTIONS
General
Beta-blocker Withdrawal
AMLODIPRESS
®
(amlodipine besylate) gives no protection against
the dangers of abrupt beta-blocker withdrawal and such
withdrawal should be done by the gradual reduction of the dose
of beta- blocker.
Cardiovascular
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.
Use in Patients with Congestive Heart Failure Although generally
calcium channel blockers should only be used with caution in
patients with heart failure, it has been observed that amlodipine
besylate had no overall deleterious effect on survival and
cardiovascular morbidity in both short-term and long-term
clinical trials in these patients. While a significant proportion of
the patients in these studies had a history of ischemic heart
disease, angina or hypertension, the studies were not designed
to evaluate the treatment of angina or hypertension in patients
with concomitant heart failure. Of note, in an amlodipine
long-term, placebo-controlled study in patients with severe
heart failure (NYHA class III and IV), the reported incidence of
pulmonary edema was higher in the amlodipine-treated group
than in the placebo group. Calcium channel blockers, including
amlodipine, may increase the risk of future cardiovascular events
and mortality.
Hypotension AMLODIPRESS
®
may occasionally precipitate
symptomatic hypotension. Careful monitoring of blood pressure
is recommended, especially in patients with a history of
cerebrovascular insufficiency, and those taking medications
known to lower blood pressure.
Peripheral Edema Mild to moderate peripheral edema was the
most common adverse event in the clinical trials (see ADVERSE
REACTIONS). The incidence of peripheral edema was dose-
dependent and ranged in frequency from 3.0 to 10.8% in 5 to 10 mg
dose range. Care should be taken to differentiate this peripheral
edema from the effects of increasing left ventricular dysfunction.
Hepatic/Biliary/Pancreatic
Use in Patients with Impaired Hepatic Function There are no
adequate studies in patients with liver dysfunction and dosage
recommendations have not been established. In a small number
of patients with mild to moderate hepatic impairment given
single dose of 5 mg, amlodipine half-life has been.
AMLODIPRESS
®
should, therefore, be administered with caution in
these patients and careful monitoring should be performed. A
lower starting dose may be required .
Patients with Severe Hepatic Impairment
or Hepatic Failure Because amlodipine
besylate is extensively metabolized by the
liver and the plasma elimination half-life
(t1/2) is 56 hours in patients with impaired
hepatic function, it should be
administered cautiously and at reduced
dosages in patients with severely
impaired hepatic function. Slow dose
titration and careful monitoring are
required in patients with severe hepatic
impairment.
Concomitant Use with Strong Inhibitors
of CYP 3A4 Use of AMLODIPRESS
®
with
drugs that result in strong inhibition of CYP
3A4, such as ketoconazole, clarithromycin,
ritonavir, may lead to increased plasma
levels of amlodipine and associated
serious events. Such concomitant use
should be avoided. An observational
study demonstrated an increased risk of
hospitalization with acute kidney injury
when amlodipine was used concomitant-
ly with clarithromycin in elderly patients (>
65 years of age) compared to when it was
used concomitantly with azithromycin,
odds ratio [amlodipine: 1.61 (95% C.I. 1.29 –
2.02)].
Sexual Health Reversible biochemical
changes in the head of spermatozoa
have been reported in some patients
treated by calcium channel blockers.
Reversible adverse effects on male rat
fertility have also been suggested.
9-SPECIFIC PATIENT POPULATIONS
Pregnants
There is no clinical experience with
amlodipine besylate in pregnant women.
AMLODIPRESS
®
should be used during
pregnancy only if the potential benefit
outweighs the potential risk to the mother
and fetus. Although amlodipine was not
teratogenic in the rat and rabbit, some
dihydropyridine compounds have been
found to be teratogenic in animals. In rats,
amlodipine has been shown to prolong
both the gestation period and the
duration of labor. There was no effect on
the fertility of rats treated with amlodipine.
Nursing Mothers
In human study, the mean maternal daily
dose of amlodipine was 6.0 mg and the
medians of the plasma and milk
concentrations of amlodipine were 15.5
and 11.5 ng/mL, respectively, with median
milk/plasma concentration ratio of 0.85.
Since amlodipine safety in newborns has
not been established, AMLODIPRESS
®
should not be given to nursing mothers. A
decision should be made whether to
discontinue nursing or discontinue the
drug, taking into account the importance of the drug to the
mother.
Pediatrics (0 – 17 years of age) The use of amlodipine besylate is
not recommended in patients less than 6 years of age since safety
and efficacy have not been established in that population. In
pediatric patients aged 6 – 17 years, safety and efficacy studies
beyond 8 weeks of duration, for the treatment of hypertension,
have not been conducted. The prescription in this population
should be based on a careful risk/benefit assessment of the
limited available information. The risk/benefit assessment should
be conducted by a qualified physician.
Geriatrics (≥ 65 years of age)
In elderly patients (≥ 65 years) clearance of amlodipine is
decreased with a resulting increase in AUC In clinical trials the
incidence of adverse reactions in elderly patients was
approximately 6% higher than that of younger population (< 65
years). Adverse reactions include edema, muscle cramps and
dizziness. AMLODIPRESS
®
should be used cautiously in elderly
patients. Dosage adjustment is advisable.
10-DRUG INTERACTIONS
As with all drugs, care should be exercised when treating patients
with multiple medications. Dihydropyridine calcium channel
blockers undergo biotransformation by the cytochrome P450
system, mainly via CYP 3A4 isoenzyme. Coadministration of
amlodipine with other drugs which follow the same route of
biotransformation may result in altered bioavailability of
amlodipine or these drugs. Dosages of similarly metabolized
drugs, particularly those of low therapeutic ratio, and especially in
patients with renal and/or hepatic impairment, may require
adjustment when starting or stopping concomitantly
administered amlodipine to maintain optimum therapeutic blood
levels.
Drugs known to be inhibitors of the cytochrome P450 system
include: azole antifungals, cimetidine, cyclosporine, erythromycin,
quinidine, terfenadine, warfarin. With concomitant use with the
CYP3A4 inhibitor erythromycin in young patients and diltiazem in
elderly patients, the plasma concentration of amlodipine
increased by 22% and 50 % respectively. Strong inhibitors of CYP3A4
(e.g., ketoconazole, itraconazole, ritonavir) may increase the
plasma concentrations of amlodipine to a greater extent than
diltiazem. Amlodipine should be used with caution together with
CYP3A4 inhibitors; and monitoring of therapy is required.
Drugs known to be inducers of the cytochrome P450 system
include: phenobarbital, phenytoin, rifampin, hypericum
perforatum (St John's wort). There is no data available regarding
the effect of CYP3A4 inducers on amlodipine. The concomitant use
of CYP3A4 inducers may give a lower plasma concentration of
amlodipine which in turn can result in decreased blood pressure
lowering effects. Amlodipine should be used with caution together
with CYP3A4 inducers and dose adjustment may be necessary to
maintain efficacy. Hence, monitoring of therapy is required.
Drugs known to be biotransformed via P450 include: benzodiaze-
pines, flecainide, imipramine, propafenone, theophylline.
Amlodipine has a low (rate of first-pass) hepatic clearance and
consequent high bioavailability, and thus, may be expected to
have a low potential for clinically
relevant effects associated with elevation of amlodipine plasma
levels when used concomitantly with drugs that compete for or
inhibit the cytochrome P450 system.
Cimetidine, Warfarin, Cyclosporin, Digoxin: Pharmacokinetic
interaction studies with amlodipine in healthy volunteers have
indicated:
• Cimetidine did not alter the pharmacokinetics of amlodipine.
• Amlodipine did not change warfarin-induced prothrombin
response time.
• Amlodipine does not significantly alter the pharmacokinetics of
cyclosporin.
• Amlodipine did not change serum digoxin levels or digoxin renal
clearance.
Antacids Concomitant administration of Maalox® (magnesium
hydroxide and aluminum hydroxide) had no effect on the
disposition of a single 5 mg dose of amlodipine in 24 subjects.
Beta-blockers: When beta-adrenergic receptor blocking drugs
are administered concomitantly with AMLODIPINE, patients should
be carefully monitored since blood pressure lowering effect of
beta-blockers may be augmented by amlodipine's reduction in
peripheral vascular resistance.
Sildenafil: A single 100 mg dose of sildenafil in subjects with
essential hypertension had no effect on AUCt or Cmax of
amlodipine. When sildenafil (100 mg) was coadministered with
amlodipine, 5 or 10 mg in hypertensive patients, the mean
additional reduction of supine blood pressure was 8 mm Hg
systolic and 7 mm Hg diastolic.
11-ADVERSE REACTIONS
Most adverse reactions reported during therapy were of mild to
moderate severity.
HYPERTENSION
The most common adverse reactions in controlled clinical trials
were: edema (8.9%), and headache (8.3%).
Autonomic Nervous System: flushing (3.1%), increased sweating
(0.9%), dry mouth (0.7%).
Cardiovascular: edema (8.9%), palpitations (2.0%), tachycardia
(0.7%), postural dizziness (0.5%).
Central and Peripheral Nervous System: headache (8.3%), dizziness
(3.0%), paresthesia (0.5%).
Gastrointestinal: nausea (2.4%), abdominal pain (1.1%), dyspepsia
(0.6%), constipation (0.5%). General: fatigue (4.1%), pain (0.5%).
Musculoskeletal: muscle cramps (0.5%).
Psychiatric: somnolence (1.4%).
Skin and Appendages : pruritus (0.7%).
ANGINA
The most common adverse reactions reported in controlled
clinical trials were: edema (9.9%) and headache (7.8%).
Autonomic Nervous System: flushing (1.9%).
Cardiovascular: edema (9.9%), palpitations (2.0%), postural
dizziness (0.6%).
Central and Peripheral Nervous System: headache (7.8%), dizziness
(4.5%), paresthesia (1.0%), hypoesthesia (0.9%).
Gastrointestinal: nausea (4.2%), abdominal pain (2.2%), dyspepsia
(1.4%), diarrhea (1.1%), flatulence (1.0%), constipation (0.9%).
General : fatigue (4.8%), pain (1.0%), asthenia (1.0%).
Musculoskeletal: muscle cramps (1.0%).
Psychiatric: somnolence (1.2%), insomnia (0.9%), nervousness (0.7%).
Respiratory System: dyspnea (1.1%).
Skin and Appendages : rash (1.0%), pruritus (0.8%).
Special Senses: vision abnormal (1.3%), tinnitus (0.6%).
Less common clinical trials Adverse reactions
Amlodipine besylate has been evaluated for safety in about 11,000
patients with hypertension and angina.
The following events occurred in 0.1% of patients in comparative
clinical trials or under conditions of open trials or marketing
experience where a causal relationship is uncertain.
Autonomic Nervous System: dry mouth, sweating increased.
Cardiovascular: arrhythmia (including ventricular
tachycardia and atrial fibrillation), bradycardia, hypotension,
peripheral ischemia, syncope, tachycardia, postural dizziness,
postural hypotension, vasculitis.
Central and Peripheral Nervous System : hypoesthesia, peripheral
neuropathy, tremor, vertigo. Gastrointestinal: anorexia,
constipation, dysphagia, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia, back pain, hot flushes, malaise,
rigors, weight gain.
Hemopoietic: leucopenia, purpura, thrombocytopenia.
Metabolic and Nutritional : hyperglycemia, thirst.
Musculoskeletal System: arthralgia, arthrosis, myalgia.
Psychiatric: sexual dysfunction (male and female), insomnia,
nervousness, depression, abnormal dreams, anxiety,
depersonalization.
Respiratory System: epistaxis.
Skin and Appendages: pruritus, rash erythematous, rash
maculopapular, erythema multiforme.
Special Senses: conjunctivitis, diplopia, eye pain, tinnitus.
Urinary System: micturition frequency, micturition disorder,
nocturia.
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.
The following events occurred in ≤ 0.1% of patients: cardiac failure,
skin discoloration*, urticaria*, skin dryness, Stevens-Johnson
syndrome, alopecia*, twitching, ataxia, hypertonia*, migraine,
apathy, amnesia, gastritis*, pancreatitis*, increased appetite,
coughing*, rhinitis*, parosmia, taste perversion*, and xerophthal-
mia.
*These events were observed in marketing experience as well.
Isolated cases of angioedema have been reported. Angioedema
may be accompanied by breathing difficulty.
12-STORAGE CONDITIONS
Keep this medicine out of the sight and reach of children.
Store below 30°C.
Keep your medicine in a cool dry place and away from light in the
original package to protect it from moisture.
Don’t use this medicine after the expiry date which is stated on the
outer packaging. The expiry date refers to the last day of that
month.
Don’t use this medicine if you notice any visible signs of deteriora-
tion.
Don’t throw away any medicines via wastewater. Ask your
pharmacist how to throw away medicines you no longer use.
These measures will help protect the environment.
Amlodipine Besylate 5mg Tablet
1-DESCRIPTION:
AMLODIPRESS
®
5mg is a white uncoated tablet, plain on both side.
2-COMPOSITION
Each tablet contains 5mg of amlodipine Besylate.
Excipients: lactose monohydrate, microcrystalline cellulose,
PVP-K30, magnesium stearate, silicon dioxide.
3-THERAPEUTIC INDICATIONS
• Hypertension: AMLODIPRESS
®
is indicated in the treatment of mild
to moderate essential hypertension.
Combination of amlodipine besylate with a diuretic, a
beta-blocking agent, or an angiotensin converting enzyme
inhibitor has been found to be compatible and showed additive
antihypertensive effect.
• Chronic Stable Angina: AMLODIPRESS
®
is indicated for the
management of chronic stable angina (effort-associated
angina) in patients who remain symptomatic despite adequate
doses of beta-blockers and/or organic nitrates or who cannot
tolerate those agents. AMLODIPRESS
®
may be tried in combination
with beta-blockers in chronic stable angina in patients with
normal ventricular function. When such concomitant therapy is
introduced, care must be taken to monitor blood pressure closely
since hypotension can occur from the combined effects of the
drugs.
4-PHARMACOLOGICAL PROPERTIES
Mechanism of action
AMLODIPRESS
®
(amlodipine besylate) is a calcium ion influx
inhibitor (calcium entry blocker or calcium ion antagonist).
Amlodipine is a member of the dihydropyridine class of calcium
antagonists.
The therapeutic effect of this group of drugs is believed to be
related to their specific cellular action of selectively inhibiting
transmembrane influx of calcium ions into vascular smooth
muscle and cardiac muscle. The contractile processes of these
tissues 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. Serum calcium concentration is not
affected by amlodipine. Within the physiologic pH range,
amlodipine is an ionized compound and its kinetic interaction
with the calcium channel receptor is characterized by the
gradual association and dissociation with the receptor binding
site. Experimental data suggest that amlodipine binds to both
dihydropyridine and nondihydropyridine binding sites.
A. Hypertension: The mechanism by which amlodipine reduces
arterial blood pressure involves direct peripheral arterial
vasodilation and reduction in peripheral vascular resistance.
B. Angina: The precise mechanism by which amlodipine relieves
angina has not been fully delineated. Amlodipine is a dilator of
peripheral arteries and arterioles which reduces the total
peripheral resistance and, therefore, reduces the workload of the
heart (afterload). The unloading of the heart is thought to decrease
ischemia and relieve effort angina by reducing myocardial energy
oxygen consumption and oxygen requirements.
5-PHARMACOKINETICS
Absorption
Absorption After oral administration of therapeutic doses of
amlodipine, absorption occurs gradually with peak plasma
concentration reached 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.
Distribution
In vivo studies have shown that approximately 93% of the
circulating drug is bound to plasma proteins in hypertensive
patients.
Metabolism
Amlodipine is metabolized through the cytochrome P450 system,
mainly via CYP 3A4 isoenzyme. 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.
Excretion
Elimination from the plasma is biphasic with a terminal elimination
half-life of about 35 – 50 hours. Steady state plasma levels of
amlodipine are reached after 7 to 8 days of consecutive daily
dosing.
6-CONTRAINDICATIONS
AMLODIPRESS
®
is contraindicated in patients:
• Who are hypersensitive to this drug or to any ingredient in the
formulation, including any nonmedicinal ingredient.
• Who are hypersensitive to other dihydropyridines. Amlodipine
besylate is a dihydropyridine calcium channel blocker.
• Who are breast-feeding.
• With severe hypotension (less than 90 mmHg systolic).
• With shock including cardiogenic shock.
• With obstruction of the outflow tract of the left ventricle (e.g. high
grade aortic stenosis).
• With hemodynamically unstable heart failure after acute
myocardial infarction.
7-POSOLOGY
For both hypertension and angina, the recommended initial dose
of AMLODIPRESS
®
(amlodipine besylate) is 5 mg once daily. If
necessary, dose can be increased after 1 – 2 weeks to a maximum
dose of 10 mg once daily.
Use in the Elderly or in Patients with Impaired Renal Function
The recommended initial dose in patients over 65 years of age or
patients with impaired renal function is 5 mg once daily. If required,
increasing in the dose should be done gradually and with caution .
Use in Patients with Impaired Hepatic Function Dosage
requirements have not been established in patients with impaired
hepatic function. When AMLODIPRESS
®
is used in these patients,
the dosage should be carefully and gradually adjusted
depending on patient’s tolerance and response. A lower starting
dose of 2.5 mg once daily should be considered.
Use in Pediatric Patients (6 – 17 years of age) 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; dose should be determined based upon the
medical need of the patients.
8-WARNINGS and PRECAUTIONS
General
Beta-blocker Withdrawal
AMLODIPRESS
®
(amlodipine besylate) gives no protection against
the dangers of abrupt beta-blocker withdrawal and such
withdrawal should be done by the gradual reduction of the dose
of beta- blocker.
Cardiovascular
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.
Use in Patients with Congestive Heart Failure Although generally
calcium channel blockers should only be used with caution in
patients with heart failure, it has been observed that amlodipine
besylate had no overall deleterious effect on survival and
cardiovascular morbidity in both short-term and long-term
clinical trials in these patients. While a significant proportion of
the patients in these studies had a history of ischemic heart
disease, angina or hypertension, the studies were not designed
to evaluate the treatment of angina or hypertension in patients
with concomitant heart failure. Of note, in an amlodipine
long-term, placebo-controlled study in patients with severe
heart failure (NYHA class III and IV), the reported incidence of
pulmonary edema was higher in the amlodipine-treated group
than in the placebo group. Calcium channel blockers, including
amlodipine, may increase the risk of future cardiovascular events
and mortality.
Hypotension AMLODIPRESS
®
may occasionally precipitate
symptomatic hypotension. Careful monitoring of blood pressure
is recommended, especially in patients with a history of
cerebrovascular insufficiency, and those taking medications
known to lower blood pressure.
Peripheral Edema Mild to moderate peripheral edema was the
most common adverse event in the clinical trials (see ADVERSE
REACTIONS). The incidence of peripheral edema was dose-
dependent and ranged in frequency from 3.0 to 10.8% in 5 to 10 mg
dose range. Care should be taken to differentiate this peripheral
edema from the effects of increasing left ventricular dysfunction.
Hepatic/Biliary/Pancreatic
Use in Patients with Impaired Hepatic Function There are no
adequate studies in patients with liver dysfunction and dosage
recommendations have not been established. In a small number
of patients with mild to moderate hepatic impairment given
single dose of 5 mg, amlodipine half-life has been.
AMLODIPRESS
®
should, therefore, be administered with caution in
these patients and careful monitoring should be performed. A
lower starting dose may be required .
Patients with Severe Hepatic Impairment
or Hepatic Failure Because amlodipine
besylate is extensively metabolized by the
liver and the plasma elimination half-life
(t1/2) is 56 hours in patients with impaired
hepatic function, it should be
administered cautiously and at reduced
dosages in patients with severely
impaired hepatic function. Slow dose
titration and careful monitoring are
required in patients with severe hepatic
impairment.
Concomitant Use with Strong Inhibitors
of CYP 3A4 Use of AMLODIPRESS
®
with
drugs that result in strong inhibition of CYP
3A4, such as ketoconazole, clarithromycin,
ritonavir, may lead to increased plasma
levels of amlodipine and associated
serious events. Such concomitant use
should be avoided. An observational
study demonstrated an increased risk of
hospitalization with acute kidney injury
when amlodipine was used concomitant-
ly with clarithromycin in elderly patients (>
65 years of age) compared to when it was
used concomitantly with azithromycin,
odds ratio [amlodipine: 1.61 (95% C.I. 1.29 –
2.02)].
Sexual Health Reversible biochemical
changes in the head of spermatozoa
have been reported in some patients
treated by calcium channel blockers.
Reversible adverse effects on male rat
fertility have also been suggested.
9-SPECIFIC PATIENT POPULATIONS
Pregnants
There is no clinical experience with
amlodipine besylate in pregnant women.
AMLODIPRESS
®
should be used during
pregnancy only if the potential benefit
outweighs the potential risk to the mother
and fetus. Although amlodipine was not
teratogenic in the rat and rabbit, some
dihydropyridine compounds have been
found to be teratogenic in animals. In rats,
amlodipine has been shown to prolong
both the gestation period and the
duration of labor. There was no effect on
the fertility of rats treated with amlodipine.
Nursing Mothers
In human study, the mean maternal daily
dose of amlodipine was 6.0 mg and the
medians of the plasma and milk
concentrations of amlodipine were 15.5
and 11.5 ng/mL, respectively, with median
milk/plasma concentration ratio of 0.85.
Since amlodipine safety in newborns has
not been established, AMLODIPRESS
®
should not be given to nursing mothers. A
decision should be made whether to
discontinue nursing or discontinue the
drug, taking into account the importance of the drug to the
mother.
Pediatrics (0 – 17 years of age) The use of amlodipine besylate is
not recommended in patients less than 6 years of age since safety
and efficacy have not been established in that population. In
pediatric patients aged 6 – 17 years, safety and efficacy studies
beyond 8 weeks of duration, for the treatment of hypertension,
have not been conducted. The prescription in this population
should be based on a careful risk/benefit assessment of the
limited available information. The risk/benefit assessment should
be conducted by a qualified physician.
Geriatrics (≥ 65 years of age)
In elderly patients (≥ 65 years) clearance of amlodipine is
decreased with a resulting increase in AUC In clinical trials the
incidence of adverse reactions in elderly patients was
approximately 6% higher than that of younger population (< 65
years). Adverse reactions include edema, muscle cramps and
dizziness. AMLODIPRESS
®
should be used cautiously in elderly
patients. Dosage adjustment is advisable.
10-DRUG INTERACTIONS
As with all drugs, care should be exercised when treating patients
with multiple medications. Dihydropyridine calcium channel
blockers undergo biotransformation by the cytochrome P450
system, mainly via CYP 3A4 isoenzyme. Coadministration of
amlodipine with other drugs which follow the same route of
biotransformation may result in altered bioavailability of
amlodipine or these drugs. Dosages of similarly metabolized
drugs, particularly those of low therapeutic ratio, and especially in
patients with renal and/or hepatic impairment, may require
adjustment when starting or stopping concomitantly
administered amlodipine to maintain optimum therapeutic blood
levels.
Drugs known to be inhibitors of the cytochrome P450 system
include: azole antifungals, cimetidine, cyclosporine, erythromycin,
quinidine, terfenadine, warfarin. With concomitant use with the
CYP3A4 inhibitor erythromycin in young patients and diltiazem in
elderly patients, the plasma concentration of amlodipine
increased by 22% and 50 % respectively. Strong inhibitors of CYP3A4
(e.g., ketoconazole, itraconazole, ritonavir) may increase the
plasma concentrations of amlodipine to a greater extent than
diltiazem. Amlodipine should be used with caution together with
CYP3A4 inhibitors; and monitoring of therapy is required.
Drugs known to be inducers of the cytochrome P450 system
include: phenobarbital, phenytoin, rifampin, hypericum
perforatum (St John's wort). There is no data available regarding
the effect of CYP3A4 inducers on amlodipine. The concomitant use
of CYP3A4 inducers may give a lower plasma concentration of
amlodipine which in turn can result in decreased blood pressure
lowering effects. Amlodipine should be used with caution together
with CYP3A4 inducers and dose adjustment may be necessary to
maintain efficacy. Hence, monitoring of therapy is required.
Drugs known to be biotransformed via P450 include: benzodiaze-
pines, flecainide, imipramine, propafenone, theophylline.
Amlodipine has a low (rate of first-pass) hepatic clearance and
consequent high bioavailability, and thus, may be expected to
have a low potential for clinically
relevant effects associated with elevation of amlodipine plasma
levels when used concomitantly with drugs that compete for or
inhibit the cytochrome P450 system.
Cimetidine, Warfarin, Cyclosporin, Digoxin: Pharmacokinetic
interaction studies with amlodipine in healthy volunteers have
indicated:
• Cimetidine did not alter the pharmacokinetics of amlodipine.
• Amlodipine did not change warfarin-induced prothrombin
response time.
• Amlodipine does not significantly alter the pharmacokinetics of
cyclosporin.
• Amlodipine did not change serum digoxin levels or digoxin renal
clearance.
Antacids Concomitant administration of Maalox® (magnesium
hydroxide and aluminum hydroxide) had no effect on the
disposition of a single 5 mg dose of amlodipine in 24 subjects.
Beta-blockers: When beta-adrenergic receptor blocking drugs
are administered concomitantly with AMLODIPINE, patients should
be carefully monitored since blood pressure lowering effect of
beta-blockers may be augmented by amlodipine's reduction in
peripheral vascular resistance.
Sildenafil: A single 100 mg dose of sildenafil in subjects with
essential hypertension had no effect on AUCt or Cmax of
amlodipine. When sildenafil (100 mg) was coadministered with
amlodipine, 5 or 10 mg in hypertensive patients, the mean
additional reduction of supine blood pressure was 8 mm Hg
systolic and 7 mm Hg diastolic.
11-ADVERSE REACTIONS
Most adverse reactions reported during therapy were of mild to
moderate severity.
HYPERTENSION
The most common adverse reactions in controlled clinical trials
were: edema (8.9%), and headache (8.3%).
Autonomic Nervous System: flushing (3.1%), increased sweating
(0.9%), dry mouth (0.7%).
Cardiovascular: edema (8.9%), palpitations (2.0%), tachycardia
(0.7%), postural dizziness (0.5%).
Central and Peripheral Nervous System: headache (8.3%), dizziness
(3.0%), paresthesia (0.5%).
Gastrointestinal: nausea (2.4%), abdominal pain (1.1%), dyspepsia
(0.6%), constipation (0.5%). General: fatigue (4.1%), pain (0.5%).
Musculoskeletal: muscle cramps (0.5%).
Psychiatric: somnolence (1.4%).
Skin and Appendages : pruritus (0.7%).
ANGINA
The most common adverse reactions reported in controlled
clinical trials were: edema (9.9%) and headache (7.8%).
Autonomic Nervous System: flushing (1.9%).
Cardiovascular: edema (9.9%), palpitations (2.0%), postural
dizziness (0.6%).
Central and Peripheral Nervous System: headache (7.8%), dizziness
(4.5%), paresthesia (1.0%), hypoesthesia (0.9%).
Gastrointestinal: nausea (4.2%), abdominal pain (2.2%), dyspepsia
(1.4%), diarrhea (1.1%), flatulence (1.0%), constipation (0.9%).
General : fatigue (4.8%), pain (1.0%), asthenia (1.0%).
Musculoskeletal: muscle cramps (1.0%).
Psychiatric: somnolence (1.2%), insomnia (0.9%), nervousness (0.7%).
Respiratory System: dyspnea (1.1%).
Skin and Appendages : rash (1.0%), pruritus (0.8%).
Special Senses: vision abnormal (1.3%), tinnitus (0.6%).
Less common clinical trials Adverse reactions
Amlodipine besylate has been evaluated for safety in about 11,000
patients with hypertension and angina.
The following events occurred in 0.1% of patients in comparative
clinical trials or under conditions of open trials or marketing
experience where a causal relationship is uncertain.
Autonomic Nervous System: dry mouth, sweating increased.
Cardiovascular: arrhythmia (including ventricular
tachycardia and atrial fibrillation), bradycardia, hypotension,
peripheral ischemia, syncope, tachycardia, postural dizziness,
postural hypotension, vasculitis.
Central and Peripheral Nervous System : hypoesthesia, peripheral
neuropathy, tremor, vertigo. Gastrointestinal: anorexia,
constipation, dysphagia, vomiting, gingival hyperplasia.
General: allergic reaction, asthenia, back pain, hot flushes, malaise,
rigors, weight gain.
Hemopoietic: leucopenia, purpura, thrombocytopenia.
Metabolic and Nutritional : hyperglycemia, thirst.
Musculoskeletal System: arthralgia, arthrosis, myalgia.
Psychiatric: sexual dysfunction (male and female), insomnia,
nervousness, depression, abnormal dreams, anxiety,
depersonalization.
Respiratory System: epistaxis.
Skin and Appendages: pruritus, rash erythematous, rash
maculopapular, erythema multiforme.
Special Senses: conjunctivitis, diplopia, eye pain, tinnitus.
Urinary System: micturition frequency, micturition disorder,
nocturia.
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.
The following events occurred in ≤ 0.1% of patients: cardiac failure,
skin discoloration*, urticaria*, skin dryness, Stevens-Johnson
syndrome, alopecia*, twitching, ataxia, hypertonia*, migraine,
apathy, amnesia, gastritis*, pancreatitis*, increased appetite,
coughing*, rhinitis*, parosmia, taste perversion*, and xerophthal-
mia.
*These events were observed in marketing experience as well.
Isolated cases of angioedema have been reported. Angioedema
may be accompanied by breathing difficulty.
12-STORAGE CONDITIONS
Keep this medicine out of the sight and reach of children.
Store below 30°C.
Keep your medicine in a cool dry place and away from light in the
original package to protect it from moisture.
Don’t use this medicine after the expiry date which is stated on the
outer packaging. The expiry date refers to the last day of that
month.
Don’t use this medicine if you notice any visible signs of deteriora-
tion.
Don’t throw away any medicines via wastewater. Ask your
pharmacist how to throw away medicines you no longer use.
These measures will help protect the environment.
Date of Revision: December 01, 2025
1-DESCRIPTION:
AMLODIPRESS
®
5mg is a white uncoated tablet, plain on both side.
2-COMPOSITION
Each tablet contains 5mg of amlodipine Besylate.
Excipients: lactose monohydrate, microcrystalline cellulose,
PVP-K30, magnesium stearate, silicon dioxide.
3-THERAPEUTIC INDICATIONS
• Hypertension: AMLODIPRESS
®
is indicated in the treatment of mild
to moderate essential hypertension.
Combination of amlodipine besylate with a diuretic, a
beta-blocking agent, or an angiotensin converting enzyme
inhibitor has been found to be compatible and showed additive
antihypertensive effect.
• Chronic Stable Angina: AMLODIPRESS
®
is indicated for the
management of chronic stable angina (effort-associated
angina) in patients who remain symptomatic despite adequate
doses of beta-blockers and/or organic nitrates or who cannot
tolerate those agents. AMLODIPRESS
®
may be tried in combination
with beta-blockers in chronic stable angina in patients with
normal ventricular function. When such concomitant therapy is
introduced, care must be taken to monitor blood pressure closely
since hypotension can occur from the combined effects of the
drugs.
4-PHARMACOLOGICAL PROPERTIES
Mechanism of action
AMLODIPRESS
®
(amlodipine besylate) is a calcium ion influx
inhibitor (calcium entry blocker or calcium ion antagonist).
Amlodipine is a member of the dihydropyridine class of calcium
antagonists.
The therapeutic effect of this group of drugs is believed to be
related to their specific cellular action of selectively inhibiting
transmembrane influx of calcium ions into vascular smooth
muscle and cardiac muscle. The contractile processes of these
tissues 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. Serum calcium concentration is not
affected by amlodipine. Within the physiologic pH range,
amlodipine is an ionized compound and its kinetic interaction
with the calcium channel receptor is characterized by the
5mg, 30 tablets Reg. N°:196425/1
Manufacturer and MAH Holder:
Council of Arab Health Ministers
Union of Arab pharmacists
This is a medicine:
- A medicine is a product which
affects your health and its consump-
tion contrary to instructions is
dangerous for you.
- Follow strictly the doctor's prescrip-
tion, the method of use and the
instructions of the pharmacist who
dispensed the medicine.
- The doctor and the pharmacist are
the experts in medicine, their benefits
and risks.
- Do not by yourself interrupt the
period of treatment prescribed.
- Do not repeat the same prescription
without consulting your doctor.
- Keep all medicine out of reach of
children.
PI078/01
