- Essential hypertension
- Chronic stable and vasospastic anginal pectoris
- Vasospastic (Prinzmetal's) angina
 

Adults
For both hypertension and angina, the usual initial dose is 5 mg amlodipine once daily which may
be increased to a maximum dose of 10 mg depending on the individual patient's response. For
angina, Amlodipine may be used as monotherapy or in combination with other antianginal
medicinal products in patients with angina that is refractory to nitrates and/or to adequate doses of
beta-blockers.
In hypertensive patients, Amlodipine has been used in combination with a thiazide diuretic, Alphablocker, beta-blockers, or angiotensin-converting enzyme inhibitors.
No dose adjustment of Amlodipine is required upon concomitant administration of thiazide
diuretics, beta-blockers, and angiotensin-converting enzyme inhibitors.

Special populations

Paediatric population:
Children with hypertension from 6 years to 17 years of age.
The recommended antihypertensive oral dose in pediatric patients ages 6-17 years is 2.5 mg once
daily as a starting dose, up-titrated to 5 mg once daily if the blood pressure goal is not achieved after 4
weeks. Doses in excess of 5 mg daily have not been studied in pediatric patients (see section 5.1
Pharmacodynamic Properties and section 5.2 Pharmacokinetic Properties).
The 2.5 mg dose cannot be obtained with Amlodipine tablets 5 mg and 10mg as these tablets are not
manufactured to break into two equal halves.

Children under 6 years old:
The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

Use in the elderly
Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated. Therefore
normal dosage regimens are recommended, but the increase of the dosage should take place with care
(see sections 4.4 and 5.2).

Patients with hepatic impairment
Dosage recommendations have not been established in patients with mild to moderate hepatic
impairment;thereforedose selection should be cautious and should start at the lower end of the dosing
range (see sections 4.4 and 5.2). The pharmacokinetics of amlodipine have not been studied in severe
hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients
with severe hepatic impairment.
See section 4.4 "Special warnings and special precautions for use".

Patients with renal impairment
Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment,
therefore the normal dosage is recommended. Amlodipine is not dialysable.

Method of administration
Tablet for oral administration.
 

The safety and efficacy of amlodipine in hypertensive crisis has not been established.

Use in patients with heart failure.
Patients with heart failure should be treated with caution. In a long-term, placebo-controlled study in
patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary
oedema was higher in the amlodipine treated group than in the placebo group (see section 5.1).
Calcium channel blockers, including amlodipine, should be used with caution in patients with
congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Use in patients with impaired hepatic function
As with all calcium antagonists, amlodipine's half-life is prolonged and AUC values are higher in
patients with impaired liver function and dosage recommendations have not been established. The
drug should therefore be administered with caution in these patients.
Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be
used, both on initial treatment and when increasing the dose. Slow dose titration and careful
monitoring may be required in patients with severe hepatic impairment.
There are no data to support the use of amlodipine alone, during or within one month of myocardial
infarction.

Elderly patients
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).
Patients with renal impairment
Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma
concentrations are not correlated with the degree of renal impairment. Amlodipine is not dialysable.
There are no data to support the use of amlodipine alone, during or within one month of myocardial
infarction.
 

In vitro data from studies with human plasma, indicate that amlodipine has no effect on protein
binding of digoxin, phenytoin, warfarin or indomethacin.

Consumption of grapefruit/grapefruit juice should be avoided while taking amlodipine. The intake of
grapefruit juice may result in increased plasma amlodipine concentrations, which may enhance the
blood pressure lowering effects of amlodipine. This interaction has been observed with other
dihydropyridine calcium antagonists and represents a class effect

Effects of other medicinal products on amlodipine:
CYP3A4 inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole
antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to
significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical
translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and
dose adjustment may thus be required.

CYP3A4 inducers
Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine
may vary. Therefore, blood pressure should be monitored and dose regulation considered both during
and after concomitant medication, particularly with strong CYP3A4 inducers (e.g. rifampicin,
Hypericum perforatum).
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as
bioavailability may be increased in some patients resulting in increased blood pressure lowering
effects.

Dantrolene (infusion)
In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with
hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of
hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as
amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of
malignant hyperthermia.

Effects of amlodipine on other medicinal products
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of
other medicinal products with antihypertensive properties.

Tacrolimus
There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the
pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid the toxicity
of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of
tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Cyclosporine
No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy
volunteers or other populations with the exception of renal transplant patients, where variable trough
concentration increases (average 0% -40%) of cyclosporine were observed. Consideration should be
given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine
dose reductions should be made as necessary.

Simvastatin
Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77%
increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in
patients on amlodipine to 20 mg daily.

Cimetidine
Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Sildenafil
When amlodipine and sildenafil were used in combination, each agent independently exerted its own
blood pressure-lowering effect.

Special Studies: Effect of amlodipine on other agents

Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80mg of atorvastatin
resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or
digoxin renal clearance in normal volunteers.

Warfarin: In healthy male volunteers, the co-administration of amlodipine does not significantly alter
the effect of warfarin on prothrombin response time. Co-administration of amlodipine with warfarin
did not change the warfarin prothrombin response time.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin
or warfarin.
 

Pregnancy
The safety of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses (see section 5.3).
Use in pregnancy is only recommended when there is no safer alternative and when the disease itself
carries great risk for the mother and foetus.

Breastfeeding
Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has
been estimated with an interquartile range of 3 - 7%, with a maximum of 15%. The effect of
amlodipine on infants is unknown. A decision on whether to continue/discontinue breast-feeding or to
continue/discontinue therapy with amlodipine should be made taking into account the benefit of
breast-feeding to the child and the benefit of amlodipine therapy to the mother.

Fertility
Reversible biochemical changes in the head of spermatozoa have been reported in some patients
treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of
amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).
 

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients
taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be
impaired. Caution is recommended especially at the start of treatment.
 

Summary of the safety profile
The most commonly reported adverse reactions during treatment are somnolence, dizziness,
headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

Tabulated list of adverse reactions
The following adverse reactions have been observed and reported during treatment with amlodipine
with the following frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).
Within each frequency grouping, adverse reactions are presented in order of decreasing
seriousness.

*mostly consistent with cholestasis
Exceptional cases of extrapyramidal syndrome have been reported.

To report any side effect(s):
• Saudi Arabia:

- The National Pharmacovigilance and Drug Safety Centre (NPC)
- SFDA Call Center: 19999
- E-mail: npc.drug@sfda.gov.sa
- Website: https://ade.sfda.gov.sa/

• United Arab Emirates
- Pharmacovigilance & Medical Device section
- P.O.Box: 1853
- Tel: 80011111
- Email : pv@mohap.gov.ae
- Drug Department Ministry of Health & Prevention Dubai, UAE
 

• Other GCC states
Please contact the relevant competent authority
 

In humans experience with intentional overdose is limited.

Symptoms
Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and
possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and
including shock with fatal outcome have been reported.

Treatment
Administration of activated charcoal to healthy volunteers immediately or up to two hours after
ingestion of amlodipine10mg has been shown to significantly decrease amlodipine absorption.

Gastric lavage may be worthwhile in some cases. Clinically significant hypotension due to amlodipine
overdosage callsfor active cardiovascular support including frequent monitoring of cardiac and
respiratory function, elevation ofextremities, and attention to circulating fluid volume and urine
output. A vasoconstrictor may be helpful in restoringvascular tone and blood pressure, provided that
there is no contraindication to its use. Intravenous calcium gluconatemay be beneficial in reversing
the effects of calcium channel blockade. Since amlodipine is highly protein-bound, dialysisis not
likely to be of benefit.
 

Pharmacotherapeutic group: calcium channel blockers – Dihydropyridine derivatives. ATC code:
C08CA01.

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

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on
vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been
fully determined but amlodipine reduces the total ischaemic burden by the following two actions:

• Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload)
against which theheart works. Since the heart rate remains stable, this unloading of the heart reduces
myocardial energy consumptionand oxygen requirements.
• The mechanism of action of amlodipine also probably involves dilatation of the main coronary
arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases
myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
In patients with hypertension, once daily dosing provides clinically significant reductions of blood
pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow
onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to
angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency
and glyceryl trinitrate tablet consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids
and is suitable for use in patients with asthma, diabetes, and gout.

Use in patients with coronary artery disease (CAD)
The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease
(CAD) has been evaluated in an independent, multicenter, randomized, double-blind, placebocontrolled study of 1997 patients;Comparison of Amlodipine vs. Enalapril to Limit Occurrences of
Thrombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 5-10 mg, 673 patients
were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to
standard care of statins, beta-blockers, diuretics and aspirin, for 2 years. The key efficacy results are
presented in Table 1. The results indicate that amlodipine treatment was associated with fewer
hospitalizations for angina and revascularization procedures in patients with CAD..

Abbreviations: CHF, congestive heart failure;CI, confidence interval;MI, myocardial infarction;TIA, transient
ischemic attack.

Use in patients with heart failure:
Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure
patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise
tolerance, left ventricular ejection fraction and clinical symptomatology.
A placebo-controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart
failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an
increase in risk of mortality or combined mortality and morbidity with heart failure.
In a follow-up, long term, placebo-controlled study (PRAISE-2) of Amlodipine in patients with
NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of
underlying ischaemic disease, on stable doses ofACE inhibitors, digitalis, and diuretics, amlodipine
had no effect on total cardiovascular mortality. In this same population, amlodipine was associated
with increased reports of pulmonary oedema despite no significant difference in the incidence of
worsening heart failure as compared to placebo.

Treatment to prevent heart attack trial (ALLHAT):
A randomized double-blind morbidity-mortality study called the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug
therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor)
as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate
hypertension.
A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of
4.9 years. The patients had at least one additional CHD risk factor, including: previous myocardial
infarction or stroke (> 6 months prior to enrollment) or documentation of other atherosclerotic CVD
(overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35mg/dL (11.6%), left ventricular hypertrophy
diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no
significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidonebased therapy: RR 0.98 95%CI (0.90-1.07) p=0.65. Among secondary endpoints, the incidence of
heart failure (component of a composite combined cardiovascular endpoint) was significantly higher
in the amlodipine group as compared to the chlorthalidone group(10.2% % vs 7.7%, RR 1.38, 95% CI
[1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between
amlodipine-based therapy and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20.

Use in children (aged 6 years and older):
In a study involving 268 children aged 6-17 years with predominantly secondary hypertension,
comparison of a 2.5mgdose, and 5.0mg dose of amlodipine with placebo, showed that both doses
reduced Systolic Blood Pressure significantly more than placebo. The difference between the two
doses was not statistically significant.
The long-term effects of amlodipine on growth, puberty and general development have not been
studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular
morbidity and mortality in adulthood have also not been established.

Absorption, distribution, plasma protein binding
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels
between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%.
The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately
97.5% of circulating amlodipine is bound to plasma proteins.

The bioavailability of amlodipine is not affected by food intake.

Biotransformation/elimination
The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily
dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the
parent compound and 60% of metabolites excreted in the urine.

Hepatic impairment
Very limited clinical data are available regarding amlodipine administration in patients with hepatic
impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a
longer half-life and an increase in AUC of approximately 40-60%.

Paediatric population
A population PK study has been conducted in 74 hypertensive children aged from 1 to 17 years (with
34 patients aged 6to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25
and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of
age the typical oral clearance (CL/F) was 22.5and 27.4 L/hr respectively in males and 16.4 and 21.3
L/hr respectively in females. Large variability in exposure between individuals was observed. Data
reported in children below 6 years is limited.

Elderly population
The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger
subjects. Amlodipineclearance tends to be decreased with resulting increases in AUC and elimination
half-life in elderly patients. Increase in AUC and elimination half-life in patients with congestive heart
failure were as expected for the patient age group studied.
 

Reproductive toxicology
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of
labour and decreased pup survival at dosages approximately 50 times greater than the maximum
recommended dosage for humans based on mg/kg.

Impairment of fertility
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 mg/m2 basis). In another rat study in which male rats were treated with amlodipine
besylate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma
follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in
the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis
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 mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug-related effects at either the gene or chromosome levels.
*Based on patient weight of 50 kg
 

Microcrystalline cellulose, Dibasic calcium phosphate anhydrous, Sodium starch glycolate and
Magnesium stearate.
 

Not applicable.
 

Keep out of the sight and reach of children.
Do not Store above 30ºC
 

Carton box containing three blisters each of 10 tablets.
 

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements