Hypertension.
Prophylaxis of chronic stable angina pectoris.
Prinzmetal's (variant) angina when diagnosed by a cardiologist.
In hypertensive patients, AMEP has been used in combination with a thiazide diuretic, alpha blocker,
beta-adrenoceptor blocking agent, or an angiotensin converting enzyme inhibitor. For angina, AMEP
may be used as monotherapy or in combination with other antianginal drugs in patients with angina that
is refractory to nitrates and/or adequate doses of beta blockers.
AMEP is well tolerated in patients with heart failure and a history of hypertension or ischaemic heart
disease.

adults: For both hypertension and angina the usual initial dose is 5mg AMEP once daily which may
be increased to a maximum dose of 10mg depending on the individual patient's response.
No dose adjustment of AMEP is required upon concomitant administration of thiazide diuretics, beta
blockers, and angiotensin-converting enzyme inhibitors.
Use in children: Children with hypertension from 6 years to 17 years of age.The recommended
antihypertensive oral dose in paediatric patients ages 6-17 years is 2.5 mg once daily as a starting
dose, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in
excess of 5 mg daily have not been studied in paediatric patients (see section 5.1 Pharmacodynamic
Properties and section 5.2 Pharmacokinetic Properties). The effect of amlodipine on blood pressure in
patients less than 6 years of age is not known.
The 2.5 mg dose cannot be obtained with AMEP tablets 5 mg as these tablets are not manufactured to
break into two equal halves.
Use in the elderly: AMEP, used at similar doses in elderly or younger patients, is equally well tolerated.
Therefore normal dosage regimens are recommended.
Patients with hepatic impairment: See section 4.4 Special warnings and precautions for use.
Patients with renal impairment: Changes in amlodipine plasma concentrations are not correlated with
degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.

AMEP is contra-indicated in patients with a known sensitivity to dihydropyridines, amlodipine or any of the excipients. AMEP should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina). Pregnancy and lactation

Use in patients with Heart Failure: In a long-term, placebo controlled study (PRAISE-2) of AMEP in
patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with
increased reports of pulmonary oedema despite no significant difference in the incidence of worsening
heart failure as compared to placebo. See section 5.1 “Pharmacodynamic Properties”.
Use in patients with impaired hepatic function: As with all calcium antagonists, amlodipine's half-life
is prolonged in patients with impaired liver function and dosage recommendations have not been
established. The drug should therefore be administered with caution in these patients.
There are no data to support the use of AMEP alone, during or within one month of a myocardial
infarction.
The safety and efficacy of AMEP in hypertensive crisis has not been established.

AMEP has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensinconverting
enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroidal antiinflammatory
drugs, antibiotics, and oral hypoglycaemic drugs.
In vitro data from studies with human plasma, indicate that amlodipine has no effect on protein binding
of digoxin, phenytoin, warfarin or indometacin.
Consumption of grapefruit/grapefruit juice should be avoided while taking AMEP. 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.
Special Studies: Effect of other agents on amlodipine
Cimetidine: Co-administration of AMEP with cimetidine did not alter the pharmacokinetics of AMEP.
Sildenafil: When AMEP 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 10mg doses of AMEP with 80mg of atorvastatin resulted in
no significant change in the steady state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of AMEP with digoxin did not change serum digoxin levels or digoxin renal
clearance in normal volunteers.
Warfarin: In healthy male volunteers, the co-administration of AMEP does not significantly alter the
effect of warfarin on prothrombin response time. Co-administration of AMEP with warfarin did not
change the warfarin prothrombin response time.
Ciclosporin: Pharmacokinetic studies with ciclosporin have demonstrated that AMEP does not
significantly alter the pharmacokinetics of ciclosporin.
Drug/Laboratory test Interactions: None known.

Although some dihydropyridine compounds have been found to be teratogenic in animals, data in the rat
and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical
experience with the preparation in pregnancy or lactation. Accordingly, AMEP should not be
administered during pregnancy, or lactation, or to women of childbearing potential unless effective
contraception is used.

Clinical experience with AMEP indicates that therapy is unlikely to impair a patient's ability to drive or
use machinery.

Adverse events that have been reported in amlodipine trials are categorised below, according to system
organ class and frequency. Frequencies are defined as: very common (>10%); common (>1%, <10%);
uncommon (>0.1%, <1%); rare (>0.01%, <0.1%) and very rare (<0.01%).
Blood and the Lymphatic System
Disorders
thrombocytopenia Very Rare
Immune System Disorders allergic reaction Very Rare
Metabolism and Nutrition Disorders Hyperglycaemia Very Rare
Psychiatric Disorders insomnia, mood changes Uncommon
Nervous System Disorders somnolence, dizziness,
headache
Common
tremor, taste perversion,
syncope, hypoaesthesia,
paraesthesia
Uncommon
peripheral neuropathy Very Rare

Eye Disorders visual disturbances Uncommon
Ear and Labyrinth Disorders Tinnitus Uncommon
Cardiac Disorders Palpitations Common
myocardial infarction,
arrhythmia, ventricular
tachycardia and atrial fibrillation)
Very Rare
Vascular Disorders Flushing Common
hypotension Uncommon
Vasculitis Very Rare
Respiratory, Thoracic and Mediastinal
Disorders
dyspnoea, rhinitis Uncommon
Coughing Very Rare
Gastrointestinal Disorders abdominal pain, nausea Common
vomiting, dyspepsia, altered
bowel habits, dry mouth
Uncommon
pancreatitis, gastritis, gingival
hyperplasia
Very Rare
Hepato-biliary Disorders hepatitis, jaundice and hepatic
enzyme elevations (mostly
consistent with cholestasis)
Very Rare
Skin and Subcutaneous Tissue
Disorders
alopecia, purpura, skin
discolouration, increased
sweating, pruritus, rash
Uncommon
angioedema, erythema
multiforme, urticaria
Very Rare
Musculoskeletal and Connective Tissue
Disorders
arthralgia, myalgia, muscle
cramps, back pain
Uncommon
Renal and Urinary Disorders micturition disorder, nocturia,
increased urinary frequency
Uncommon
Reproductive System and Breast
Disorders
impotence, gynaecomastia Uncommon
General Disorders and Administration oedema, fatigue Common

Site Conditions
chest pain, asthenia, pain,
malaise
Uncommon
Investigations weight increase, weight
decrease
Uncommon

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.
Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion
of amlodipine 10mg has been shown to significantly decrease amlodipine absorption. Gastric lavage
may be worthwhile in some cases.Clinically significant hypotension due to AMEP overdosage calls for
active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation
of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be
helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its
use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel
blockade. Since AMEP is highly protein-bound, dialysis is not likely to be of benefit.

5.1 Pharmacodynamic properties
AMEP 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 AMEP is due to a direct relaxant effect on vascular
smooth muscle. The precise mechanism by which AMEP relieves angina has not been fully determined
but AMEP reduces total ischaemic burden by the following two actions.
1) AMEP dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload)
against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces
myocardial energy consumption and oxygen requirements.
2) The mechanism of action of AMEP 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 AMEP administration.
In patients with angina, once daily administration of AMEP 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.
AMEP 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 Heart Failure: Haemodynamic studies and exercise based controlled clinical trials
in NYHA Class II-IV heart failure patients have shown that AMEP 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 AMEP 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 AMEP in patients with NYHA III and IV
heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease,
on stable doses of ACE inhibitors, digitalis, and diuretics, AMEP had no effect on total cardiovascular
mortality. In this same population AMEP was associated with increased reports of pulmonary oedema
despite no significant difference in the incidence of worsening heart failure as compared to placebo.
A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering
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 < 35 mg/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 amlodipinebased
therapy and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20 .
In a study involving 268 children aged 6-17 years with predominantly secondary hypertension,
comparison of a 2.5mg dose, 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.
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.
Use in the elderly: The time to reach peak plasma concentrations of amlodipine is similar in elderly and
younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and
elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with
congestive heart failure were as expected for the patient age group studied.
A population PK study has been conducted in 74 hypertensive children aged from 12 months to 17
years (with 34 patients aged 6 to 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 22.5 and 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.

None

Microcrystalline cellulose, E460
Dibasic calcium phosphate anhydrous
Sodium starch glycollate
Magnesium stearate, E572

Not applicable

3 years

Do not store above 25oC

AMEP 5 mg is available as:
Packs of 14, 28 & 56 tablets. Aluminium/PVC blister strips

No special requirements