-Preventive treatment of angina: stable angina and spontaneous angina (including
Prinzmtal’s angina).
-Hypertension

Posology
Adults
For both hypertension and angina the usual initial dose is 5 mg Amodip once daily which may
be increased to a maximum dose of 10 mg depending on the individual patient's response.
In hypertensive patients, Amodip has been used in combination with a thiazide diuretic, alpha
blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Amodip
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.
No dose adjustment of Amodip is required upon concomitant administration of thiazide
diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.

Special populations
Elderly
Amodip used at similar doses in elderly or younger patients is equally well tolerated. Normal
dosage regimens are recommended in the elderly, but increase of the dosage should take
place with care (see sections 4.4 and 5.2).
Hepatic impairment
Dosage recommendations have not been established in patients with mild to moderate
hepatic impairment; therefore dose 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 has not been studied in severe hepatic impairment.
Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe
hepatic impairment.
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.
Paediatric population
Children and adolescents 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 sections 5.1 and 5.2).
Doses of amlodipine 2.5 mg are not possible with this medicinal product.
Children under 6 years old
No data are available.
Method of administration
Hard capsule for oral administration.

The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Patients with cardiac 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
The half life of amlodipine is prolonged and AUC values are higher in patients with impaired
liver function; dosage recommendations have not been established. 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.
Use in elderly patients
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).
Use in renal failure
Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma
concentrations are not correlated with degree of renal impairment. Amlodipine is not
dialyzable.

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. 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: There is no data available regarding the effect of CYP3A4 inducers on
amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericum
perforatum) may give a lower plasma concentration of amlodipine.
Amlodipine should be used with caution together with CYP3A4 inducers.
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.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin,
digoxin, warfarin or cyclosporin.
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 to 20 mg daily in patients on amlodipine.

Pregnancy category C
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 greater risk for the mother and foetus.
Breast-feeding
It is not known whether amlodipine is excreted in breast milk. 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.

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.

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.

In humans experience with intentional overdose is limited

Symptoms
Available data suggest that gross over dosage 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

Clinically significant hypotension due to amlodipine over dosage 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.
Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal
up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the
absorption rate of amlodipine.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers
with mainly vascular effects. ATC Code: C08CA01.
Amlodipine capsules are 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 mechanisms of the antihypertensive action of Amlodipine capsules are due to a direct
relaxant effect on vascular smooth muscle. The precise mechanism by which Amlodipine
capsules relieves angina has not been fully determined but Amlodipine capsules reduces
total ischaemic burden by the following two actions.
1) Amlodipine capsules dilate peripheral arterioles and thus, reduce 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 Amlodipine capsules 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 capsules
administration.
In patients with angina, once daily administration of Amlodipine capsules 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 capsules have 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, multi-center, randomized, doubleblind,
placebo-controlled 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.

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 capsules did not lead to clinical
deteriorations 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
capsules 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 capsules 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, Amlodipine capsules had no effect on total cardiovascular mortality. In this same
population Amlodipine capsules were 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
chlorthalidone-based 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.

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.
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.
Use in 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%.
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.
Use in children
A population PK study has been conducted in 74 hypertensive children aged from 1 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.

Reproductive toxicology
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged
duration of labor 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 a mg/m2 basis). In another rat study in which male
rats were treated with amlodipine besilate 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 a 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

6.1 List of excipients:
Ingredients
Quantity
mg/Capsule
Specification
Source(s)
Microcrystalline cellulose 75.556 USP
Pregelatinized Maize Starch 20.000 BP
Magnesium Stearate 0.500 BP

Not Applicable.

Store below 30°C.

The immediate packaging material is PVC/PVDC/ALU blisters.
Pack size: 30 Capsules.

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