Amlotan 5 mg tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Amlodipine (as amlodipine besilate ph. eur.)
Available from:
Athlone Laboratories Ltd
ATC code:
C08CA; C08CA01
INN (International Name):
Amlodipine (as amlodipine besilate ph. eur.)
Dosage:
5 milligram(s)
Pharmaceutical form:
Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Dihydropyridine derivatives; amlodipine
Authorization status:
Not marketed
Authorization number:
PA0298/015/001
Authorization date:
2006-08-18

PATIENT INFORMATION LEAFLET

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 your 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 that are not listed in this leaflet. See section 4.

What is in this leaflet:

What Amlotan Tablets are and what they are used for

What you need to know before you take Amlotan Tablets

How to take Amlotan Tablets

Possible side effects

How to store Amlotan Tablets

Contents of the pack and other information

The name of your medicine is Amlotan5mg Tablets or Amlotan10mg Tablets. We

refer to them as Amlotan Tablets or Amlotan throughout this leaflet.

Amlotan Tablets contain the active substance amlodipine which belongs to a group of medicines called

calcium antagonists.

Amlotan Tablets may be used to treat:

high blood pressure (hypertension); and

a certain type of chest pain called angina, a rare form of which is Prinzmetal’s or variant angina.

In patients with high blood pressure, these medicines work by relaxing blood vessels, so that blood passes

through them more easily. In patients with angina, Amlotan works by improving blood supply to the heart

muscle which then receives more oxygen and as a result chest pain is prevented. This medicine does not

provide immediate relief of chest pain from angina.

Do not take Amlotan Tablets:

if you have ever had an allergic reaction to amlodipine or any of the ingredients in the tablet

listed in section 6, or to any other calcium antagonist. An allergic reaction may include a rash,

itching, difficulty breathing or swelling of the face, lips, throat or tongue;

if you have very low blood pressure (hypotension) so that you feel faint or dizzy;

if you have cardiogenic shock (a condition where your heart cannot pump enough blood for your

body’s needs);

if you have heart failure due to a heart attack;

if you have narrowing of the heart valve of the aorta (aortic stenosis)

Amlotan 5mg AND 10mg TABLETS

Amlodipine

1.

WHAT AMLOTAN TABLETS ARE AND WHAT THEY ARE USED FOR

2.

WHAT YOU NEED TO KNOW BEFORE YOU TAKE AMLOTAN TABLETS

Warnings and precautions

Talk to your doctor or pharmacist before taking Amlotan tablets if you have had any of the following

conditions:

Recent heart attack

Heart failure

Liver disease

You are elderly and your dose needs to be increased

Severe increase in blood pressure (Hypertensive crisis).

Children and adolescents

Amlotan has not been studied in children under the age of 6 years. Amlotan should only be used for

hypertension in children and adolescents from 6 years to 17 years of age (see section 3). For more

information, talk to your doctor.

Other medicines and Amlotan

Tell your doctor or pharmacist if you are taking or have recently taken other medicines, including

medicines obtained without a prescription.

Amlotan may affect or be affected by other medicines, such as:

diltiazem, verapamil (heart medicines)

ketoconazole, itraconazole (antifungal medicines used to treat thrush and ringworm)

ritonavir, indinavir, nelfinavir (antivirals used in treatment of HIV infections)

rifampicin, erythromycin, clarithromycin (antibiotics)

Hypericum perforatum - St John’s wort (a herbal remedy for mild depression)

dantrolene (infusion for severe body temperature abnormalities)

simvastatin (a drug used to control elevated cholesterol)

tacrolimus, sirolimus, temsirolimus, and everlimus (medicines used to alter the way your immue

system works)

cyclosporine (immunosuppressive drug)

Amlotan may lower your blood pressure even more if you are already taking other medicines to treat

your high blood pressure.

If you see another doctor or go into hospital for any reason, tell them that you are taking Amlotan

Tablets.

Amlotan Tablets with food and drink

You should not drink grapefruit juice or eat grapefruit while taking this medicine. Grapefruit and

grapefruit juice can lead to an increase in the blood levels of Amlotan, which can cause an

unpredictable increase in its blood pressure lowering effect.

Pregnancy and Breast-feeding

Pregnancy

The safety of Amlotan in human pregnancy has not been established. If you think you might be

pregnant, or are planning to get pregnant, you must tell your doctor before you take Amlotan Tablets.

Breast-feeding

Amlotan has been shown to pass into breast milk in small amounts. If you are breast-feeding or about

to start breast-feeding you must tell your doctor before taking Amlotan Tablets.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Amlotan Tablets may affect your ability to drive or use machines. If the tablets make you feel sick,

dizzy or tired, or give you a headache, do not drive or use machines and contact your doctor immediately.

Amlotan contains Sodium

Amlotan 5mg and 10mg tablets contain sodium. This medicine contains less than 1 mmol sodium

(23mg) per tablet, which means it is essentially ‘sodium-free’.

Swallow these tablets with a glass of water at the same time each day. You can take the tablets either

before or after meals. Do not take Amlotan with grapefruit juice.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or

pharmacist if you are not sure.

The recommended dose is:

Adults

One 5mg tablet once a day. Your doctor may increase the dose to one 10mg tablet once a day.

Use in children and adolescents

For children and adolescents, (6-17 years old), the recommended usual starting dose is 2.5mg a day. The

maximum recommended dose is 5mg a day. Amlotan2.5mg is not currently available and the 2.5mg dose

cannot be obtained with Amlotan 5mg as these tablets are not manufactured to break into two equal

halves.

Elderly

As for adults (one 5mg tablet a day). Your doctor will closely monitor your response to any increase in

the dose.

Patients with liver disease

Your doctor may give you a different dose to normal.

It is important to keep taking the tablets. Do not wait until our tablets are finished before seeing your

doctor.

If you take more Amlotan Tablets than you should

If you (or someone else) swallow a lot of tablets all together, or if you think a child has swallowed any of

the tablets, contact your nearest hospital casualty department or your doctor immediately. Take your

medication and the packaging with you to the doctor or casualty department. If you have taken an

overdose, you may appear flushed (your skin will look red), or you may feel dizzy, lightheaded, faint, or

weak. If blood pressure drop is severe enough shock can occur. Your skin could feel cool or clammy and

you could lose consciousness. Seek immediate medical attention if you take too many Amlotan tablets.

If you forget to take Amlotan Tablets

Do not worry. If you forget to take a tablet, leave out that dose completely. Take your next dose at the

right time.

Do not take a double dose to make up for a forgotten dose.

3.

HOW TO TAKE AMLOTAN TABLETS

If you stop taking Amlotan Tablets

Your doctor will advise you how long to take this medicine. Your condition may return if you stop using

this medicine before you are advised.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

Like all medicines, this medicine can cause side effects, although not everybody gets them. If any of

the following reactions happen, stop taking Amlotan Tablets and tell your doctor immediately

or contact the casualty department at your nearest hospital: -

sudden wheeziness, chest pain, shortness of breath, difficulty breathing or swallowing swelling of

the eyelids, face, lips

swelling of the tongue and throat which causes great difficulty breathing

severe skin reactions including intense skin rash, hives, reddening

of the skin

over your whole

body, severe itching, blistering peeling and swelling of the skin, inflammation of mucous

membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis) or other allergic

reactions

heart attack, abnormal heart beat,

inflamed pancreas which can cause severe abdominal and back pain accompanied with feeling

very unwell

The following very common side effects have been reported. If any of these cause you problems or if they

last for more than one week, you should contact your doctor.

Very common: (may affect more than 1 in 10 people)

Oedema (fluid retention)

The following common side effects have been reported. If any of these cause you problems or if they last

for more than one week, you should contact your doctor.

Common (may affect up to 1 in 10 people)

Headache, dizziness, sleepiness (especially at the beginning of treatment)

Palpitations (irregular or forceful heart beat), flushing

Abdominal pain, feeling sick (nausea)

Altered bowel habits, diarrhea, constipation, indigestion

Tiredness, weakness

Visual disturbances, double vision

Muscle cramps

Ankle swelling

Other side effects that have been reported include the following list. If any of these get serious, or if you

notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Uncommon (may affect up to 1 in 100 people)

Mood changes, anxiety, depression, sleeplessness

Trembling, taste abnormalities, fainting

Numbness or tingling sensation in your limbs, loss of pain sensation

Ringing in the ears

Low blood pressure

Sneezing/runny nose caused by inflammation of the lining of the nose (rhinitis)

4.

POSSIBLE SIDE EFFECTS

Cough

Dry mouth, vomiting (being sick)

Hair loss, increased sweating, itchy skin, red patches on skin, skin discolouration

Disorder in passing urine, increased need to urinate at night, increased number of times of passing

urine

Inability to obtain an erection, discomfort or enlargement of the breasts in men

Pain, feeling unwell

Joint or muscle pain, back pain

Weight increase or decrease

Rare (may affect up to 1 in 1,000 people)

Confusion

Very rare (may affect up to 1 in 10,000 people)

Decreased numbers of white blood cells, decrease in blood platelets which may result in

unusual bruising or easy bleeding

Excess sugar in blood (hyperglycaemia)

A disorder of the nerves which can cause muscular weakness, tingling or numbness

Swelling of the gums

Abdominal bloating (gastritis)

Abnormal liver function, inflammation of the liver (hepatitis) yellowing of the skin

(jaundice) liver enzyme increase which may have an effect on some medical tests

Increased muscle tension

Inflammation of the blood vessels, often with skin rash

Sensitivity to light

Disorders combining rigidity, tremor and/or movement disorders

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the

medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA

Pharmacovigilance, Earlsfort Terrace IRL - Dublin 2; Tel: +353 16764971; Fax: +353 1 6762517. Website:

www.hpra.ieE-mail: medsafety@hpra.ie.

Keep this medicine out of the sight and reach of children.

Do not take your medicine after the expiry date, which is stated on the pack after ‘EXP’. The expiry date

refers to the last day of that month.

Do not store the tablets above

C. Store in the original

package.

Do not use this medicine if you notice any visible signs of deterioration.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use.

These measures will help to protect the environment.

5. HOW TO STORE AMLOTAN TABLETS

What Amlotan Tablets contain

The active substance is Amlodipine as amlodipine mesilate monohydrate. Each tablet

contains 5mg or 10mg of amlodipine.

The other ingredients are microcrystalline cellulose, anhydrous calcium hydrogen phosphate,

sodium starch glycolate type A and magnesium stearate.

What Amlotan Tablets look like and the contents of the pack

Amlotan Tablets are white to off-white, round and biconvex and come in two strengths – 5mg and

10mg.

The 5mg tablets have the number ‘5’ embossed on one side and the 10mg tablets have the number ‘10’

embossed on one side, together with a breakline.

Amlotan Tablets are available in blister packs containing 10, 14, 20, 28, 30, 50, 98, 100 or 200 tablets.

Not all pack sizes may be marketed.

Marketing authorisation holder:

Athlone Pharmaceuticals Limited, Ballymurray, Co. Roscommon, Ireland.

This medicinal product is authorised in the member states of the EEA under the following names.

United Kingdom:

Amlodipine 5mg Tablets

Amlodipine 10mg Tablets

Ireland:

Amlotan 5mg Tablets

Amlotan 10mg Tablets

This leaflet was last revised: February 2019

6. CONTENTS OF THE PACK AND OTHER INFORMATION

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amlotan 5 mg tablet

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg amlodipine (as amlodipine mesilate monohydrate).

Excipients:

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

The tablets are white to off-white, round biconvex and embossed with “5” on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Hypertension

Chronic stable angina pectoris

Vasospastic (Prinzmetal’s) angina

4.2 Posology and method of administration

Posology 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 (as a single dose) depending on the individual patient's response.

In hypertensive patients, amlodipine has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an

angiotensin converting enzyme inhibitor. 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.

No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta blockers, and

angiotensin-converting enzyme inhibitors.

Special populations Elderly patients

Amlodipine 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).

Patients with 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 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

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.

Paediatric population

Children and adolescents with hypertension from 6 years to 17 years of age.

The recommended antihypertensive oral dose in paediatric patients aged 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 as these tablets are not manufactured

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to break into two equal halves.

Children under 6 years old

No data are available.

Method of administration

Tablet for oral administration.

4.3 Contraindications

Amlodipine is contraindicated in patients with:

hypersensitivity to dihydropyridine derivatives, amlodipine or any of the excipients listed in section 6.1

Severe hypotension

shock (including cardiogenic shock)

obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis)

haemodynamically unstable heart failure after acute myocardial infarction

4.4 Special warnings and precautions for use

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

Patients with cardiac failure

Patients with cardiac 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.

Patients with hepatic impairment

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

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 degree of renal impairment. Amlodipine is not dialysable.

4.5 Interaction with other medicinal products and other forms of interactions

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.

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Dantrolene (infusion)

In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after

administration

verapamil

intravenous

dantrolene.

risk

hyperkalaemia,

recommended

that

co-administration

calcium

channel

blockers

such

amlodipine

avoided

patients

susceptible

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

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.

Mechanistic Target of Rapamycin (mTOR) Inhibitors

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A4 substrates. Amlodipine is a weak CYP3A4 inhibitor.

With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.

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.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

4.6 Fertility, pregnancy and lactation

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 greater risk for the

mother and foetus.

Breast-feeding

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 woman.

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).

4.7 Effects on ability to drive and use machines

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.

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4.8 Undesirable effects

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 (≥1/1000 to <1/100); rare (≥1/10 000 to <1/1000);

very

rare

(<1/10,000);

known

(cannot

estimated

from

available

data

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Very rare

Leukocytopenia,thrombocytopenia

Immune system

disorders

Very rare

Allergic reactions

Metabolism and nutrition disorders

Very rare

Hyperglycaemia

Psychiatric disorders

Uncommon

Depression, mood changes

(including anxiety), insomnia

Rare

Confusion

Nervous system disorders

Common

Somnolence, dizziness, headache (especially at thebeginning of the

treatment)

System organ class

Frequency

Adverse reactions

Uncommon

Tremor, dysgeusia, syncope, hypoesthesia,

paresthesia

Very rare

Hypertonia,peripheral neuropathy

Eye disorders

Common

Visual disturbance (including

diplopia)

Ear and labyrinth disorders

Uncommon

Tinnitus

Cardiac disorders

Common

Palpitations

Uncommon

Arrhythmia (including bradycardia, ventricular

tachycardia and atrial

fibrillation)

Very rare

Myocardial infarction

Vascular disorders

Common

Flushing

Uncommon

Hypotension

Very rare

Vasculitis

Respiratory, thoracic and mediastinal

disorders

Common

Dyspnoea,

uncommon

Cough, rhinitis

Gastrointestinal disorders

Common

Abdominal pain, nausea, dyspepsia, altered bowel

habits (including diarrhoea and constipation)

Uncommon

Vomiting, dry

mouth

Very rare

Pancreatitis, gastritis, gingivalhyperplasia

Hepatobiliary disorders

Very rare

Hepatitis, jaundice, hepatic

enzymes increased*

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Skin and subcutaneous tissue disorders

Uncommon

Alopecia, purpura, skin

discolouration, hyperhidrosis, pruritus, rash,

exanthema, urticaria

Very rare

Angiodema, erythema multiforme, exfoliative

dermatitis, Stevens-Johnson syndrome, Quincke

oedema,photosensitivity

Not Known

Toxic epidermal necrolysis

Musculoskeletal and

connective tissue disorders

Common

Ankle swelling, muscle

cramps

Uncommon

Arthralgia, myalgia, back pain

Renal and urinary disorders

Uncommon

Micturition disorder, nocturia,

increased urinary frequency

Reproductive system and breast disorders

Uncommon

Impotence, gynecomastia

General disorders and administration site

conditions

Very common

Oedema

Common

fatigue, asthenia

Uncommon

Chest pain, pain,

malaise

Investigations

Uncommon

Weight increased, weight

decreased

*mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected

adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace IRL - Dublin 2; Tel: +353 16764971; Fax: +353 1 6762517.

Website: www.hpra.ie, E-mail: medsafety@hpra.ie.

4.9 Overdose

In humans, experience with intentional overdose is limited.

Symptoms

Available data suggest that gross overdoses 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 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.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of

amlodipine 10mg has been shown to reduce the absorption rate of amlodipine.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers with mainly vascular effects. 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 total ischaemic

burden by the following two actions:

1. Amlodipine 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 also probably involves dilatation of the main coronary arteries and coronary arterioles, both in

normal and ischaemic regions. This dilation 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 onset angina, 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.

Clinical efficacy and safety

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, double-blind, 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- 10mg, 673 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.

Table 1. Incidence of significant clinical outcomes

for CAMELOT

Cardiovascular event rates,No. (%)

Amlodipine vs.

Placebo

Outcomes

Amlodipine

Placebo

Enalapril

Hazard Ratio (95%

P Value

Primary Endpoint

Adverse cardiovascular events

110 (16.6)

151 (23.1)

136 (20.2)

0.69 (0.54-0.88)

.003

Individual Components

Coronary revascularization

78 (11.8)

103 (15.7)

95 (14.1)

0.73 (0.54-0.98)

Hospitalization for angina

51 (7.7)

84 (12.8)

86 (12.8)

0.58 (0.41-0.82)

.002

Nonfatal MI

14 (2.1)

19 (2.9)

11 (1.6)

0.73 (0.37-1.46)

Stroke or TIA

6 (0.9)

12 (1.8)

8 (1.2)

0.50 (0.19-1.32)

Table 1. Incidence of significant clinical outcomes for

CAMELOT

Cardiovascular event rates,No. (%)

Amlodipine vs. Placebo

Cardiovascular death

5 (0.8)

2 (0.3)

5 (0.7)

2.46 (0.48-12.7)

Hospitalization for CHF

3 (0.5)

5 (0.8)

4 (0.6)

0.59 (0.14-2.47)

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Resuscitated cardiac arrest

4 (0.6)

1 (0.1)

New-onset peripheral vascular disease

5 (0.8)

2 (0.3)

8 (1.2)

2.6 (0.50-13.4)

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 or underlying ischaemic disease, on stable doses of ACE inhibitors,

digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was

associated increased reports of pulmonary oedema.

Treatment to prevent heart attack trial (ALLHAT)

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.

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 2.5mg dose,

and 5.0 mg 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.

5.2 Pharmacokinetic properties

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

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extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites

excreted in 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 “area under the curve” (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 1to 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.

In patients with renal failure

Amlodipine is extensively metabolised to inactive metabolites. 10% of the parent compound is excreted unchanged in urine.

Changes in amlodipine concentration are not correlated with degree of renal impairment. Therefore the normal dosage is

recommended. Amlodipine is not dialysable.

5.3 Preclinical safety data

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 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 10mg 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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose

Anhydrous calcium hydrogen phosphate

Sodium starch glycolate type A

Magnesium stearate.

6.2 Incompatibilities

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Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 30°C. Store in the original package.

6.5 Nature and contents of container

White opaque PVC/PVDC- aluminium blister. Pack sizes: 10, 14, 20, 28, 30, 50, 98, 100 and 200 tablets. Not all pack sizes may

be marketed.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal

product and other handling of the product

No special requirements.

6.6 Special precautions for disposal

No special requirements.

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

7 MARKETING AUTHORISATION HOLDER

Athlone Laboratories Ltd.

Ballymurray

Co. Roscommon

8 MARKETING AUTHORISATION NUMBER

PA0298/015/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18th August 2006

Date of last renewal: 11th May 2011.

10 DATE OF REVISION OF THE TEXT

September 2019

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