AMLODIPINE PFIZER 10 Milligram Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
AMLODIPINE BESILATE
Available from:
Pfizer Limited
ATC code:
C08CA01
INN (International Name):
AMLODIPINE BESILATE
Dosage:
10 Milligram
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Dihydropyridine derivatives
Authorization status:
Authorised
Authorization number:
PA0019/055/002
Authorization date:
2011-12-09

Pfleet Number: 2017-0032096

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Package leaflet: Information for the user

Amlodipine Pfizer® 5 mg and 10 mg tablets

Amlodipine

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or pharmacist.

- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Amlodipine Pfizer is and what it is used for

2. What you need to know before you take Amlodipine Pfizer

3. How to take Amlodipine Pfizer

4. Possible side effects

5. How to store Amlodipine Pfizer

6. Contents of the pack and other information

1. What Amlodipine Pfizer is and what it is used for

Amlodipine Pfizer contains the active substance amlodipine which belongs to a group of medicines

called calcium antagonists.

Amlodipine Pfizer is used to treat high blood pressure (hypertension) or 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 this medicine works by relaxing blood vessels, so that blood

passes through them more easily. In patients with angina Amlodipine Pfizer 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.

2. What you need to know before you take Amlodipine Pfizer

Do not take Amlodipine Pfizer

If you are allergic (hypersensitive) to amlodipine, or any of the other ingredients of this

medicine listed in section 6, or to any other calcium antagonists. This may be itching,

reddening of the skin or difficulty in breathing.

If you have severe low blood pressure (hypotension).

If you have narrowing of the aortic heart valve (aortic stenosis) or cardiogenic shock (a

condition where your heart is unable to supply enough blood to the body).

If you suffer from heart failure after a heart attack.

Warnings and precautions

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Talk to your doctor or pharmacist before taking Amlodipine Pfizer.

You should inform your doctor if you have or have had any of the following conditions:

Recent heart attack

Heart failure

Severe increase in blood pressure (Hypertensive crisis)

Liver disease

You are elderly and your dose needs to be increased

Children and adolescents

Amlodipine Pfizer has not been studied in children under the age of 6 years. Amlodipine Pfizer

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 Amlodipine Pfizer

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

including medicines obtained without a prescription.

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

ketoconazole, itraconazole (anti-fungal medicines)

ritonavir, indinavir, nelfinavir (so called protease inhibitors used to treat HIV)

rifampicin, erythromycin, clarithromycin (antibiotics)

hypericum perforatum (St. John’s Wort)

verapamil, diltiazem (heart medicines)

dantrolene (infusion for severe body temperature abnormalities)

tacrolimus, sirolimus, temsirolimus, and everolimus (medicines used to alter the way

yourimmune system works)

simvastatin (cholesterol lowering medicine)

cyclosporine (an immunosuppressant)

Amlodipine Pfizer may lower your blood pressure even more if you are already taking other

medicines to treat your high blood pressure.

Amlodipine Pfizer with food and drink

Grapefruit juice and grapefruit should not be consumed by people who are taking Amlodipine

Pfizer. This is because grapefruit and grapefruit juice can lead to an increase in the blood levels of

the active ingredient amlodipine, which can cause an unpredictable increase in the blood pressure

lowering effect of Amlodipine Pfizer.

Pregnancy and breast-feeding

Pregnancy

The safety of amlodipine in human pregnancy has not been established.

Pfleet Number: 2017-0032096

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If you think you might be pregnant, or are planning to get pregnant, you must tell your doctor

before you take Amlodipine Pfizer.

Breast-feeding

Amlodipine 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 Amlodipine Pfizer.

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

Driving and using machines

Amlodipine Pfizer 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.

Amlodipine Pfizer contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, which means it is essentially

‘sodium-free’.

3. How to take Amlodipine Pfizer

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 initial dose is Amlodipine Pfizer 5 mg once daily. The dose can be increased to

Amlodipine Pfizer 10 mg once daily.

This medicine can be used before or after food and drinks. You should take this medicine at the

same time each day with a drink of water. Do not take Amlodipine Pfizer with grapefruit juice.

Use in children and adolescents

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

The maximum recommended dose is 5 mg a day.

Amlodipine Pfizer

5 mg tablets can be divided

into halves to provide a 2.5 mg dose.

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

your doctor.

If you take more Amlodipine Pfizer than you should

Taking too many tablets may cause your blood pressure to become low or even dangerously low.

You may feel dizzy, lightheaded, faint or weak. If blood pressure drop is severe enough shock can

occur. Your skin could feel cool and clammy and you could lose consciousness. Seek immediate

medical attention if you take too many Amlodipine Pfizer tablets.

If you forget to take Amlodipine Pfizer

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.

Pfleet Number: 2017-0032096

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If you stop taking Amlodipine Pfizer

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.

4. Possible side effects

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

Visit your doctor immediately if you experience any of the following side effects after taking this

medicine.

Sudden wheeziness, chest pain, shortness of breath or difficulty in breathing

Swelling of eyelids, face or 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 may cause severe abdominal and back pain accompanied with

feeling very unwell

The following very common side effect has been reported. If this causes you problems or if it lasts

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 (awareness of your heart beat), flushing

Abdominal pain, feeling sick (nausea)

Altered bowel habits, diarrhoea, 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.

Pfleet Number: 2017-0032096

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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/running nose caused by inflammation of the lining of the nose (rhinitis)

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 blood vessels, often with skin rash

Sensitivity to light

Disorders combining rigidity, tremor, and/or movement disorders

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via HPRA

Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you can help provide

more information on the safety of this medicine.

5. How to store Amlodipine Pfizer

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

Pfleet Number: 2017-0032096

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Do not use this medicine after the expiry date which is stated on the pack after ‘EXP’. The expiry

date refers to the last day of that month.

Tablets

Do not store above 25°C.

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 protect the environment.

6. Contents of the pack and other information

What Amlodipine Pfizer contains

The active substance in Amlodipine Pfizer 5 mg tablets is amlodipine (as besilate).

The active substance in Amlodipine Pfizer 10 mg tablets is amlodipine (as besilate).

The other ingredients are calcium hydrogen phosphate anhydrous, magnesium stearate,

microcrystalline cellulose and sodium starch glycolate Type A.

What Amlodipine Pfizer looks like and contents of the pack

5 mg tablets: White to off-white, emerald-shaped tablets engraved AML 5 and breaker score on one

side and Pfizer logo on the other side.

10 mg tablets: White to off-white, emerald-shaped tablets engraved AML-10 on one side and Pfizer

logo on the other side.

Amlodipine Pfizer 5 mg tablets are available in blisters containing 4, 10, 14, 20, 28, 30, 50, 60, 98,

100, 300, 500 tablets, calendar packs containing 28 and 98 tablets and in unit dose blister strips

containing 50x1 and 500x1 tablets.

Amlodipine Pfizer 10 mg tablets are available in blisters containing 4, 10, 14, 20, 28, 30, 50, 60, 90,

98, 100, 300, 500 tablets, calendar packs containing 28 and 98 tablets and in unit dose blister strips

containing 50x1 and 500x1 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

Manufacturer

R-Pharm Germany GmbH

Pfleet Number: 2017-0032096

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Heinrich-Mack-Str. 35

89257 Illertissen

Germany

This medicinal product is authorised in the Member States of the EEA under the following

names:

Tablets:

Austria, Bulgaria, Denmark, Estonia, Finland, Germany, Hungary, Iceland, Italy, Latvia, Lithuania,

Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Sweden: Norvasc

Czech Republic: Zorem

Ireland, Malta, United Kingdom: Istin

Ireland: Amlodipine Pfizer 5 mg tablets, Amlodipine Pfizer 10 mg tablets

Italy: Amlodipina Pfizer Italia

Spain: Norvas 5 mg comprimidos, Norvas 10 mg comprimidos

United Kingdom: Amlodipine 5 mg tablets, Amlodipine 10 mg tablets

This leaflet was last revised in 01/2018.

Ref: dxAML 15_0

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amlodipine Pfizer 10 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains amlodipine besilate equivalent to 10 mg amlodipine.

Excipients:

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White to off-white, emerald-shaped tablets engraved AML-10 on one side and Pfizer logo on the other 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 Pfizer once daily which may be increased

to a maximum dose of 10 mg depending on the individual patient’s response.

In hypertensive patients, Amlodipine Pfizer has been used in combination with a thiazide diuretic, alpha blocker, beta

blocker, or an angiotensin converting enzyme inhibitor. For angina, Amlodipine Pfizer 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

Amlodipine Pfizer

is required upon concomitant

administration of

thiazide diuretics,

beta

blockers, and angiotensin-converting enzyme inhibitors.

Special populations

Elderly patients

Amlodipine Pfizer

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.

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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 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).

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 to 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 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.

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 interaction

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals,

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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 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 CYP3A substrates. Amlodipine is a weak

CYP3A 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.

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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.

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).

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.

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 (

1/1,000 to <1/100); rare (

1/10,000 to

<1/1,000); very rare (<1/10,000); not known (cannot be estimated from the 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 the

beginning of the treatment)

Uncommon

Tremor, dysgeusia, syncope, hypoaesthesia, paraesthesia

Very rare

Hypertonia, peripheral neuropathy

Eye disorders

Common

Visual disturbance (including diplopia)

Ear and labyrinth disorders

Uncommon

Tinnitus

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*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 1 6764971;

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, gingival hyperplasia

Hepatobiliary disorders

Very rare

Hepatitis, jaundice, hepatic enzyme increased*

Skin and subcutaneous tissue

disorders

Uncommon

Alopecia, purpura, skin discolouration, hyperhidrosis,

pruritus, rash, exanthema, urticaria

Very rare

Angioedema, 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, gynaecomastia

General disorders and

administration site conditions

Very

common

Oedema

Common

Fatigue, asthenia

Uncommon

Chest pain, pain, malaise

Investigations

Uncommon

Weight increased, weight decreased

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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 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

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

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers with mainly vascular

effects. ATC Code: C08CA01.

Amlodipine is a calcium ion influx inhibitor

the dihydropyridine group (slow channel

blocker

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 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

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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-centre,

randomized,

double-blind,

placebo-controlled study of

1997 patients;

Comparison of Amlodipine vs.

Enalapril

to Limit

Occurrences of Thrombosis (CAMELOT).

Of these patients,

were treated with amlodipine 5

10 mg,

673 patients were treated with enalapril

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 Pfizer 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 Pfizer 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 Pfizer 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 Pfizer had no effect on total cardiovascular mortality. In

Table 1.

Incidence of significant clinical outcomes for CAMELOT

Cardiovascular event rates,

No. (%)

Amlopidine vs. Placebo

Outcomes

Amlopidine

Placebo

Enalapril

Hazard Ratio

(95% CI)

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)

Cardiovascular death

5 (0.8)

2 (0.3)

5 (0.7)

2.46

(0.48

12.7)

Hospitalization for

3 (0.5)

5 (0.8)

4 (0.6)

0.59

(0.14

2.47)

Resuscitated cardiac

arrest

4 (0.6)

1 (0.1)

New-onset peripheral

vascular disease

5 (0.8)

2 (0.3)

8 (1.2)

(0.50

13.4)

Abbreviations: CHF, congestive heart failure; CI, confidence interval; MI, myocardial infarction;

TIA, transient ischemic attack.

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this same population Amlodipine Pfizer was associated with 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

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%

[0.90-1.07]

p=0.65. Among secondary endpoints,

the incidence of

heart

failure (component

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 2.5 mg

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 has 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

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%.

Elderly population

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.

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Paediatric population

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.

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 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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose,

Calcium hydrogen phosphate anhydrous,

Sodium starch glycolate, Type A,

Magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

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PVC-PVDC/Aluminium foil blisters containing 4, 10, 14, 20, 28, 30, 50, 60, 90, 98, 100, 300, 500 tablets

PVC-PVDC/Aluminium foil blisters in calendar packs containing 28 and 98 tablets

PVC-PVDC/Aluminium foil blister strips containing 50x1 and 500x1 tablets

Not all pack sizes may be marketed

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA0019/055/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9

December 2011

Date of last renewal: 8th February 2013

10 DATE OF REVISION OF THE TEXT

February 2018

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