Amlodipine Bluefish 5 mg tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Amlodipine besilate
Available from:
Bluefish Pharmaceuticals AB
ATC code:
C08CA; C08CA01
INN (International Name):
Amlodipine besilate
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:
Marketed
Authorization number:
PA1436/016/001
Authorization date:
2010-05-07

PACKAGE LEAFLET: INFORMATION FOR THE USER

Amlodipine Bluefish 5 mg tablets

Amlodipine Bluefish 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 or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

In this leaflet:

What Amlodipine Bluefish is and what it is used for

What you need to know before you take Amlodipine Bluefish

How to take Amlodipine Bluefish

Possible side effects

How to store Amlodipine Bluefish

Contents of the pack and other information

1.

WHAT AMLODIPINE BLUEFISH IS AND WHAT IT IS USED FOR

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

medicines called calcium antagonists.

Amlodipine Bluefish 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 your medicine works by relaxing blood vessels, so that blood

passes through them more easily. In patients with angina Amlodipine Bluefish works by improving

blood supply to the heart muscle which then receives more oxygen and as a result chest pain is

prevented. Your medicine does not provide immediate relief of chest pain from angina.

2.

WHAT YOU NEED TO KNOW BEFORE YOU TAKE AMLODIPINE BLUEFISH

Do not take Amlodipine Bluefish

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

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

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 Bluefish has not been studied in children under the age of 6

years. Amlodipine Bluefish should only 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 Bluefish

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

including medicines obtained without a prescription.

Amlodipine Bluefish 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)

simvastatin (a cholesterol lowering medicine)

tacrolimus (medicine used to alter the way your immune system works)

cyclosporine (an immunosuppressant)

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

medicines to treat your high blood pressure.

Amlodipine Bluefish with food and drink

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

Bluefish. 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 Bluefish.

Pregnancy

The safety of amlodipine 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 Amlodipine

Bluefish.

Breast-feeding

It is not known whether amlodipine is passed into breast milk. If you are breast-feeding or about to

start breast-feeding you must tell your doctor before taking Amlodipine Bluefish.

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

Driving and using machines

Amlodipine Bluefish 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.

3.

HOW TO TAKE AMLODIPINE BLUEFISH

Always take your medicine exactly as your doctor has told you. You should check with your doctor

or pharmacist if you are not sure.

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

Amlodipine Bluefish 10 mg once daily.

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

same time each day with a drink of water. Do not take Amlodipine Bluefish 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 2.5 mg is not currently available and the 2.5 mg dose cannot be obtained with

Amlodipine Bluefish 5mg tablets as these tablets are not manufactured to break into two equal

halves.

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 Bluefish 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 Bluefish tablets

If you forget to take Amlodipine Bluefish

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 missed dose.

If you stop taking Amlodipine Bluefish

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

using your 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, Amlodipine Bluefish can cause side effects, although not everybody gets them.

Visit your doctor immediately if you experience any of the following very rare, severe 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) 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 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)

Ankle swelling (oedema), tiredness

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, weakness

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

Visual disturbances, double vision, ringing in the ears

Low blood pressure

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

Altered bowel habits, diarrhoea, constipation, indigestion, 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

Weakness, pain, feeling unwell

Joint or muscle pain, muscle cramps, back pain

Weight increase or decrease

Rare: may affect up to 1 in 1000 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 (red blood cell damage)

Excess sugar in blood (hyperglycaemia)

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

Cough, 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

Not known: frequency cannot be estimated from the available data

trembling, rigid posture, mask-like face, slow movements and a shuffling, unbalanced walk

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

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

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5.

HOW TO STORE AMLODIPINE BLUEFISH

Keep out of the reach and sight of children.

Do not use Amlodipine Bluefish after the expiry date which is stated on the carton. The expiry date

refers to the last day of that month.

No special storage conditions.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how

to dispose of medicines no longer required. These measures will help to protect the environment.

6.

CONTENTS OF THE PACK AND OTHER INFORMATION

What Amlodipine Bluefish contains

The active substance is amlodipine as amlodipine besylate

Each tablet contains 5 mg amlodipine as amlodipine besylate

Each tablet contains 10 mg amlodipine as amlodipine besylate

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

starch glycolate (Type A), magnesium stearate

What Amlodipine Bluefish looks like and contents of the pack

5 mg: white or almost white, flat, bevelled edges, cylinder shaped tablet imprinted with “C” on one

side and “58” on the other side.

10 mg: white or almost white, flat, bevelled edges, round tablet imprinted with “C” on one side and

“59” on the other side.

PVC/PVdC - aluminium blister

14, 20, 28, 30, 50 and 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Bluefish Pharmaceuticals AB

P.O.Box 49013

10028 Stockholm

Sweden

Manufacturer

Bluefish Pharmaceuticals AB

Gavlegatan 22

113 30 Stockholm

Sweden

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

names:

Name

of

the

Member

State

Name of the medicinal product

Austria

Amlodipin Bluefish 5 mg/10 mg Tabletten

Czech

Republic

Amlodipin Bluefish 5 mg/ 10 mg tablety

Denmark

Amlodipin Bluefish

Finland

Amlodipin Bluefish 5 mg/10 mg tablettia/tabletter

Hungary

Amlodipin Bluefish 5 mg/10 mg tabletta

Ireland

Amlodipine Bluefish 5 mg/10 mg tablets

Italy

Amlodipine Bluefish 5 mg/10 mg compresse

Poland

Amlodipine Bluefish

Slovakia

Amlodipine Bluefish 5 mg/ 10 mg tabletky

Spain

Amlodipine Bluefish 5 mg/ 10 mg comprimidos

Sweden

(RMS)

Amlodipin Bluefish 5 mg/ 10 mg tabletter

This leaflet was last approved in

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amlodipine Bluefish 5 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5 mg of amlodipine (as amlodipine besilate)

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

White or almost white, flat, cylinder shaped tablet with bevelled edges and approximate dimensions of 7.9 x 5.6 mm,

imprinted with “C” on one side and “58” 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 Bluefish once daily which may be

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

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

beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Amlodipine Bluefish 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 Bluefish is required upon concomitant administration of thiazide diuretics, beta

blockers, and angiotensin-converting enzyme inhibitors.

Special populations

Elderly

Amlodipine Bluefish 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 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.

Renal impairment

Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal

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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 section 5.1 and 5.2).

Doses of amlodipine 2.5mg are not possible with this medicinal product

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

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,

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.

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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,

macrolides like erythromycin or

clarithromycin,

verapamil

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

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

grapefruit

juice is

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,

recommended that

the coadministration 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.

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%)

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

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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.

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

Insomnia, mood changes (including anxiety), depression

Rare

Confusion

Nervous system disorders

Common

Somnolence,

dizziness,

headache

(especially

beginning of the treatment)

Uncommon

Tremor, dysgeusia, syncope, hypoesthesia, paresthesia

Very Rare

Hypertonia,

peripheral neuropathy

Not known

Extrapyramidal disorder

Eye disorders

Uncommon

Visual disturbance (including diplopia)

Ear and labyrinth disorders

Uncommon

Tinnitus

Cardiac disorders

Common

Palpitations

Very Rare

Myocardial

infarction,

arrhythmia (including bradycardia,

ventricular tachycardia and atrial fibrillation)

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*mostly consistent with cholestasis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal

product

is important.

allows continued

monitoring of

the benefit/risk balance of

the medicinal

product.

Healthcare professionals are asked to report

suspected adverse reactions 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

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.

Vascular disorders

Common

Flushing

Uncommon

Hypotension

Very Rare

Vasculitis

Respiratory,

thoracic

and

medicinal disorders

Uncommon

Dyspnoea, rhinitis

Very Rare

Cough

Gastrointestinal disorders

Common

Abdominal pain,

nausea

Uncommon

Vomiting,

dyspepsia,

altered

bowel

habits

(including

diarrhoea and constipation), dry mouth

Very Rare

Pancreatitis, gastritis, gingival hyperplasia

Hepatobiliary disorders

Very Rare

Hepatitis, jaundice, hepatic enzymes increased*

Skin

and

subcutaneous

tissue

disorders

Uncommon

Alopecia,

purpura,

skin

discolouration,

hyperhydrosis,

pruritus, rash, exanthema

Very Rare

Angioedema,

erythema multiforme,

urticaria,

exfoliative

dermatitis,

Stevens-Johnson syndrome,

Quincke oedema,

photosensitivity

Not known

Toxic Epidermal Necrolysis

Musculoskeletal

and

connective

tissue disorders

Common

Ankle swelling

Uncommon

Arthralgia, myalgia, muscle cramps, 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

Common

Oedema, fatigue

Uncommon

Chest pain, asthenia, pain, malaise

Investigations

Uncommon

Weight increase, weight decrease

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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.

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 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 of amlodipine also probably involves dilatation of the main coronary arteries and coronary

arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with

coronary artery spasm (Prinzmetal's or variant angina).

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the

supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not

a feature of amlodipine administration.

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and

time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet

consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for

use in patients with asthma, diabetes, and gout.

Use in patients with coronary artery disease (CAD)

The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been

evaluated in an independent, 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, 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.

Table 1.

Incidence of significant clinical outcomes for CAMELOT

Cardiovascular event rates,

No. (%)

Amlopidine vs. Placebo

Outcomes

Amlopidine

Placebo

Enalapril

Hazard

Ratio (95%

P Value

Primary Endpoint

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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 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 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-

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)

2.6 (0.50-

13.4)

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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 6years and older)-

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.

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.

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 12 months to 17 years (with 34

patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given

either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance

(CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in

exposure between individuals was observed. Data reported in children below 6 years is limited.

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

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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

Tablet:

Microcrystalline cellulose

Calcium hydrogen phosphate, anhydrous

Sodium starch glycolate (Type A)

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

No special storage conditions.

6.5 Nature and contents of container

White opaque PVC/PVdC aluminium blister.

14, 20, 28, 30, 50 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Bluefish Pharmaceuticals AB

P.O. Box 49013

10028 Stockholm

Sweden

8 MARKETING AUTHORISATION NUMBER

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PA1436/016/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 7

May 2010

Date of last renewal: 26

October 2012

10 DATE OF REVISION OF THE TEXT

April 2018

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