Amlodipine Krka 10 mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Amlodipine
Available from:
Krka d.d., Novo mesto
ATC code:
C08CA; C08CA01
INN (International Name):
Amlodipine
Dosage:
10 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:
PA1347/034/002
Authorization date:
2013-03-01

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70 mm ± 0,5 mm

70 mm ± 0,5 mm

- PMS-433U-KRKA

PL. AMLODIPINE KRKA TBL IE first page

Package leaflet: Information for the patient

Amlodipine Krka 5 mg

tablets

Amlodipine Krka 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.

What is in this leaflet

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

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

3. How to take Amlodipine Krka

4. Possible side effects

5. How to store Amlodipine Krka

6. Contents of the pack and other information

1. What Amlodipine Krka is and what it is used

Amlodipine Krka contains the active substance amlodipine which

belongs to a group of medicines called calcium antagonists.

Amlodipine Krka 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 Krka 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 Krka

Do not take Amlodipine Krka if you:

are allergic 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.

have severe low blood pressure (severe 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)

suffer from heart failure after an acute heart attack

Warnings and precautions

Talk to your doctor or pharmacist before taking Amlodipine Krka.

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 Krka has not been studied in children under the age of

6 years. Amlodipine Krka 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 Krka

Tell your doctor or pharmacist if you are taking, have recently

taken or might take any other medicines.

Amlodipine Krka 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 used for

infections caused by bacteria)

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 your immune system works)

simvastatin (used to lower levels of cholesterol)

cyclosporine (an immunosuppressant)

Amlodipine Krka may lower your blood pressure even more if you

are already taking other medicines to treat your high blood

pressure.

Taking Amlodipine Krka with food and drink

Grapefruit juice and grapefruit should not be consumed by people

who are taking Amlodipine Krka. 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 Krka.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant

or are planning to have a baby, ask your doctor or pharmacist for

advice before taking this medicine.

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 Krka.

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 Krka.

Driving and using machines

Amlodipine Krka 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 Krka contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per

tablet, that is to say essentially “sodium-free”.

3. How to take Amlodipine Krka

Always take this medicine exactly as your doctor has told you.

Check with your doctor or pharmacist if you are not sure.

The usual initial dose is Amlodipine Krka 5 mg once daily. The

dose can be increased to Amlodipine Krka 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 Krka 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. The tablet can be divided into equal doses.

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 Krka 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 Krka tablets.

If you forget to take Amlodipine Krka

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.

If you stop taking Amlodipine Krka

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.

Article name.: PL. AMLODIPINE KRKA TBL

Prepared by: A. Mohorič

Date: 30.11.2018

DPMockUp081966_1

iKRKk

CONFIDENTIAL

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130 mm ± 0,5 mm

smer branja kode

PL. AMLODIPINE KRKA TBL IE

second page

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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 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, 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 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

Fluid retention (oedema)

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

Ankle swelling

Muscle cramps

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/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

(red blood cell damage)

Excess sugar in blood (hyperglycaemia)

A disorder of the nerves which can cause 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

Not known: cannot be estimated from the available data

Trembling, rigid posture, mask-like face, slow movements and a

shuffling, unbalanced walk

Reporting of side effects

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 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 Krka

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

Do not use this medicine after the expiry date which is stated on

the packaging after EXP. The expiry date refers to the last day of

that month.

Keep the blisters in the outer carton in order to protect from light.

This medicinal product does not require any special temperature

storage conditions.

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 Krka contains

The active substance is amlodipine.

Amlodipine Krka 5 mg tablets

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

Amlodipine Krka 10 mg tablets

Each tablet contains 10 mg amlodipine (as amlodipine besilate).

The other ingredients (excipients) are microcrystalline cellulose

(E460), pregelatinised maize starch, sodium starch glycolate

(type A), colloidal anhydrous silica and magnesium stearate

(E470b).

See section 2 ”Amlodipine Krka contains sodium”.

What Amlodipine Krka looks like and contents of the pack

5 mg:

The tablets are white, round (diameter 8.0 mm), slightly biconvex

with beveled edges, scored on one side.

The tablet can be divided into equal doses.

10 mg:

The tablets are white, round (diameter 10.5 mm), slightly biconvex

with beveled edges.

The tablets are available in carton boxes of 28, 30, 56, 60, 84, 90,

98 or 100 tablets in blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto,

Slovenia

This medicinal product is authorised in the Member States of

the EEA under the following names:

Estonia, Lithuania, Bulgaria,

Latvia, Poland, Slovakia

Alneta

Slovenia

Amlodipin Krka

Hungary

Amlodipin Pharma-Regist

Ireland

Amlodipine Krka

This leaflet was last revised in

CONFIDENTIAL

Health Products Regulatory Authority

30 September 2019

CRN008T51

Page 1 of 10

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amlodipine Krka 10 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg amlodipine (as amlodipine besilate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

Tablets are white, round (diameter 10.5 mm), slightly biconvex with beveled edges.

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 Krka once daily which may be increased to a

maximum dose of 10 mg 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 Krka is required upon concomitant administration of thiazide diuretics, beta blockers, and

angiotensin-converting enzyme inhibitors.

Special populations

Elderly

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).

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

dosage is recommended. Amlodipine is not dialysable.

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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)

- Haemodynamically unstable heart failure after acute myocardial infarction

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

4.4 Special warnings and precautions for use

The safety and efficacy of amlodipine in hypertensive crisis have 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 dialysable.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium-free".

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).

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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 add 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.

Clarithromycin: Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving

clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co administered with

clarithromycin.

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.

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 mother.

Fertility

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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 (≥1/1000 to <1/100),

- rare (≥1/10,000 to <1/1000),

- very rare (<1/10,000).

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 at the beginning of the treatment)

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

Common

Dyspnoea

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Page 5 of 10

disorders

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 enzymes 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, gynecomastia

General

disorders and

administration

site conditions

Very common

Oedema

Common

Fatigue, asthenia

Uncommon

Chest pain, pain, malaise

Investigations

Uncommon

Weight increase, weight decrease

*mostly consistent with cholestasis

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, Fax: +353 1 6762517;

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

4.9 Overdose

In humans, experience with intentional overdose of amlodipine is limited.

Symptoms

Available data suggest that gross overdosage could result in excessive peripheral vasodilation 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 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

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30 September 2019

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Page 6 of 10

5.1 Pharmacodynamic properties

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

Code: C08CA01.

Mechanism of action

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.

Pharmacodynamic effects

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 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.

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

5-10 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% 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 CHF

3 (0.5)

5 (0.8)

4 (0.6)

0.59 (0.14-2.47)

Resuscitated cardiac arrest

4 (0.6)

1 (0.1)

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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 in patients 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 of underlying ischaemic disease, on stable doses of ACE inhibitors,

digitalis, and diuretics, amlodipine had no effect on total or 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-cause mortality between amlodipine-based therapy

and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20.

Paediatric population (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 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.

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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

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 in this study.

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/h respectively

in males and 16.4 and 21.3 L/h 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

Cellulose, microcrystalline (E460)

Maize starch, pregelatinised

Sodium starch glycolate (type A)

Silica, colloidal anhydrous

Magnesium stearate (E470b)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

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5 years

6.4 Special precautions for storage

Keep the blisters in the outer carton in order to protect from light.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Blister (OPA/Al/PVC//Al foil): 28, 30, 56, 60, 84, 90, 98 or 100 tablets, in a carton box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

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

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7 MARKETING AUTHORISATION HOLDER

Krka d.d., Novo mesto

Šmarješka cesta 6

8501 Novo mesto

Slovenia

8 MARKETING AUTHORISATION NUMBER

PA1347/034/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 1

March 2013

Date of last renewal: 17

October 2017

10 DATE OF REVISION OF THE TEXT

September 2019

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