Amlodipine/Valsartan Denk 10 mg/160 mg Filmdragerad tablett

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Bipacksedel Bipacksedel (PIL)

20-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

20-04-2018

Aktiva substanser:
amlodipinbesilat; valsartan
Tillgänglig från:
Denk Pharma GmbH & Co KG
ATC-kod:
C09DB01
INN (International namn):
amlodipine besylate; valsartan
Dos:
10 mg/160 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
valsartan 160 mg Aktiv substans; amlodipinbesilat 13,9 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 7 tabletter; Blister, 98 tabletter; Blister, 90 tabletter; Blister, 60 tabletter; Blister, 56 tabletter; Blister, 30 tabletter; Blister, 14 tabletter; Blister, 28 tabletter; Blister, 7 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
54739
Tillstånd datum:
2017-01-27

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

03-08-2018

Produktens egenskaper Produktens egenskaper - engelska

03-08-2018

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

17-11-2016

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Package leaflet: information for the user

Amlodipine/Valsartan Denk 5 mg/80

mg film-coated tablets

Amlodipine/Valsartan Denk 5

mg/160 mg film-coated tablets

Amlodipine/Valsartan Denk 10

mg/160 mg film-coated tablets

amlodipine/valsartan

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

What Amlodipine/Valsartan Denk is and what it is used for

What you need to know before you take Amlodipine/Valsartan Denk

How to take Amlodipine/Valsartan Denk

Possible side effects

How to store Amlodipine/Valsartan Denk

Contents of the pack and other information

1.

What Amlodipine/Valsartan Denk is and what it is used for

Amlodipine/Valsartan Denk tablets contain two substances called amlodipine and valsartan. Both

of these substances help to control high blood pressure.

Amlodipine belongs to a group of substances called “calcium channel blockers”.

Amlodipine stops calcium from moving into the blood vessel wall which stops the blood

vessels from tightening.

Valsartan belongs to a group of substances called “angiotensin-II receptor antagonists”.

Angiotensin II is produced by the body and makes the blood vessels tighten, thus increasing

the blood pressure. Valsartan works by blocking the effect of angiotensin II.

This means that both of these substances help to stop the blood vessels tightening. As a result,

the blood vessels relax and blood pressure is lowered.

Amlodipine/Valsartan Denk is used to treat high blood pressure in adults whose blood pressure

is not controlled enough with either amlodipine or valsartan on its own.

2.

What you need to know before you take Amlodipine/Valsartan Denk

Do not take Amlodipine/Valsartan Denk

if you are allergic to amlodipine or to any other calcium channel blockers. This may

involve itching, reddening of the skin or difficulty in breathing.

if you are allergic to valsartan or any of the other ingredients of this medicine (listed in

section6). If you think you may be allergic, talk to your doctor before taking

Amlodipine/Valsartan Denk.

if you have severe liver problems or bile problems such as biliary cirrhosis or cholestasis.

if you are more than 3 months pregnant. (It is also better to avoid Amlodipine/Valsartan

Denk in early pregnancy, see Pregnancy section).

if you have severe low blood pressure (hypotension).

if you have narrowing of the aortic 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.

if you have diabetes or impaired kidney function and you are treated with a blood

pressure lowering medicine containing aliskiren.

If any of the above applies to you, do not take Amlodipine/Valsartan Denk and talk to your

doctor

Warnings and precautions

Talk to your doctor before taking Amlodipine/Valsartan Denk:

if you have been sick (vomiting or diarrhoea).

if you have liver or kidney problems.

if you have had a kidney transplant or if you had been told that you have a narrowing of

your kidney arteries.

if you have a condition affecting the renal glands called “primary hyperaldosteronism”.

if you have had heart failure or have experienced a heart attack. Follow your doctor’s

instructions for the starting dose carefully. Your doctor may also check your kidney

function.

if your doctor has told you that you have a narrowing of the valves in your heart (called

“aortic or mitral stenosis”) or that the thickness of your heart muscle is abnormally

increased (called “obstructive hypertrophic cardiomyopathy”).

if you have experienced swelling, particularly of the face and throat, while taking other

medicines (including angiotensin converting enzyme inhibitors). If you get these

symptoms, stop taking Amlodipine/Valsartan Denk and contact your doctor straight

away. You should never take Amlodipine/Valsartan Denk again.

if you are taking any of the following medicines used to treat high blood pressure:

an ACE inhibitor (for example enalapril, lisinopril, ramipril), in particular if you

have diabetes-related kidney problems.

aliskiren.

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes

(e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take Amlodipine/Valsartan Denk”.

If any of these apply to you, tell your doctor before taking

Amlodipine/Valsartan Denk. Children and adolescents

The use of Amlodipine/Valsartan Denk in children and adolescents is not recommended (aged

below 18 years old).

Other medicines and Amlodipine/Valsartan Denk

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

medicines. Your doctor may need to change your dose and/or to take other precautions. In some

cases you may have to stop taking one of the medicines. This applies especially to the medicines

listed below:

ACE inhibitors or aliskiren (see also information under the headings “Do not take

Amlodipine/Valsartan Denk” and “Warnings and precautions”);

diuretics (a type of medicine also called “water tablets” which increases the amount of

urine you produce);

lithium (a medicine used to treat some types of depression);

potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium

and other substances that may increase potassium levels;

certain types of painkillers called non-steroidal anti-inflammatory medicines (NSAIDs)

or selective cyclooxygenase-2 inhibitors (COX-2 inhibitors). Your doctor may also check

your kidney function;

anticonvulsant agents (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin,

primidone);

St. John’s wort;

nitroglycerin and other nitrates, or other substances called “vasodilators”;

medicines used for HIV/AIDS (e.g. ritonavir, indinavir, nelfinavir);

medicines used to treat fungal infections (e.g. ketoconazole, itraconazole);

tacrolimus (used to control your body’s immune response, enabling your body to accept the

transplanted organ).

medicines used to treat bacterial infections (such as rifampicin, erythromycin,

talithromycin);

clarithromycin (for infections caused by bacteria);

verapamil, diltiazem (heart medicines);

simvastatin (a medicine used to control high cholesterol levels);

dantrolene (infusion for severe body temperature abnormalities);

medicines used to protect against transplant rejection (ciclosporin).

Amlodipine/Valsartan Denk with food and drink

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

Amlodipine/Valsartan Denk. This is because grapefruit and grapefruit juice can lead to an

increase in the blood levels of the active substance amlodipine, which can cause an

unpredictable increase in the blood pressure lowering effect of Amlodipine/Valsartan Denk.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will

normally advise you to stop taking Amlodipine/Valsartan Denk before you become pregnant or as

soon as you know you are pregnant and will advise you to take another medicine instead of

Amlodipine/Valsartan Denk. Amlodipine/Valsartan Denk is not recommended in early pregnancy

(first 3 months), and must not be taken when more than 3 months pregnant, as it may cause serious

harm to your baby if used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Amlodipine has been

shown to pass into breast milk in small amounts. Amlodipine/Valsartan Denk is not recommended

for mothers who are breast-feeding, and your doctor may choose another treatment for you if you

wish to breast-feed, especially if your baby is newborn, or was born prematurely.

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

Driving and using machines

This medicine may make you feel dizzy. This can affect how well you can concentrate. So, if you

are not sure how this medicine will affect you, do not drive, use machinery, or do other activities

that you need to concentrate on.

3.

How to take Amlodipine/Valsartan Denk

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are

not sure. This will help you get the best results and lower the risk of side effects.

The usual dose of Amlodipine/Valsartan Denk is one tablet per day.

It is preferable to take your medicine at the same time each day.

Swallow the tablets with a glass of water.

You can take Amlodipine/Valsartan Denk with or without food. Do not take

Amlodipine/Valsartan Denk with grapefruit or grapefruit juice.

Depending on how you respond to the treatment, your doctor may suggest a higher or lower

dose. Do not exceed the prescribed dose.

Amlodipine/Valsartan Denk and older people (age 65 years or over)

Your doctor should exercise caution when increasing your dose.

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

If you take more Amlodipine/Valsartan Denk than you should

If you have taken too many tablets of Amlodipine/Valsartan Denk, or if someone else has taken

your tablets, consult a doctor immediately.

If you forget to take Amlodipine/Valsartan Denk

If you forget to take this medicine, take it as soon as you remember. Then take your next dose at

its usual time. However, if it is almost time for your next dose, skip the dose you missed. Do not

take a double dose to make up for a forgotten tablet.

If you stop taking Amlodipine/Valsartan Denk

Stopping your treatment with Amlodipine/Valsartan Denk may cause your disease to get worse.

Do not stop taking your medicine unless your doctor tells you to.

4.

Possible side effects

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

Some side effects can be serious and need immediate medical attention:

A few patients have experienced these serious side effects

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

If

any of the following happen, tell your doctor straight away:

Allergic reaction with symptoms such as rash, itching, swelling of face or lips or tongue, difficulty

breathing, low blood pressure (feeling of faintness, light-headedness).

Other possible side effects of Amlodipine/Valsartan Denk:

Common (may affect up to 1 in 10 people)

: Influenza (flu); blocked nose, sore throat and

discomfort when swallowing; headache; swelling of arms, hands, legs, ankles or feet; tiredness;

asthenia (weakness); redness and warm feeling of the face and/or neck.

Uncommon (may affect up to 1 in 100 people)

: Dizziness; nausea and abdominal pain; dry mouth;

drowsiness, tingling or numbness of the hands or feet; vertigo; fast heart beat including

palpitations; dizziness on standing up; cough; diarrhoea; constipation; skin rash, redness of the

skin; joint swelling, back pain; pain in joints.

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

: Feeling anxious; ringing in the ears (tinnitus);

fainting; passing more urine than normal or feeling more of an urge to pass urine; inability to get

or maintain an erection; sensation of heaviness; low blood pressure with symptoms such as

dizziness, light- headedness; excessive sweating; skin rash all over your body; itching; muscle

spasm.

If any of these affect you severely, tell your doctor.

Side effects reported with amlodipine or valsartan alone and either not observed with

Amlodipine/Valsartan Denk or observed with a higher frequency than with

Amlodipine/Valsartan Denk:

Amlodipine

Consult a 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 the

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 of being very unwell.

The following 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):

Dizziness, sleepiness; palpitations (awareness of

your heart beat); flushing, ankle swelling (oedema); abdominal pain, feeling sick (nausea).

Uncommon (may affect up to 1 in 100 people):

Mood changes, anxiety, depression, sleeplessness,

trembling, taste abnormalities, fainting, loss of pain sensation; visual disturbances, visual

impairment, ringing in the ears; low blood pressure; sneezing/runny nose caused by inflammation

of the lining of the nose (rhinitis); indigestion, vomiting (being sick); hair loss, increased sweating,

itchy 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, muscle pain, muscle cramps; 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 number of white blood cells, decrease

in blood platelets which may result in unusual brusing or easy bleeding (red blood cell damage);

excess sugar in blood (hyperglycaemia); 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 (frequency cannot be estimated from the available data):

Trembling, rigid posture,

mask-like face, slow movements and a shuffling, unbalanced walk.

Valsartan

Not known (frequency cannot be estimated from the available data):

Decrease in red blood cells,

fever, sore throat or mouth sores due to infections; spontaneous bleeding or bruising; high level

of potassium in the blood; abnormal liver test results; decreased renal functions and severely

decreased renal functions; swelling mainly of the face and the throat; muscle pain; rash, purplish-

red spots; fever; itching; allergic reaction; blistering skin (sign of a condition called dermatitis

bullous).

If you experience any of these, tell your doctor straight away.

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 the national

reporting system listed in Appendix V. By reporting side effects you can help provide more

information on the safety of this medicine.

5.

How to store Amlodipine/Valsartan Denk

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 carton and

blister. The expiry date refers to the last day of that month.

Do not store above 30°C.

Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.

6.

Contents of the pack and other information

What Amlodipine/Valsartan Denk contains

The active substances of Amlodipine/Valsartan Denk are amlodipine (as amlodipine

besilate) and valsartan. Each tablet contains 5 mg amlodipine and 80 mg valsartan.

The active substances of Amlodipine/Valsartan Denk are amlodipine (as amlodipine

besilate) and valsartan. Each tablet contains 5 mg amlodipine and 160 mg valsartan.

The active substances of Amlodipine/Valsartan Denk are amlodipine (as amlodipine

besilate) and valsartan. Each tablet contains 10 mg amlodipine and 160 mg valsartan.

The other ingredients are cellulose microcrystalline, povidone, croscarmellose sodium, talc,

magnesium stearate, hypromellose, macrogol, titanium dioxide (E171); [

5mg/80mg and

5mg/160mg tablets only]:

iron oxide, yellow (E172).

What Amlodipine/Valsartan Denk looks like and contents of the pack

Amlodipine/Valsartan Denk 5 mg/80 mg tablets are 8mm, round, biconvex and yellow with

“I” on one side and “LD” on the other side.

Amlodipine/Valsartan Denk 5 mg/160 mg tablets are 13.5mm long and 7 mm wide, oval,

biconvex and yellow with “2” on one side and “LD” on the other side.

Amlodipine/Valsartan Denk 10 mg/160 mg tablets are 13.5mm long and 7 mm wide, oval,

biconvex and white with “3” on one side and “LD” on the other side.

Pack sizes: 7, 14, 28, 30, 56, 60, 90, 98 or 280 film-coated tablets

Not all pack sizes may be available in your country.

Marketing Authorisation Holder

<[To be completed nationally]>

Manufacturer

Denk Pharmar GmbH & Co.KG

Prinzregentenstr. 79

81675 München

Balkanpharma Dupnitza AD

3 Samokovsko Shosse Str.

Dupnitza 2600,

Bulgaria

This leaflet was last revised in 2018-08-03.

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Amlodipine/Valsartan Denk 5 mg/80 mg film-coated tablets

Amlodipine/Valsartan Denk 5 mg/160 mg film-coated tablets

Amlodipine/Valsartan Denk 10 mg/160 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 80 mg of valsartan.

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate) and 160 mg of valsartan.

Each film-coated tablet contains 10 mg of amlodipine (as amlodipine besylate) and 160 mg of valsartan.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

5mg/80mg

Yellow, 8mm round, biconvex, film-coated tablet, imprinted with “I” on one side and “LD” on the

other side.

5mg/160mg

Yellow, 13.5 x 7mm oval, biconvex, film-coated tablet, imprinted with “2” on one side and “LD” on the

other side.

10mg/160mg

White, 13.5 x 7mm oval, biconvex, film-coated tablet, imprinted with “3” on one side and “LD” on the

other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of essential hypertension.

Amlodipine/Valsartan Denk is indicated in adults whose blood pressure is not adequately controlled on

amlodipine or valsartan monotherapy.

4.2

Posology and method of administration

Posology

The recommended dose of Amlodipine/Valsartan Denk is one tablet per day.

Amlodipine/Valsartan Denk 5 mg/80 mg may be administered in patients whose blood pressure is not

adequately controlled with amlodipine 5 mg or valsartan 80 mg alone.

Amlodipine/Valsartan Denk 5 mg/160 mg may be administered in patients whose blood pressure is not

adequately controlled with amlodipine 5 mg or valsartan 160 mg alone.

Amlodipine/Valsartan Denk 10 mg/160 mg may be administered in patients whose blood pressure is not

adequately controlled with amlodipine 10 mg or valsartan 160 mg alone or with Amlodipine/Valsartan

Denk 5 mg/160 mg.

Amlodipine/Valsartan Denk can be used with or without food.

Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before

changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy

to the fixed-dose combination may be considered.

For convenience, patients receiving valsartan and amlodipine from separate tablets/capsules may be

switched to Amlodipine/Valsartan Denk containing the same component doses.

Renal impairment

There are no available clinical data in severely renally impaired patients. No dosage adjustment is

required for patients with mild to moderate renal impairment. Monitoring of potassium levels and

creatinine is advised in moderate renal impairment.

Hepatic impairment

Amlodipine/Valsartan Denk is contraindicated in patients with severe hepatic impairment (see section

4.3).

Caution should be exercised when administering Amlodipine/Valsartan Denk to patients with hepatic

impairment or biliary obstructive disorders (see section 4.4). In patients with mild to moderate hepatic

impairment without cholestasis, the maximum recommended dose is 80 mg valsartan. Amlodipine

dosage recommendations have not been established in patients with mild to moderate hepatic

impairment. When switching eligible hypertensive patients (see section 4.1) with hepatic impairment to

amlodipine or /…/, the lowest available dose of amlodipine monotherapy or of the amlodipine

component, respectively, should be used.

Elderly (age 65 years or over)

In elderly patients, caution is required when increasing the dosage. When switching eligible elderly

hypertensive patients (see section 4.1) to amlodipine or /…/, the lowest available dose of amlodipine

monotherapy or of the amlodipine component, respectively, should be used.

Paediatric population

The safety and efficacy of Amlodipine/Valsartan Denk in children aged below 18 years have not been

established. No data are available.

Method of administration

Oral use.

It is recommended to take Amlodipine/Valsartan Denk with some water.

4.3

Contraindications

Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the

excipients listed in section 6.1.

Severe hepatic impairment, biliary cirrhosis or cholestasis.

Concomitant use of Amlodipine/Valsartan Denk with aliskiren-containing products in patients

with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m

) (see sections 4.5 and 5.1).

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Severe hypotension.

Shock (including cardiogenic shock).

Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy

and 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 have not been established.

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless

continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to

alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if

appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Sodium- and/or volume-depleted patients

Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with

amlodipine/valsartan in placebo-controlled studies. In patients with an activated renin-angiotensin

system (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who are

receiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this

condition prior to administration of amlodipine/valsartan or close medical supervision at the start of

treatment is recommended.

If hypotension occurs with amlodipine/valsartan , the patient should be placed in the supine position and,

if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood

pressure has been stabilised.

Hyperkalaemia

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing

potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be

undertaken with caution and with frequent monitoring of potassium levels.

Renal artery stenosis

Amlodipine/valsartan should be used with caution to treat hypertension in patients with unilateral or

bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may

increase in such patients.

Kidney transplantation

To date there is no experience of the safe use of amlodipine/valsartan in patients who have had a recent

kidney transplantation.

Hepatic impairment

Valsartan is mostly eliminated unchanged via the bile. The half-life of amlodipine is prolonged and

AUC values are higher in patients with impaired liver function; dosage recommendations have not been

established. Particular caution should be exercised when administering amlodipine/valsartan to patients

with mild to moderate hepatic impairment or biliary obstructive disorders.

In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended

dose is 80 mg valsartan.

Renal impairment

No dosage adjustment of amlodipine/valsartan is required for patients with mild to moderate renal

impairment (GFR >30 ml/min/1.73 m

). Monitoring of potassium levels and creatinine is advised in

moderate renal impairment.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist

valsartan as their renin-angiotensin system is affected by the primary disease.

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of

the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some of these

patients previously experienced angioedema with other medicinal products, including ACE inhibitors.

Amlodipine/valsartan should be discontinued immediately in patients who develop angioedema and

should not be re-administered.

Heart failure/post-myocardial infarction

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal

function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal

function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE

inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive

azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with

valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include

assessment of renal function.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New

York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine

was associated with increased reports of pulmonary oedema despite no significant difference in the

incidence of worsening heart failure as compared to placebo.

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.

Aortic and mitral valve stenosis

As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or

significant aortic stenosis that is not high grade.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of

hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade

of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore not recommended

(see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist

supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Amlodipine/valsartan has not been studied in any patient population other than hypertension.

4.5

Interaction with other medicinal products and other forms of interaction

Interactions common to the combination

No drug-drug interaction studies have been performed with amlodipine/valsartan and other medicinal

products.

To be taken into account with concomitant use

Other antihypertensive agents

Commonly used antihypertensive agents (e.g. alpha blockers, diuretics) and other medicinal products

which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for treatment

of benign prostate hyperplasia) may increase the antihypertensive effect of the combination.

Interactions linked to amlodipine

Concomitant use not recommended

Grapefruit or grapefruit juice

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.

Caution required with concomitant use

CYP3A4 inhibitors

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

antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to

significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations

may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin,

primidone], rifampicin, Hypericum perforatum)

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).

There is a risk of increased tacrolimus blood levels when co administered with amlodipine. In order to

avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tracrolimus requires

monitoring of tacrolimus when appropriate.

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.

Simvastatin

Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77%

increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose

of simvastatin to 20 mg daily in patients on amlodipine.

Dantrolene (infusion)

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

hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of

hyperkalaemia, 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.

To be taken into account with concomitant use

Others

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

warfarin or ciclosporin.

Interactions linked to valsartan

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during

concomitant administration of lithium with angiotensin converting enzyme inhibitors or angiotensin II

receptor antagonists, including valsartan. Therefore, careful monitoring of serum lithium levels is

recommended during concomitant use. If a diurectic is also used, the risk of lithium toxicity may

presumably be increased further with Amlodipine/Valsartan Denk.

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other

substances that may increase potassium levels

If a medicinal product that affects potassium levels is to be prescribed in combination with valsartan,

monitoring of potassium plasma levels is advised.

Caution required with concomitant use

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors,

acetylsalicylic acid (>3 g/day), and non-selective NSAIDs

When angiotensin II antagonists are administered simultaneously with NSAIDs attenuation of the

antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and

NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum

potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as

well as adequate hydration of the patient.

Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir)

The results of an

in vitro

study with human liver tissue indicate that valsartan is a substrate of the

hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of

inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may

increase the systemic exposure to valsartan.

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren

Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE

inhibitors, ARBs or aliskiren is associated with a higher frequency of adverse events such as

hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the

use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Others

In monotherapy with valsartan, no interactions of clinical significance have been found with the

following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin,

hydrochlorothiazide, amlodipine, glibenclamide.

4.6

Fertility, pregnancy and lactation

Pregnancy

Amlodipine

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.

Valsartan

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester

of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third

trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors

during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot

be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor

Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is

considered essential, patients planning pregnancy should be changed to alternative antihypertensive

treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed,

treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be

started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human

foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal

toxicity (renal failure, hypotension, and hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of

renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections

4.3 and 4.4).

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.

No information is available regarding the use of valsartan during breast-feeding. Amlodipine/Valsartan

Denk is therefore not recommended and alternative treatments with better established safety profiles

during breast- feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility

There are no clinical studies on fertility with amlodipine/valsartan.

Valsartan

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up

to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m

basis

(calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Amlodipine

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

Patients taking amlodipine/valsartan and driving vehicles or using machines should take into account

that dizziness or weariness may occasionally occur.

Amlodipine can have mild 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.

4.8

Undesirable effects

Summary of the safety profile

The safety of amlodipine/valsartan has been evaluated in five controlled clinical studies with 5,175

patients, 2,613 of whom received valsartan in combination with amlodipine. The following adverse

reactions were found to be the most frequently occurring or the most significant or severe:

nasopharyngitis, influenza, hypersensitivity, headache, syncope, orthostatic hypotension, oedema, pitting

oedema, facial oedema, oedema peripheral, fatigue, flushing, asthenia and hot flush.

Tabulated list of adverse reactions

Adverse reactions have been ranked under headings of frequency using the following convention: 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).

Frequency

MedDRA System

organ class

Adverse reactions

Amlodipine/

Valsartan

Amlodipine

Valsartan

Nasopharyngitis

Common

Infections and

infestations

Influenza

Common

Decrease in haemoglobin and

in haematocrit

Not known

Leukopenia

Very rare

Neutropenia

Not known

Blood and

lymphatic system

disorders

Thrombocytopenia, sometimes

with purpura

Very rare

Not known

Immune system

disorders

Hypersensitivity

Rare

Very rare

Not known

Metabolism and

Anorexia

Uncommon --

MedDRA System

organ class

Adverse reactions

Frequency

Amlodipine/

Valsartan

Amlodipine

Valsartan

Hypercalcaemia

Uncommon --

Hyperglycaemia

Very rare

Hyperlipidaemia

Uncommon --

Hyperuricaemia

Uncommon --

Hypokalaemia

Common

nutrition disorders

Hyponatraemia

Uncommon --

Depression

Uncommon

Anxiety

Rare

Insomnia/sleep disturbances

Uncommon

Mood swings

Uncommon

Psychiatric

disorders

Confusion

Rare

Coordination abnormal

Uncommon --

Dizziness

Uncommon Common

Dizziness postural

Uncommon --

Dysgeusia

Uncommon

Extrapyramidal syndrome

Not known

Headache

Common

Common

Hypertonia

Very rare

Paraesthesia

Uncommon Uncommon

Peripheral neuropathy,

neuropathy

Very rare

Somnolence

Uncommon Common

Syncope

Uncommon

Tremor

Uncommon

Nervous system

disorders

Hypoesthesia

Uncommon

Visual disturbance

Rare

Uncommon

Eye disorders

Visual impairment

Uncommon Uncommon

Tinnitus

Rare

Uncommon

Ear and labyrinth

disorders

Vertigo

Uncommon --

Uncommon

Palpitations

Uncommon Common

Syncope

Rare

Tachycardia

Uncommon --

Arrhythmias (including

bradycardia, ventricular

tachycardia, and atrial

fibrillation)

Very rare

Cardiac disorders

Myocardial infarction

Very rare

Flushing

Common

Hypotension

Rare

Uncommon

Orthostatic hypotension

Uncommon --

Vascular disorders

Vasculitis

Very rare

Not known

Cough

Uncommon Very rare

Uncommon

Dyspnoea

Uncommon

Pharyngolaryngeal pain

Uncommon --

Respiratory,

thoracic and

mediastinal

disorders

Rhinitis

Uncommon

Abdominal discomfort,

abdominal pain upper

Uncommon Common

Uncommon

Change of bowel habit

Uncommon

Constipation

Uncommon --

Gastrointestinal

disorders

Diarrhoea

Uncommon Uncommon

MedDRA System

organ class

Adverse reactions

Frequency

Amlodipine/

Valsartan

Amlodipine

Valsartan

Dry mouth

Uncommon Uncommon

Dyspepsia

Uncommon

Gastritis

Very rare

Gingival hyperplasia

Very rare

Nausea

Uncommon Common

Pancreatitis

Very rare

Vomiting

Uncommon

Liver function abnormal ,

including increase of serum

bilirubin

Very rare*

Not known

Hepatitis

Very rare

Hepatobiliary

disorders

Intrahepatic cholestasis,

jaundice

Very rare

Alopecia

Uncommon

Angioedema

Very rare

Not known

Dermatitis bullous

Not known

Erythema

Uncommon --

Erythema multiforme

Very rare

Exanthema

Rare

Uncommon

Hyperhidrosis

Rare

Uncommon

Photosensitivity reaction

Uncommon

Pruritus

Rare

Uncommon

Not known

Purpura

Uncommon

Rash

Uncommon Uncommon

Not known

Skin discolouration

Uncommon

Urticaria and other forms of

rash

Very rare

Exfoliative dermatitis

Very rare

Stevens-Johnson syndrome

Very rare

Quincke oedema

Very rare

Skin and

subcutaneous tissue

disorders

Toxic Epidermal Necrolysis

Not known

Arthralgia

Uncommon Uncommon

Back pain

Uncommon Uncommon

Joint swelling

Uncommon --

Muscle spasm

Rare

Uncommon

Myalgia

Uncommon

Not known

Ankle swelling

Common

Musculoskeletal

and connective

tissue disorders

Sensation of heaviness

Rare

Blood creatinine increased

Not known

Micturition disorder

Uncommon

Nocturia

Uncommon

Pollakiuria

Rare

Uncommon

Polyuria

Rare

Renal and

urinary disorders

Renal failure and impairment

Not known

Impotence

Uncommon

Erectile dysfunction

Rare

Reproductive

system and breast

disorders

Gynaecomastia

Uncommon

Asthenia

Common

Uncommon

Discomfort, malaise

Uncommon

Fatigue

Common

Common

Uncommon

General disorders

and administration

site conditions

Facial oedema

Common

MedDRA System

organ class

Adverse reactions

Frequency

Amlodipine/

Valsartan

Amlodipine

Valsartan

Flushing, hot flush

Common

Non cardiac chest pain

Uncommon

Oedema

Common

Common

Oedema peripheral

Common

Pain

Uncommon

Pitting oedema

Common

Blood potassium increased

Not known

Weight increase

Uncommon

Investigations

Weight decrease

Uncommon

Mostly consistent with cholestasis

Additional information on the combination

Peripheral oedema, a recognised side effect of amlodipine, was generally observed at a lower incidence

in patients who received the amlodipine/valsartan combination than in those who received amlodipine

alone. In double-blind, controlled clinical trials, the incidence of peripheral oedema by dose was as

follows:

Valsartan (mg)

% of patients who experienced

peripheral oedema

Amlodipine (mg)

10.3

The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the

amlodipine/valsartan combination.

Additional information on the individual components

Adverse reactions previously reported with one of the individual components (amlodipine or valsartan)

may be potential adverse reactions with amlodipine/valsartan as well, even if not observed in clinical

trials or during the post-marketing period.

Amlodipine

Common

Somnolence, dizziness, palpitations, abdominal pain, nausea, ankle swelling.

Uncommon

Insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope,

hypoesthesia, visual disturbance (including diplopia), tinnitus, hypotension, dyspnoea,

rhinitis, vomiting, dyspepsia, alopecia, purpura, skin discolouration, hyperhidrosis,

pruritus, exanthema, myalgia, muscle cramps, pain, micturition disorder, increased urinary

frequency, impotence, gynaecomastia, chest pain, malaise, weight increase, weight

decrease.

Rare

Confusion.

Very rare

Leukocytopenia, thrombocytopenia, allergic reactions, hyperglycaemia, hypertonia,

peripheral neuropathy, myocardial infarction, arrhythmia (including bradycardia,

ventricular tachycardia and atrial fibrillation), vasculitis, pancreatitis, gastritis, gingival

hyperplasia, hepatitis, jaundice, hepatic enzymes increased*, angioedema, erythema

multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema,

photosensitivity.

* mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported.

Valsartan

Not known

Decrease in haemoglobin, decrease in haematocrit, neutropenia, thrombocytopenia,

increase of serum potassium, elevation of liver function values including increase of

serum bilirubin, renal failure and impairment, elevation of serum creatinine, angioedema,

myalgia, vasculitis, hypersensitivity including serum sickness.

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 the national reporting system listed in Appendix V.

4.9

Overdose

Symptoms

There is no experience of overdose with amlodipine/valsartan. The major symptom of overdose with

valsartan is possibly pronounced hypotension with dizziness. Overdose with amlodipine may result in

excessive peripheral vasodilation and, possibly, reflex tachycardia. Marked and potentially prolonged

systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment

If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of

activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine

has been shown to significantly decrease amlodipine absorption. Clinically significant hypotension due

to amlodipine/valsartan overdose 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.

Both valsartan and amlodipine are unlikely to be removed by haemodialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; angiotensin II antagonists,

combinations; angiotensin II antagonists and calcium channel blockers, ATC code: C09DB01

Amlodipine/valsartan combines two antihypertensive compounds with complementary mechanisms to

control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium

antagonist class and valsartan to the angiotensin II antagonist class of medicines. The combination of

these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than

either component alone.

Amlodipine/Valsartan

The combination of amlodipine and valsartan produces dose-related additive reduction in blood pressure

across its therapeutic dose range. The antihypertensive effect of a single dose of the combination

persisted for 24 hours.

Placebo-controlled trials

Over 1,400 hypertensive patients received amlodipine/valsartan once daily in two placebo-controlled

trials. Adults with mild to moderate uncomplicated essential hypertension (mean sitting diastolic blood

pressure ≥95 and <110 mmHg) were enrolled. Patients with high cardiovascular risks – heart failure,

type I and poorly controlled type II diabetes and history of myocardial infarction or stroke within one

year – were excluded.

Active-controlled trials in patients who were non-responders to monotherapy

A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation of

blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients not

adequately controlled on valsartan 160 mg in 75% of patients treated with amlodipine/valsartan 10

mg/160 mg and 62% of patients treated with amlodipine/valsartan 5 mg/160 mg, compared to 53% of

patients remaining on valsartan 160 mg. The addition of amlodipine 10 mg and 5 mg produced an

additional

reduction

systolic/diastolic

blood

pressure

6.0/4.8

mmHg

3.9/2.9

mmHg,

respectively, compared to patients who remained on valsartan 160 mg only.

A multicentre, randomised, double-blind, active-controlled, parallel-group trial showed normalisation of

blood pressure (trough sitting diastolic blood pressure <90 mmHg at the end of the trial) in patients not

adequately controlled on amlodipine 10 mg in 78% of patients treated with amlodipine/valsartan 10

mg/160 mg, compared to 67% of patients remaining on amlodipine 10 mg. The addition of valsartan 160

mg produced an additional reduction in systolic/diastolic blood pressure of 2.9/2.1 mmHg compared to

patients who remained on amlodipine 10 mg only.

Amlodipine/valsartan was also studied in an active-controlled study of 130 hypertensive patients with

mean sitting diastolic blood pressure ≥110 mmHg and <120 mmHg. In this study (baseline blood

pressure 171/113 mmHg), an amlodipine/valsartan regimen of 5 mg/160 mg titrated to 10 mg/160 mg

reduced sitting blood pressure by 36/29 mmHg as compared to 32/28 mmHg with a regimen of

lisinopril/hydrochlorothiazide 10 mg/12.5 mg titrated to 20 mg/12.5 mg.

In two long-term follow-up studies the effect of amlodipine/valsartan was maintained for over one year.

Abrupt withdrawal of amlodipine/valsartan has not been associated with a rapid increase in blood

pressure.

Age, gender, race or body mass index (≥30 kg/m

, <30 kg/m

) did not influence the response to

amlodipine/valsartan.

Amlodipine/valsartan has not been studied in any patient population other than hypertension. Valsartan

has been studied in patients with post myocardial infarction and heart failure. Amlodipine has been

studied in patients with chronic stable angina, vasospastic angina and angiographically documented

coronary artery disease.

Amlodipine

The amlodipine component of amlodipine/valsartan inhibits the transmembrane entry 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, causing reductions in peripheral vascular

resistance and in blood pressure. Experimental data suggest that amlodipine binds to both

dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and

vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells

through specific ion channels.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces

vasodilation, resulting in a reduction of supine and standing blood pressures. These decreases in blood

pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with

chronic dosing.

Plasma concentrations correlate with effect in both young and elderly patients.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a

decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal

plasma flow, without change in filtration fraction or proteinuria.

As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and

during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have

generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left

ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been

associated with a negative inotropic effect when administered in the therapeutic dose range to intact

animals and humans, even when co-administered with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or

humans. In clinical studies in which amlodipine was administered in combination with beta blockers to

patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were

observed.

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid- Lowering

treatment to prevent Heart Attack Trial (ALLHAT) was performed to compare newer therapies:

amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE- inhibitor) as

first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderate

hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 4.9

years. The patients had at least one additional coronary heart disease risk factor, including: previous

myocardial infarction or stroke (>6 months prior to enrollment) or documentation of other

atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%), high density lipoprotein

- cholesterol <35 mg/dl or <0.906 mmol/l (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 coronary heart disease or non-fatal myocardial infarction.

There was no significant difference in the primary endpoint between amlodipine-based therapy and

chlorthalidone-based therapy: risk ratio (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% versus

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.

Valsartan

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on

the receptor subtype AT

, which is responsible for the known actions of angiotensin II. The increased

plasma levels of angiotensin II following AT

receptor blockade with valsartan may stimulate the

unblocked receptor subtype AT

, which appears to counterbalance the effect of the AT

receptor.

Valsartan does not exhibit any partial agonist activity at the AT

receptor and has much (about 20,000-

fold) greater affinity for the AT

receptor than for the AT

receptor.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I to angiotensin II

and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance

P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where

valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (p <0.05)

lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9%,

respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy,

19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic experienced

coughing, compared to 68.5% of those treated with an ACE inhibitor (p <0.05). Valsartan does not bind

to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Administration of valsartan to patients with hypertension results in a drop in blood pressure without

affecting pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs

within 2 hours, and the peak drop in blood pressure is achieved within 4–6 hours. The antihypertensive

effect persists over 24 hours after administration. During repeated administration, the maximum

reduction in blood pressure with any dose is generally attained within 2–4 weeks and is sustained during

long-term therapy. Abrupt withdrawal of valsartan has not been associated with rebound hypertension or

other adverse clinical events.

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination

with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in

Diabetes]) have examined the use of the combination of an ACE inhibitor with an ARB.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular

disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON- D

was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and

mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared

to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also

relevant for other ACE inhibitors and ARBs.

ACE inhibitors and ARBs should therefore not be used concomitantly in patients with diabetic

nephropathy (see section 4.4).

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints)

was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE inhibitor or

an ARB in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or

both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular

death and stroke were both numerically more frequent in the aliskiren group than in the placebo group

and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal

dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

5.2

Pharmacokinetic properties

Linearity

Amlodipine and valsartan exhibit linear pharmacokinetics.

Amlodipine/Valsartan

Following oral administration of amlodipine/valsartan, peak plasma concentrations of valsartan and

amlodipine are reached in 3 and 6–8 hours, respectively. The rate and extent of absorption of

amlodipine/valsartan are equivalent to the bioavailability of valsartan and amlodipine when administered

as individual tablets.

Amlodipine

Absorption

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of

amlodipine are reached in 6–12 hours. Absolute bioavailability has been calculated as between 64% and

80%. Amlodipine bioavailability is unaffected by food ingestion.

Distribution

Volume of distribution is approximately 21 l/kg.

In vitro

studies with amlodipine have shown that

approximately 97.5% of circulating drug is bound to plasma proteins.

Biotransformation

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites.

Elimination

Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30

to 50 hours. Steady-state plasma levels are reached after continuous administration for

7–8 days. Ten per

cent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.

Valsartan

Absorption:

Following oral administration of valsartan alone, peak plasma concentrations of valsartan

are reached in 2–4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured

by AUC) to valsartan by about 40% and peak plasma concentration (C

) by about 50%, although from

about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This

reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic

effect, and valsartan can therefore be given either with or without food.

Distribution

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres,

indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum

proteins (94–97%), mainly serum albumin.

Biotransformation

Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A

hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan

AUC). This metabolite is pharmacologically inactive.

Elimination

Valsartan shows multiexponential decay kinetics (t

½α

<1 h and t

½ß

about 9 h). Valsartan is primarily

eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug.

Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance

is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

Special populations

Paediatric population (age below 18 years)

No pharmacokinetic data are available in the paediatric population.

Elderly (age 65 years or over)

Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly

patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and

elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the young,

therefore caution is required when increasing the dosage.

Renal impairment

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected

for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation

was seen between renal function and systemic exposure to valsartan.

Hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic

impairment. Patients with hepatic impairment have decreased clearance of amlodipine with resulting

increase of approximately 40–60% in AUC. On average, in patients with mild to moderate chronic liver

disease exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers

(matched by age, sex and weight). Caution should be exercised in patients with liver disease (see

section 4.2).

5.3

Preclinical safety data

Amlodipine/Valsartan

Adverse reactions observed in animal studies with possible clinical relevance were as follows:

Histopathological signs of inflammation of the glandular stomach was seen in male rats at an exposure

of about 1.9 (valsartan) and 2.6 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mg

amlodipine. At higher exposures, there were ulceration and erosion of the stomach mucosa in both

females and males. Similar changes were also seen in the valsartan alone group (exposure 8.5–11.0

times the clinical dose of 160 mg valsartan).

An increased incidence and severity of renal tubular basophilia/hyalinisation, dilation and casts, as well

as interstitial lymphocyte inflammation and arteriolar medial hypertrophy were found at an exposure of

8–13 (valsartan) and 7–8 (amlodipine) times the clinical doses of 160 mg valsartan and 10 mg

amlodipine. Similar changes were found in the valsartan alone group (exposure 8.5–11.0 times the

clinical dose of 160 mg valsartan).

In an embryo-foetal development study in the rat, increased incidences of dilated ureters, malformed

sternebrae, and unossified forepaw phalanges were noticed at exposures of about 12 (valsartan) and 10

(amlodipine) times the clinical doses of 160 mg valsartan and 10 mg amlodipine. Dilated ureters were

also found in the valsartan alone group (exposure 12 times the clinical dose of 160 mg valsartan). There

were only modest signs of maternal toxicity (moderate reduction of body weight) in this study. The no-

observed-effect-level for developmental effects was observed at 3- (valsartan) and 4- (amlodipine) fold

the clinical exposure (based on AUC).

For the single compounds there was no evidence of mutagenicity, clastogenicity or carcinogenicity.

Amlodipine

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/m

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/m

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

Valsartan

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led to

lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in

the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the

maximum recommended human dose on a mg/m

basis (calculations assume an oral dose of

320 mg/day and a 60-kg patient).

In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a

reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of

changes in renal haemodynamics (slightly raised blood urea nitrogen, and renal tubular hyperplasia and

basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the

maximum recommended human dose on a mg/m

basis (calculations assume an oral dose of

320 mg/day and a 60-kg patient).

In marmosets at comparable doses, the changes were similar though more severe, particularly in the

kidney where the changes developed to a nephropathy including raised urea and creatinine.

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were

considered to be caused by the pharmacological action of valsartan which produces prolonged

hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of

the renal juxtaglomerular cells does not seem to have any relevance.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Cellulose microcrystalline

Povidone (K-29/32)

Croscarmellose sodium,

Talc

Magnesium stearate

Coating:

Hypromellose

Titanium dioxide (E171)

Macrogol

5mg/80mg and 5mg/160mg tablets only:

Iron oxide, yellow (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

Do not store above 30°C

6.5

Nature and contents of container

PVC/PVDC-AL blisters

Pack sizes: 7, 14, 28, 30, 56, 60, 90, 98 or 280 film-coated tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: DD month YYYY

Date of latest renewal: DD month YYYY

10.

DATE OF REVISION OF THE TEXT

2018-08-03

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