Amlodipine/Valsartan Genericon 10 mg/160 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Köp det nu

Bipacksedel Bipacksedel (PIL)

05-12-2018

Produktens egenskaper Produktens egenskaper (SPC)

05-12-2018

Aktiva substanser:
amlodipinbesilat; valsartan
Tillgänglig från:
Genericon Pharma Ges.m.b.H.
ATC-kod:
C09DB01
INN (International namn):
amlodipine besylate; valsartan
Dos:
10 mg/160 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
amlodipinbesilat 13,9 mg Aktiv substans; valsartan 160 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 7 tabletter; Blister, 14 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 60 tabletter; Blister, 56 tabletter; Blister, 90 tabletter; Blister, 98 tabletter; Blister, 280 tabletter
Bemyndigande status:
Avregistrerad
Godkännandenummer:
53780
Tillstånd datum:
2017-01-27

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

05-12-2018

Produktens egenskaper Produktens egenskaper - engelska

05-12-2018

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

16-11-2016

Läs hela dokumentet

PACKAGE LEAFLET

Package leaflet: information for the patient

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

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

Amlodipine/Valsartan Genericon 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 Genericon is and what it is used for

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

How to take Amlodipine/Valsartan Genericon

Possible side effects

How to store Amlodipine/Valsartan Genericon

Contents of the pack and other information

1.

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

Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon

Do not take Amlodipine/Valsartan Genericon

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 section

6). If you think you may be allergic, talk to your doctor before taking Amlodipine/Valsartan

Genericon.

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

Genericon 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 Genericon and talk to

your doctor

Warnings and precautions

Talk to your doctor before taking Amlodipine/Valsartan Genericon:

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 Genericon and contact your doctor straight away. You should

never take Amlodipine/Valsartan Genericon 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 Genericon”.

If any of these apply to you, tell your doctor before taking Amlodipine/Valsartan Genericon.

Children and adolescents

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

below 18 years old).

Other medicines and Amlodipine/Valsartan Genericon

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 Genericon” 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, clarithromycin,

talithromycin);

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 Genericon with food and drink

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

Amlodipine/Valsartan Genericon. 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 Genericon.

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 Genericon 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 Genericon. Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon

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 Genericon 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 Genericon with or without food. Do not take

Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon than you should

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

your tablets, consult a doctor immediately.

If you forget to take Amlodipine/Valsartan Genericon

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 Genericon

Stopping your treatment with Amlodipine/Valsartan Genericon 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 Genericon:

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 Genericon or observed with a higher frequency than with

Amlodipine/Valsartan Genericon:

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 Genericon

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 Genericon contains

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

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

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

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

The active substances of Amlodipine/Valsartan Genericon 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 Genericon looks like and contents of the pack

Amlodipine/Valsartan Genericon 5 mg/80 mg tablets are 8mm, round, biconvex and yellow with “I”

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

Amlodipine/Valsartan Genericon 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 Genericon 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

Balkanpharma Dupnitza AD

3 Samokovsko Shosse Str.

Dupnitza 2600,

Bulgaria

Genericon Pharma Gesellschaft m.b.H.

A-8054 Graz

E-Mail: genericon@genericon.at

This leaflet was last revised in

December 2018.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

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

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

Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon is one tablet per day.

Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon 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 Genericon 5 mg/160 mg.

Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon is contraindicated in patients with severe hepatic impairment

(see section 4.3).

Caution should be exercised when administering Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon 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 Genericon 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 Genericon 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 Genericon or close

medical supervision at the start of treatment is recommended.

If hypotension occurs with Amlodipine/Valsartan Genericon, 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 Genericon 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 Genericon 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 Genericon 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 Genericon 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

treated

with

angiotensin

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 Genericon 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 Genericon 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 Genericon 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

tacrolimus requires monitoring of tacrolimus and dose adjustment of tacrolimus when

appropriate.

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 Genericon.

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

Amlodipine/Valsartan Genericon during breast-feeding, therefore Amlodipine/Valsartan

Genericon is 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 Genericon.

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 Genericon 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/V

alsartan

Genericon

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

Anorexia

Uncommon

Hypercalcaemia

Uncommon

Hyperglycaemia

Very rare

Hyperlipidaemia

Uncommon

Hyperuricaemia

Uncommon

Hypokalaemia

Common

Metabolism and

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

Cardiac disorders

Tachycardia

Uncommon

Frequency

MedDRA System

organ class

Adverse reactions

Amlodipine/V

alsartan

Genericon

Amlodipine

Valsartan

Arrhythmias (including

bradycardia, ventricular

tachycardia, and atrial

fibrillation)

Very rare

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

Diarrhoea

Uncommon

Uncommon

Dry mouth

Uncommon

Uncommon

Dyspepsia

Uncommon

Gastritis

Very rare

Gingival hyperplasia

Very rare

Nausea

Uncommon

Common

Pancreatitis

Very rare

Gastrointestinal

disorders

Vomiting

Uncommon

Liver function test 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

Skin and

subcutaneous tissue

disorders

Quincke oedema

Very rare

Toxic Epidermal Necrolysis

Not known

Musculoskeletal

Arthralgia

Uncommon

Uncommon

Frequency

MedDRA System

organ class

Adverse reactions

Amlodipine/V

alsartan

Genericon

Amlodipine

Valsartan

Back pain

Uncommon

Uncommon

Joint swelling

Uncommon

Muscle spasm

Rare

Uncommon

Myalgia

Uncommon

Not known

Ankle swelling

Common

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

Facial oedema

Common

Flushing, hot flush

Common

Non cardiac chest pain

Uncommon

Oedema

Common

Common

Oedema peripheral

Common

Pain

Uncommon

General disorders

and administration

site conditions

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 Genericon 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.

Not known

Toxic Epidermal Necrolysis

* 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 Genericon. 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 Genericon 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 Genericon 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 Genericon 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

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 in systolic/diastolic blood pressure

of 6.0/4.8 mmHg and 3.9/2.9 mmHg, respectively, compared to patients who remained on

valsartan 160 mg only.

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 Genericon 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 Genericon

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 Genericon was

maintained for over one year. Abrupt withdrawal of Amlodipine/Valsartan Genericon 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 Genericon.

Amlodipine/Valsartan Genericon 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 Genericon 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 Genericon, 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 Genericon 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, toxicity to

reproduction and development.

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

05 December 2018

Liknande Produkter

Sök varningar relaterade till denna produkt

Visa dokumenthistorik

Dela den här informationen