Consumer medicine information

Exforge

Amlodipine; Valsartan

BRAND INFORMATION

Brand name

Exforge

Active ingredient

Amlodipine; Valsartan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Exforge.

What is in this leaflet

This leaflet answers some common questions about EXFORGE.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What EXFORGE is used for

EXFORGE is used to control high blood pressure, also called hypertension.

Everybody has blood pressure. This pressure helps get your blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

High blood pressure increases the workload of the heart and blood vessels. If it continues for a long time, it can damage the blood vessels in the brain, heart and kidneys. This can lead to stroke, heart failure or kidney failure. High blood pressure increases the risk of heart attacks. Lowering your blood pressure reduces the chance of these disorders happening.

EXFORGE contains valsartan and amlodipine besylate. These medicines reduce blood pressure in two different ways.

  1. Valsartan blocks the effect of angiotensin II, which is a substance in the body that tightens blood vessels and makes your blood pressure rise. When the effect of angiotensin II is blocked, your blood vessels relax and your blood pressure goes down.
  2. Amlodipine besylate blocks the movement of calcium into the cells of the heart and blood vessels. As a result, they relax blood vessels and increase the supply of blood and oxygen to the heart while reducing its workload.

EXFORGE is used to treat high blood pressure in patients whose blood pressure is not controlled enough with either amlodipine or valsartan on its own.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

There is not enough information to recommend the use of EXFORGE in children.

This medicine is only available with a doctor's prescription. It is not addictive.

Before you take EXFORGE

When you must not take it

Do not take EXFORGE if you have ever had an allergic reaction after taking:

  • valsartan or amlodipine besylate (the active ingredients in EXFORGE)
  • medicines belonging to a group of chemicals called dihydropyridines, used to treat blood pressure and other heart problems.
  • any of the other ingredients listed at the end of this leaflet

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take EXFORGE if you are pregnant or intend to become pregnant. EXFORGE is not recommended for use in pregnancy. Like other similar medicines, it could affect your unborn baby.

Do not take EXFORGE if you have any of the following medical conditions:

  • severe kidney disease or are having dialysis
  • severe liver disease including biliary cirrhosis
  • cholestasis, which is reduced or stopped bile flow

Do not take Exforge if you are also taking other blood pressure lowering medicines containing aliskiren and have type 2 diabetes.

Do not take EXFORGE after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if you have/have had any of the following health problems/medical conditions:

  • severe kidney problems or received a kidney transplant
  • liver problems
  • heart problems, including obstructed blood flow from narrowing of valves (stenosis) or enlarged septum (HOCM)
  • a condition known as primary hyperaldosteronism (Conn's syndrome), a hormone disorder causing fluid retention
  • swelling, mainly of the face and throat, while taking other medicines (including an ACE inhibitor or aliskiren)
  • suffering from several episodes of vomiting or diarrhoea or are taking a diuretic (a drug increasing the amount of urine).

Your doctor may want to take special precautions if you have any of the above conditions.

Tell your doctor if you are breast-feeding a baby. Ask your doctor about the risks and benefits of taking EXFORGE in this case. It is not known if valsartan or amlodipine, the active ingredients of EXFORGE, pass into the breast milk and could affect your baby.

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives. Your doctor will want to know if you are prone to allergies.

If you have not told your doctor about any of these things, tell him/her before you take EXFORGE.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and EXFORGE may interfere with each other. Your doctor may need to change the dose or take other precautions. In some cases you may have to stop taking one of the medicines. This applies especially to the medicines listed below:

These include:

  • medicines used to treat high blood pressure and some other heart conditions including fluid tablets or diuretic medicines, ACE-inhibitors, aliskiren and beta blockers
  • simvastatin (a medicine used to help lower cholesterol levels), since the dose may have to be reduced when taken with Exforge
  • some antibiotics (rifampicin), anti-rejection drugs (ciclosporin), antiretrovirals (ritonavir) which may increase the effect of valsartan
  • tablets, preparations or supplements which increase the potassium levels in your blood (such as certain types of diuretics, potassium supplements, salt substitutes etc), lithium (a medicine used to treat some types of depression)
  • anticonvulsant agents (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John's wort
  • nitroglycerin and other nitrates, or other substances called "vasodilators"
  • medicines used for HIV/AIDS (e.g. ritonavir) or for treatment of fungal infections (e.g. ketoconazole)
  • certain types of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs) or Selective Cyclooxygenase-2 Inhibitors (Cox-2 Inhibitors).
  • intravenous dantrolene used to treat malignant hyperthermia

Your doctor may also check your kidney function.

Your doctor and pharmacist have a more complete list of medicines to be careful of while taking EXFORGE.

How to take EXFORGE

Follow carefully all directions given to you by your doctor and pharmacist. These instructions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how many tablets to take each day. The usual dose is one tablet a day.

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

When to take it

Take your EXFORGE dose at the same time each day. This also helps you remember to take it, especially if you take it as part of your usual routine (e.g. at breakfast time). This medicine will keep working for the whole 24 hours until the next dose is due.

How to take it

Swallow the tablet with a full glass of water.

Always take EXFORGE in the same way, with or without food. You can take it with or without food but it will work best if you always take it in the same way every day.

How long to take it

Take this medicine until your doctor tells you to stop even if you feel quite well. People who have high blood pressure often feel well and do not notice any signs of this problem.

If you forget to take it

If it is almost time for your next dose, skip the missed dose and take the next one when you are meant to.

Otherwise, take the dose as soon as you remember and then go back to taking it as you would normally.

Do not take a double dose to make up for the one that you missed. This may increase the chance of side effects.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (Overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone number: 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much EXFORGE. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy. Too much EXFORGE may make you feel dizzy, light headed or faint. You may experience rapid, shallow breathing or cold, clammy skin. Your heartbeat may be faster than usual. This is because your blood pressure is too low.

While you are taking EXFORGE

Things you must do

If you become pregnant while taking EXFORGE, tell your doctor immediately. You should not take this medicine while you are pregnant.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Be sure to keep all of your doctor's appointments so that your progress can be checked. Do this even if you feel well. People with high blood pressure often do not notice any signs of this problem. But it is important to keep track of your progress. Your doctor will want to check your blood pressure and your kidney and liver function from time to time.

If you are going to have surgery, tell your doctor and anaesthetist that you are taking EXFORGE. EXFORGE may affect some medicines you receive during surgery.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking EXFORGE.

Tell any other doctor, dentist or pharmacist who treats you that you are taking EXFORGE.

Things you must not do

Do not use EXFORGE to treat any other complaints unless your doctor says you can.

Do not give this medicine to anyone else, even if their condition seems to be similar to yours.

Things to be careful of

Avoid eating grapefruit or drinking grapefruit juice. Grapefruit juice can affect the metabolism of some medicines, including amlodipine.

Be careful driving, operating machinery or doing jobs that require you to be alert while you are taking EXFORGE until you know how it affects you. This medicine can cause tiredness, sleepiness or dizziness in some people. If you have these symptoms, do not drive or do anything else that could be dangerous.

If this medicine makes you feel dizzy or light-headed, be careful when getting up from a sitting or lying position. Dizziness can usually be prevented by getting up slowly and flexing leg muscles and toes to get the blood flowing. When getting out of bed, dangle your legs over the side for a minute or two before standing up.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking EXFORGE, even if you do not think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of these side effects and they worry you:

  • headache
  • buzzing, whistling, ringing or other persistent noise in the ears
  • dizziness, spinning sensation, changes in vision, uncoordinated movements
  • dizziness on standing up, especially when getting up from a sitting or lying position
  • sleepiness, tiredness, weakness or difficulty sleeping
  • pain in the back or joints
  • muscle pain, muscle tenderness or weakness, cramps
  • runny nose or congested sinuses
  • dry cough, sore throat or hoarse voice
  • dry mouth
  • bleeding, tender or enlarged gums
  • stomach upset, pain, diarrhoea or constipation
  • nausea (feeling sick) or vomiting
  • tingling or numbness in hands or feet
  • rash, redness, blistering or peeling of skin, itching
  • excessive sweating
  • feeling anxious or sad
  • problems with sexual function
  • breast enlargement in men
  • unusual hair loss or thinning
  • passing more urine than normal or frequent urge to urinate
  • redness and warm feeling of the face and/or neck
  • swelling of the ankles, feet, face or hands
  • flushing
  • palpitations
  • indigestion
  • unusual tiredness or weakness
  • weight gain
  • feeling nervous, depressed or moody
  • distorted sense of taste
  • sensitivity to light

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other parts of the body; shortness of breath, wheezing or troubled breathing
  • feeling of fast or irregular heart beat (pounding, racing, skipping beats)
  • chest pain
  • tiredness or lack of energy, being short of breath when exercising
  • bleeding or bruising more easily than normal
  • constant "flu-like" symptoms such as chills, fever, sore throat, aching joints, sores in mouth, swollen glands
  • severe dizziness or fainting
  • stomach pain with nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine

The above list includes serious side effects which may require medical attention. These side effects do not occur frequently.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After using EXFORGE

Storage

  • Keep your tablets in the original container until it is time to take them.
  • Store them in a cool dry place below 30°C (room temperature).
  • Do not store EXFORGE or any other medicine in the bathroom or near a sink.
  • Do not leave EXFORGE in the car or on window sills.

Heat and dampness can destroy some medicines. EXFORGE will keep well if it is cool and dry.

Keep medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking EXFORGE, or it has passed its expiry date, ask your pharmacist what to do with any tablets that are left over.

Product description

What it looks like

EXFORGE 5/80 (5 mg of amlodipine and 80 mg valsartan) tablets are dark yellow, round and imprinted with NVR on one side and NV on the other. Packs of 7 and 28.

EXFORGE 5/160 (5 mg of amlodipine and 160 mg valsartan) tablets are dark yellow, oval and imprinted with NVR on one side and ECE on the other. Packs of 7 and 28.

EXFORGE 10/160 (10 mg of amlodipine and 160 mg valsartan) tablets are light yellow, oval and imprinted with NVR on one side and UIC on the other. Packs of 7 and 28.

EXFORGE 5/320 (5 mg of amlodipine and 320 mg valsartan) tablets are very dark yellow, oval and imprinted with NVR on one side and CSF on the other. Packs of 7 and 28.

EXFORGE 10/320 (10 mg of amlodipine and 320 mg valsartan) tablets are dark yellow, oval and imprinted with NVR on one side and LUF on the other. Packs of 7 and 28.

Ingredients

EXFORGE tablets contain amlodipine besylate (5 mg or 10 mg) and valsartan (80 mg,160 or 320 mg) as the active ingredient.

The tablets contain the following non active ingredients:

  • Cellulose - microcrystalline
  • crospovidone
  • silica - colloidal anhydrous
  • magnesium stearate
  • hypromellose
  • macrogol 4000
  • titanium dioxide
  • iron oxide yellow
  • talc - purified

EXFORGE 5/320 mg tablets do not contain titanium dioxide.

EXFORGE 5/320 and 10/320 mg tablets also contain sodium starch glycollate.

EXFORGE 10/160 and 5/320 mg tablets also contain iron oxide red.

Sponsor

EXFORGE is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone: 1 800 671 203

® = Registered Trademark

This leaflet was prepared in August 2020.

Australian Registration Numbers:

EXFORGE 5/80 (5 mg of amlodipine and 80 mg valsartan) tablets
(AUST R 130787)

EXFORGE 5/160 (5 mg of amlodipine and 160 mg valsartan) tablets
(AUST R 130834)

EXFORGE 10/160 (10 mg of amlodipine and 160 mg valsartan) tablets
(AUST R 130841)

EXFORGE 5/320 (5 mg of amlodipine and 320 mg valsartan) tablets
(AUST R 161820)

EXFORGE 10/320 (10 mg of amlodipine and 320 mg valsartan) tablets
(AUST R 161824)

(Internal reference only: exf260820c.doc based on PI exf260820i.doc)

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Exforge

Active ingredient

Amlodipine; Valsartan

Schedule

S4

 

1 Name of Medicine

Amlodipine besylate/valsartan.

2 Qualitative and Quantitative Composition

Exforge 5/80, Exforge 5/160, Exforge 10/160, Exforge 5/320 and Exforge 10/320 are available as film coated tablets in five strengths containing amlodipine besylate (5 or 10 mg) and valsartan (80, 160 or 320 mg) as: 5/80 mg, 5/160 mg, 10/160 mg, 5/320 mg and 10/320 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Exforge 5/80 (5 mg amlodipine and 80 mg valsartan).

Dark yellow, round film-coated tablet with bevelled edge, debossed with NVR on one side and NV on the other.

Exforge 5/160 (5 mg amlodipine and 160 mg valsartan).

Dark yellow, ovaloid film-coated tablet with bevelled edge, debossed with NVR on one side and ECE on the other.

Exforge 10/160 (10 mg amlodipine and 160 mg valsartan).

Light yellow, ovaloid film-coated tablet with bevelled edge, debossed with NVR on one side and UIC on the other.

Exforge 5/320 (5 mg amlodipine and 320 mg valsartan).

Very dark yellow, ovaloid film-coated tablet with bevelled edge, debossed with NVR on one side and CSF on the other.

Exforge 10/320 (10 mg amlodipine and 320 mg valsartan).

Dark yellow, ovaloid film-coated tablet with bevelled edge, debossed with NVR on one side and LUF on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Exforge is indicated for the treatment of hypertension. Treatment should not be initiated with this fixed dose combination.

4.2 Dose and Method of Administration

Exforge 5/80, Exforge 5/160, Exforge 10/160, Exforge 5/320 and Exforge 10/320 are available as film coated tablets in five strengths containing amlodipine besylate (5 or 10 mg) and valsartan (80, 160 or 320 mg) as: 5/80 mg, 5/160 mg, 10/160 mg, 5/320 mg and 10/320 mg.
The recommended dose is one tablet per day of either Exforge 5/80 mg, 5/160 mg, 10/160 mg, 5/320 mg or 10/320 mg. Both amlodipine and valsartan monotherapy can be taken with or without food. Exforge should be consistently taken with or without food. It is recommended to take Exforge with some water.
For convenience, patients adequately controlled on valsartan and amlodipine may be switched to Exforge containing the same component doses from separate tablets. A patient whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy may be switched to combination therapy with Exforge 5/80, 5/160, 10/160, 5/320 and 10/320 mg. When clinically appropriate, direct change from monotherapy to the fixed dose combination may be considered.

4.3 Contraindications

Hypersensitivity to the active substances, dihydropyridine derivatives or to any of the excipients.
Severe hepatic impairment; biliary cirrhosis and cholestasis.
Severe renal impairment (GFR < 30 mL/min/1.73 m2) and patients undergoing dialysis.
Pregnancy.
Concomitant use with aliskiren in patients with type 2 diabetes mellitus (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Hypotension, sodium and/or volume depleted patients.

Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with Exforge 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 Exforge or close medical supervision at the start of treatment is recommended.
If hypotension occurs with Exforge, the patient should be placed in the supine position and, if necessary, given an i.v. infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.

Increased angina and/or acute myocardial infarction.

Rarely patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina and/or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase.

Beta-blocker withdrawal.

Amlodipine is not a beta-blocker and, therefore, gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Renal artery stenosis.

Exforge should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis, stenosis to a solitary kidney. Short-term administration of valsartan to twelve patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal haemodynamics, serum creatinine or blood urea nitrogen (BUN). However, since other drugs that affect the renin angiotensin aldosterone system (RAAS) may increase blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis, monitoring of both parameters is recommended as a safety measure.

Kidney transplantation.

To date there is no experience of the safe use of Exforge in patients who have had a recent kidney transplantation.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy.

As with all other vasodilators, special caution is indicated when using Exforge in patients with haemodynamically relevant aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

Hyperkalaemia.

Concomitant use with potassium supplements, potassium sparing diuretics, salt substitutes containing potassium or other drugs that may increase potassium levels (heparin, etc) should be used with caution and with frequent monitoring of potassium.

Concomitant use with ACE inhibitors.

Concomitant use of an angiotensin II receptor blocker and an ACE inhibitor may increase the risk of hyperkalaemia, renal failure, hypotension and syncope.

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 drugs including ACE inhibitors. Exforge should be immediately discontinued in patients who develop angioedema, and Exforge should not be readministered.

Dual blockade of the renin angiotensin system (RAS).

Caution is required while coadministering ARBs, including valsartan, with other agents blocking the RAS such as ACEIs or aliskiren (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in patients with heart failure/ postmyocardial infarction.

In general, calcium channel blockers should be used with caution in patients with heart failure. As a consequence of inhibiting 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 angiotensin-converting enzyme (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.
Use of valsartan in patients with heart failure or postmyocardial infarction commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed. Patients with more complicated postmyocardial infarction courses may be at increased risk for hypotension and/or renal dysfunction. Caution should be observed when initiating therapy in patients with heart failure or postmyocardial infarction. An assessment of renal function should always be conducted in patients with heart failure or postmyocardial infarction.
An increase in the mortality rate among patients who received a combination of valsartan, ACE inhibitors and beta-blockers has been observed in clinical trials. Concurrent administration of ACE inhibitors, beta-blockers and valsartan is not recommended.

Hepatic injury.

Cases of clinically significant liver disease have occurred with some angiotensin II receptor antagonists. Hepatitis has been reported rarely with valsartan.

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism will not generally respond to antihypertensive drugs acting through the renin angiotensin aldosterone system therefore use of Exforge in these patients is not recommended.

Use in hepatic impairment.

Caution should be exercised when administering Exforge to patients with hepatic impairment or biliary obstructive disorders (see Section 4.4 Special Warnings and Precautions for Use). Liver function should be monitored in patients with mild to moderate hepatic impairment. The daily dose of Exforge should not exceed 5/80 mg in patients with mild to moderate hepatic impairment without cholestasis. Exforge is contraindicated in severe hepatic impairment.
Valsartan is mostly eliminated unchanged via the bile whereas amlodipine is extensively metabolised by the liver. In patients with mild to moderate hepatic impairment without cholestasis, Exforge should be used with caution (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic properties in patients with impaired hepatic function) and careful monitoring of liver function tests should be performed. The daily dose of Exforge should not exceed 5/80 mg. Patients with severe hepatic impairment, biliary cirrhosis or cholestasis should not take Exforge (see Section 4.3 Contraindications).

Use in renal impairment.

No dosage adjustment is required for patients with mild to moderate renal impairment. Monitoring of creatinine and potassium levels is advised for patients with moderate renal impairment. Exforge is contraindicated in severe renal impairment and patients undergoing dialysis.
No dosage adjustment of Exforge is required for patients with mild to moderate renal impairment. Monitoring of creatinine and potassium levels is advised for patients with moderate renal impairment. Patients with severe renal impairment should not take Exforge (see Section 4.3 Contraindications).

Use in the elderly.

Caution is advised when increasing the dose in elderly patients (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Exforge in children and adolescents (below the age of 18 years) have not been established.
Exforge is not recommended for use in patients aged below 18 years due to a lack of safety and efficacy data.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interaction studies have been conducted with Exforge and other drugs, although studies have been conducted with the individual amlodipine and valsartan components, as described below.

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.

Amlodipine.

Simvastatin.

Coadministration of simvastatin with multiple doses of amlodipine increases exposure to simvastatin compared to when simvastatin is administered alone. It is recommended that the dose of simvastatin be reduced to an appropriate dose in accordance with the product information of simvastatin for patients concomitantly on amlodipine.

CYP3A4 inhibitors.

A study in elderly patients has shown that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4 (plasma concentration increases by approximately 50% and the effect of amlodipine is increased). The possibility that more potent inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem cannot be excluded. Caution should therefore be exercised when coadministering amlodipine with CYP3A4 inhibitors.

CYP3A4 inducers (anticonvulsant agents (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, Hypericum perforatum (St John's Wort)).

Coadministration may lead to reduced plasma concentrations of amlodipine. Clinical monitoring is indicated, with possible dosage adjustment of amlodipine during the treatment with the inducer and after its withdrawal.
In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin converting enzyme inhibitors, long acting nitrates, sublingual nitroglycerin (glyceryl trinitrate), digoxin, warfarin, atorvastatin, aluminium/ magnesium antacid, cimetidine, nonsteroidal anti-inflammatory drugs, antibiotics, ethanol and oral hypoglycaemic drugs.

Ciclosporin.

The pharmacokinetics of ciclosporin were not altered when ciclosporin was coadministered with amlodipine in renal transplant patients. The patients were not taking corticosteroids.

Grapefruit juice.

Grapefruit juice is known to inhibit the cytochrome P450 system, thereby affecting pharmacokinetics of drugs such as calcium channel blockers. 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.

Sildenafil.

A single 100 mg dose of sildenafil in 16 patients with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Dantrolene (infusion).

Due to risk of hyperkalaemia, it is recommended that the concomitant administration of calcium channel blockers such as amlodipine with intravenous dantrolene be avoided in patients susceptible to malignant hyperthermia, and in the management of malignant hyperthermia.

Valsartan.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use. If a diuretic is also used, the risk of lithium toxicity may presumably be increased further with Exforge.

Potassium.

Concomitant use with potassium supplements, potassium sparing diuretics, salt substitutes containing potassium or other drugs that may increase potassium levels (heparin, etc) requires caution and frequent monitoring of potassium levels.

Hepatic transporters.

Coadministration with inhibitors of the hepatic uptake transporter OATP1B1 (such as rifampicin, ciclosporin) or hepatic efflux transporter MRP2 (e.g. ritonavir) may increase the systemic exposure to valsartan.

Dual blockade of the renin angiotensin system (RAS) with ARBs, ACEIs or aliskiren.

The concomitant use of ARBs, including valsartan, with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalaemia, and changes in renal function compared to therapy with one RAS blocker. It is recommended to monitor blood pressure, renal function and electrolytes in patients on Exforge and other agents that affect the RAS (see Section 4.4 Special Warnings and Precautions for Use).
The concomitant use of ARBs including valsartan, or ACEIs, with aliskiren is contraindicated in patients with type 2 diabetes mellitus (see Section 4.3 Contraindications).

Combination use of ACE inhibitors or angiotensin receptor antagonist, thiazide diuretics and anti-inflammatory drugs (NSAIDs or COX-2 inhibitors).

When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, the use of an ACE inhibiting drug (ACE-inhibitors) or angiotensin receptor antagonist, a thiazide diuretic (including hydrochlorothiazide) and an anti-inflammatory drug (NSAID or COX-2 inhibitor) at the same time increases the risk of renal impairment. Concomitant use of angiotensin II antagonists and NSAIDs in patients who are elderly, volume depleted (including those on diuretic therapy) or have compromised renal function may lead to an increased risk of worsening renal function, including possible acute renal failure. This includes use in fixed combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly when initiating or modifying treatment.

In monotherapy with valsartan.

No drug interactions of clinical significance have been found with the following drugs: cimetidine, warfarin, frusemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide.
As valsartan is not metabolised to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with valsartan. Although valsartan is highly bound to plasma proteins, in vitro studies have not shown any interaction at this level with a range of molecules which are also highly protein bound, such as diclofenac, frusemide and warfarin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No specific fertility studies were conducted with valsartan/ amlodipine combination, however, testes, ovaries and secondary sex organs were evaluated in other toxicity studies with this combination. The primary and secondary sex organs were not affected in these toxicity studies, in which rats and marmosets were treated with this combination for up to 13 weeks.

Valsartan.

Fertility of male and female rats was not affected at oral doses up to 200 mg/kg/day, with systemic exposure similar to that in human patients at the maximum recommended dose.

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 but in one rat study, adverse effects were found on male fertility.
(Category D)
Exforge must not be used during pregnancy (see Section 4.3 Contraindications) or in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the renin angiotensin aldosterone system (RAAS) should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Exforge must be discontinued as soon as possible.
Drugs that act on the renin-angiotensin-aldosterone system (RAAS) can cause foetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors (a specific class of drugs acting on the RAAS).
Due to the mechanism of action of angiotensin II antagonists, a risk to the foetus cannot be excluded. The use of drugs that act directly on the renin angiotensin aldosterone system (RAAS) during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have inadvertently taken valsartan. Pregnant women who are taking angiotensin II receptor antagonists (ARAs) should be changed as quickly as possibly to other antihypertensive medication to maintain normal blood pressure. It is generally advisable not to use ARAs for the management of hypertension in women who are likely to become pregnant.
Calcium channel blockers carry the potential to produce foetal hypoxia associated with maternal hypotension. Accordingly, they should not be used in pregnant women unless the potential benefit outweighs the risk to the foetus.
In the event that neonates are exposed to Exforge in utero and oliguria or hypotension occurs, direct attention towards support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
There was no evidence of teratogenicity in rats dosed with the amlodipine/ valsartan combinations during organogenesis at doses up to 20/320 mg/kg/day PO. Foetotoxicity was observed in association with maternal toxicity (≥ 10/160 mg/kg/day) in rats at amlodipine/ valsartan doses of 20/320 mg/kg/day and included decreased fetal weights, dilated ureters and delayed/ incomplete ossification. The (AUC) exposures at these doses were 3-10 x the expected human exposure to amlodipine/ valsartan at the maximum proposed clinical dose (10/160 mg/day).
No teratogenic effects were observed when valsartan alone was administered orally to mice and rats at a dose of 600 mg/kg/day and to rabbits at a dose of 10 mg/kg/day during the period of organogenesis. However, foetal losses were observed at the highest dose level in rabbits, and foetal weight was reduced at 600 mg/kg/day in rats and at 5 mg/kg/day in rabbits.
Administration of 600 mg/kg/day valsartan to rats prior to parturition and during lactation caused a decrease in birthweight, a reduction in postnatal growth and survival, and a slight delay in physical development of the offspring. A reduction of red blood cell parameters and evidence of changes in renal haemodynamics were observed at 200-600 mg/kg/day.
No teratogenic effects were found when 18 mg/kg/day amlodipine (base) was administered in rats or 10 mg/kg/day in rabbits. Amlodipine (7 mg/kg/day as base) administered orally to rats at or near parturition induced a prolongation of gestation time, an increase in number of stillbirths and decreased postnatal survival.
It is not known whether valsartan and/or amlodipine are excreted in human milk. There are no studies with the amlodipine besylate/ valsartan combination in lactating animals. Valsartan was excreted in the milk of lactating rats. A peri/postnatal study in rats with valsartan showed reductions in postnatal growth and survival, and a slight delay in physical development of the offspring when valsartan was administered to rats prior to parturition and during lactation at 600 mg/kg/day. No effects were observed at 200 mg/kg/day. It is, therefore, not advisable for women who are breastfeeding to use Exforge.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles or using machines it should be taken into account that occasionally dizziness or weariness may occur.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

Adverse reactions with suspected relationship to Exforge.

The safety of Exforge has been evaluated in five controlled clinical studies with 5,175 patients, 2,613 of whom received amlodipine in combination with valsartan.
Adverse drug reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. See Table 1.

Laboratory evaluation.

Very few hypertensive patients treated with amlodipine/ valsartan showed notable changes in laboratory test results from baseline. There was a slightly higher incidence of notably increased blood urea nitrogen in the amlodipine/ valsartan (5.5%) and valsartan monotherapy (5.5%) groups as compared to the placebo group (4.7%).
In controlled trials, the incidence of notable laboratory changes with amlodipine/valsartan 10/320 mg, 5/320 mg and placebo were as follows: BUN (> 50% increase): 5.0%, 1.6%, and 4.7%, respectively; potassium (> 20% increase): 2.0%, 3.3%, and 3.4%; ALT (> 150% increase): 2.0%, 0.0%, and 0.9%; creatinine (> 50% increase): 0.5%, 0.0%, and 0.6%; CK (> 300% increase): 1.0%, 0.0%, and 0.9%. In a long-term, open label, uncontrolled clinical trial of 5/320 mg, increases in BUN greater than 50% were observed in 10.9% of the patients treated, increases in serum potassium greater than 20% were observed in 9.4% of the patients treated, increases in ALT greater than 150% were observed in 2.8% of the patients treated, increases in creatinine greater than 50% were observed in 1.3% of the patients treated, and increases in CK greater than 300% were observed in 1% of the patients treated.

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 shown in Table 2.
The mean incidence of peripheral oedema evenly weighted across all doses was 5.1% with the amlodipine/valsartan combination.
An orthostatic blood pressure change, defined as a decrease of at least 20 mmHg in systolic blood pressure or a decrease of at least 10 mmHg in diastolic blood pressure when a patient moved from a sitting position to a standing position, was observed in 9.5% of patients receiving amlodipine/valsartan 5/320 mg, 8.7% receiving amlodipine/valsartan 10/320 mg compared to 7.4% receiving placebo.

Additional information on individual components.

Adverse reactions previously reported with one of the individual components may occur with Exforge even if not observed in clinical trials.

Amlodipine.

Other additional adverse experiences reported in clinical trials and postmarketing reports with amlodipine monotherapy, irrespective of their causal association with the study drug, were as follows.
The most commonly observed adverse event was vomiting.
Less commonly observed adverse events were peripheral ischaemia, alopecia, anorexia, altered bowel habits, dyspepsia, dysphagia, flatulence, dyspnoea, epistaxis, rhinitis, gastritis, gingival hyperplasia, gynaecomastia, hyperglycaemia, impotence, increased urinary frequency, malaise, sexual dysfunction, insomnia, nervousness, depression, abnormal dreams, depersonalisation, mood changes, pain, rigors, weight gain, arthrosis, muscle cramps, myalgia, hypoaesthesia, dysgeusia, tremor, peripheral neuropathy, pancreatitis, leucopenia, thrombocytopenia, purpura vasculitis, conjunctivitis, diplopia, eye pain, photosensitivity, micturition frequency and disorder, nocturia, sweating increased, thirst, angioedema and erythema multiforme.
Rarely observed adverse events were cardiac failure, pulse irregularity, extrasystoles, skin discolouration, urticaria, skin dryness, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, increased appetite, loose stools, coughing, dysuria, parosmia, taste perversion, xerophthalmia and weight decrease.
As with other calcium channel blockers, the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: myocardial infarction, angina, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), chest pain, Stevens-Johnson syndrome, allergic reactions.
There have been infrequent, postmarketing reports of hepatitis, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis). Some cases severe enough to require hospitalisation have been reported in association with use of amlodipine. In many instances, causal association is uncertain.
Exceptional cases of extrapyramidal syndrome have been reported.
In a long term placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of nonischaemic 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.

Risk of myocardial infarction or increased angina.

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. Arrhythmia (including ventricular tachycardia and atrial fibrillation) has also been reported with calcium channel blocker therapy. These adverse events may not be distinguishable from the natural history of the underlying disease.

Valsartan.

Other additional adverse experiences reported in clinical trials and postmarketing reports with valsartan monotherapy in the hypertension indication, irrespective of their causal association with the study drug, were as follows.
Viral infections, upper respiratory infections, pharyngitis, sinusitis, rhinitis, neutropenia, thrombocytopenia, insomnia, libido decrease, myalgia, dyspepsia, flatulence, muscle cramps, chest pain, anorexia, vomiting, dyspnoea, elevated liver enzymes and very rare reports of hepatitis. Altered renal function (especially in patients treated with diuretics or in patients with renal impairment), acute renal failure, renal insufficiency, angioedema and hypersensitivity (vasculitis, serum sickness) can occur.

Laboratory findings.

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan.

Creatinine.

Minor elevations in creatinine occurred in 0.8% of patients taking valsartan and 0.6% given placebo in controlled trials of hypertensive patients. In heart failure patients, increases in serum creatinine greater than 50% were observed in 3.9% of valsartan treated patients compared to 0.9% of placebo treated patients. In postmyocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan treated patients, 4.8% of valsartan plus captopril treated patients, and 3.4% of captopril treated patients.

Blood urea nitrogen.

In heart failure trials, increases in blood urea nitrogen (BUN) greater than 50% were observed in 16.6% of patients treated with valsartan compared to 6.3% of patients treated with placebo.

Haematocrit and haemoglobin.

Greater than 20% decreases in haemoglobin and haematocrit were observed in 0.4% and 0.8%, respectively, of valsartan patients compared with 0.1% and 0.1% in placebo treated patients. One valsartan patient discontinued treatment for microcytic anaemia.

Liver function tests.

Occasional elevations (greater than 150%) of liver function values were reported in patients treated with valsartan. Three patients (< 0.1%) treated with valsartan discontinued treatment for elevated liver function values. Elevated liver enzymes have also been reported in postmarketing surveillance.

Neutropenia.

Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo.

Serum potassium.

In patients with hypertension, increases in serum potassium greater than 20% were observed in 4.4% of patients treated with valsartan compared to 2.9% of placebo treated patients. No patients treated with valsartan discontinued therapy for hyperkalaemia. In heart failure patients, increases in serum potassium greater than 20% were observed in 10.0% of valsartan treated patients compared to 5.1% of placebo treated patients.

Postmarketing experience.

Amlodipine.

Gynaecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalisation, have been reported in association with use of amlodipine.

Valsartan.

The following additional adverse reactions have been reported in postmarketing experience with valsartan.

Blood and lymphatic.

There are very rare reports of thrombocytopenia.

Hypersensitivity.

There are rare reports of angioedema.

Digestive.

Elevated liver enzymes and very rare reports of hepatitis.

Renal.

Impaired renal function.

Clinical laboratory tests.

Hyperkalemia.

Dermatologic.

Alopecia.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. Dermatitis bullous and hyponatraemia of unknown incidence have been reported.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Symptoms.

There is no experience of overdose with Exforge yet. Overdose with valsartan may result in pronounced hypotension with dizziness which could lead to depressed level of consciousness, circulatory collapse and/or shock. Overdose with amlodipine may result in excessive peripheral vasodilation with marked hypotension and possibly reflex tachycardia. Dysrhythmias may occur following overdose with any calcium antagonists. Hypotension and bradycardia are usually seen within one to five hours following overdose. Hypotension can persist for longer than 24 hours despite treatment. Cardiac rhythm disturbances have been noted to persist for up to seven days. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Treatment.

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

Mechanism of action.

Exforge 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 (Ang II) antagonist class of medicines. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Amlodipine.

The amlodipine component of Exforge 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 nondihydropyridine 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 coadministered 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.

Valsartan.

Valsartan is an orally active, potent and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The AT2 receptor subtype has not been definitely shown to be associated with cardiovascular homeostasis. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has about a 20,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang 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 cough. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (p < 0.05) less in patients treated with valsartan than in those treated with an ACE inhibitor (2.4% 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 cough compared with 68.9% 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 reduction of 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 reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after dose 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.

Clinical trials.

Over 1,400 hypertensive patients received Exforge once daily in 2 placebo controlled trials. Over 1100 patients received Exforge once daily in 2 active controlled trials. Adults with mild to moderate uncomplicated essential hypertension (mean sitting diastolic blood pressure ≥ 95 mmHg 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.
Study A2201 was a double blind, placebo controlled, dose response study of 1911 patients with mild to moderate hypertension receiving combinations of amlodipine and valsartan (2.5/40, 2.5/80, 2.5/160, 2.5/320, 5/40, 5/80, 5/160, 5/320 mg) or amlodipine alone (2.5 or 5 mg), valsartan alone (40, 80, 160 or 320 mg) or placebo. At week 8 endpoint, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures (see Tables 3 and 4), however, the control rates varied (see Table 5).
Study A2307 was a double blind, placebo controlled, dose response study of 1250 patients with mild to moderate hypertension treated with two combinations of amlodipine and valsartan (10/160, 10/320 mg) or amlodipine alone (10 mg), valsartan alone (160 or 320 mg) or placebo. At week 8 endpoint, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures (see Tables 6 and 7), however, the control rates varied (see Table 8).
Study A2305 was a double blind, active controlled study of 947 patients with mild to moderate hypertension who were not adequately controlled on valsartan 160 mg. Patients received treatment of two combinations of amlodipine and valsartan (10/160, 5/160 mg) or valsartan alone (160 mg). At week 8 endpoint, the combination treatments were statistically significantly superior to their monotherapy component in reduction of diastolic and systolic blood pressures. (See Table 9.)
Study A2306 was a double blind, active controlled study of 944 patients with mild to moderate hypertension who were not adequately controlled on amlodipine 10 mg. Patients received a combination of amlodipine and valsartan (10/160 mg) or amlodipine alone (10 mg). At week 8 endpoint, the combination treatment was statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures. (See Table 10.)
Exforge was also studied in an active controlled study of 130 hypertensive patients with diastolic blood pressure ≥ 110 mmHg and < 120 mmHg. In this study (baseline blood pressure 171/113 mmHg), an Exforge regimen of 5/160 mg titrated to 10/160 mg reduced sitting blood pressure at week 6 endpoint by 36/29 mmHg as compared to 32/28 mmHg with a regimen of lisinopril/ hydrochlorothiazide 10/12.5 mg titrated to 20/12.5 mg (not available in Australia).
Two open label one year extension studies (A2201E and A2307E) of the combination of amlodipine and valsartan were conducted in patients with mild to moderate hypertension recruited from study 2201 and study 2307, respectively. Patients needed to successfully complete the core studies with well controlled blood pressure and no serious drug-related adverse experiences. The results demonstrated that amlodipine/valsartan 160/5, 160/10 and 5/320 mg are effective in providing long term blood pressure.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable oedema, combination therapy may achieve similar blood pressure control with less oedema.
Age, gender and race did not influence the response to Exforge.
No clinical outcomes studies have been conducted on cardiovascular morbidity and mortality with Exforge.
There have been no studies conducted to evaluate as a primary endpoint the additional blood pressure lowering effects on the direct titration of patients from Exforge 10/160 mg or below to the higher strengths of 5/320 mg or 10/320 mg.

5.2 Pharmacokinetic Properties

Amlodipine/ valsartan.

Following oral administration of Exforge peak plasma concentrations of amlodipine and valsartan are reached in 6-8 and 3 hours, respectively. The rate and extent of absorption of Exforge are equivalent to the bioavailability of amlodipine and valsartan when administered as individual tablets.

Absorption.

Amlodipine.

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.

Valsartan.

Peak plasma concentrations are reached 2 to 4 hours after dosing. The amount absorbed varies widely. Mean absolute bioavailability is 23% and the bioavailability relative to an oral solution is 59%.
The pharmacokinetics of valsartan are linear over the dose range 80-320 mg. There is no change in the kinetics of valsartan on repeated administration and little accumulation when dosed once daily. Plasma concentrations are similar in males and females.

Distribution.

Amlodipine.

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 in hypertensive patients.

Valsartan.

Valsartan is highly bound to serum protein (94-97%), mainly serum albumin. Steady-state volume of distribution is low (about 17 L) indicating that valsartan does not distribute into tissues extensively.

Metabolism.

Amlodipine.

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

Valsartan.

When valsartan is given with food, the area under the plasma concentration time curve (AUC) of valsartan is reduced by 48% although, from about 8 h postdosing, plasma valsartan concentrations are similar for the fed and fasted group.
Valsartan does not undergo extensive biotransformation. Only approximately 25% of absorbed drug is metabolised. The primary metabolite is valeryl 4-hydroxy valsartan, which is pharmacologically inactive. The enzyme(s) responsible for valsartan metabolism have not been identified.

Excretion.

Amlodipine.

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.

Valsartan shows biexponential decay kinetics with a t1/2α of about 1 h and a t1/2β of about 9.5 hours. After oral dosing, 83% of the dose is excreted in the faeces and 13% in the urine, mainly as unchanged compound. Following intravenous administration, renal clearance of valsartan accounts for about 30% of total plasma clearance. Plasma clearance is relatively slow (about 2 L/h) when compared with hepatic blood flow (about 90 L/h).

Pharmacokinetic properties in children.

No pharmacokinetic data are available in the paediatric population.

Pharmacokinetic properties in the elderly (aged 65 years or older).

Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in AUC and elimination half-life.
Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly compared to younger patients.

Pharmacokinetic properties in patients with impaired renal function.

The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.
As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, there is no apparent correlation between renal function (measured by creatinine clearance) and systemic exposure to valsartan (measured by AUC) in patients with different degrees of renal failure. A trial in 5 normotensive patients undergoing haemodialysis demonstrated that complete loss of renal function does not lead to a gross increase in the exposure to valsartan and does not have a major impact on the kinetics of valsartan. This study also confirmed that valsartan is not removed from the plasma by haemodialysis.

Pharmacokinetic properties in patients with impaired hepatic function.

Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%. In a small number of patients with mild to moderate hepatic impairment given single doses of 5 mg, amlodipine half-life has been prolonged. Worsening of liver function test values may occur.
About 70% of the absorbed valsartan dose is excreted in the bile, mainly as unchanged compound. The AUC with valsartan has been observed to approximately double in patients with mild or moderate hepatic impairment including patients with biliary obstructive disorders (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment). There are no data available on the use of valsartan in patients with severe hepatic dysfunction (see Section 4.3 Contraindications).
Care should be exercised in patients with liver disease (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with the amlodipine/ valsartan combination.

Valsartan.

Genotoxicity studies showed that valsartan does not cause gene mutation in bacterial or mammalian cells, nor does it induce chromosomal damage in vitro or in vivo.

Amlodipine.

Did not induce gene mutation in bacteria or mouse lymphoma cells, and was not clastogenic in human lymphocytes, Chinese hamster V79 fibroblast cells (in vitro) or mouse bone marrow cells (in vivo).

Carcinogenicity.

No carcinogenicity studies have been conducted with the amlodipine/ valsartan combination.

Valsartan.

In animal studies, there was no clear evidence of carcinogenic activity when valsartan was administered in the diet to male and female mice at doses up to 160 mg/kg/day for two years, but systemic exposure (plasma AUC value) at this dose level was lower than that achieved in humans. There was no clear evidence of carcinogenic activity in male or female rats at up to 200 mg/kg/day with plasma concentrations approximately 1.5 times the concentrations achieved in humans (based on AUC) at the maximum recommended dose (320 mg).

Amlodipine.

The carcinogenic potential of amlodipine has not been fully elucidated. Amlodipine did not induce any tumours when tested in rats at oral doses up to 2.5 mg/kg. This dose gave rise to plasma levels that are similar to those achieved clinically.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cellulose-microcrystalline, crospovidone, silica-colloidal anhydrous, magnesium stearate, hypromellose, titanium dioxide (except 5/320 mg), iron oxide yellow, macrogol 4000, talc purified, iron oxide red (10/160 mg and 5/320 mg only) and sodium starch glycollate (5/320 mg and 10/320 mg only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30 degrees Celsius. Protect from moisture.

6.5 Nature and Contents of Container

Exforge 5/80 (5 mg amlodipine and 80 mg valsartan).

Blister packs of 7, 14, 28, 30 and 56.

Exforge 5/160 (5 mg amlodipine and 160 mg valsartan).

Blister packs of 7, 14, 28, 30 and 56.

Exforge 10/160 (10 mg amlodipine and 160 mg valsartan).

Blister packs of 7, 14, 28, 30 and 56.

Exforge 5/320 (5 mg amlodipine and 320 mg valsartan).

Blister packs of 7, 14, 28, 30 and 56.

Exforge 10/320 (10 mg amlodipine and 320 mg valsartan).

Blister packs of 7, 14, 28, 30 and 56.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Amlodipine besylate is a white or almost white powder that is slightly soluble in water and sparingly soluble in ethanol. Valsartan is a white to practically white microcrystalline and slightly bitter tasting powder. It is soluble in ethanol and methanol and slightly soluble in water.

Chemical structure.

Amlodipine (as the besylate salt).


(3-ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)- 6-methyl-1,4-dihydropyridine- 3,5-dicarboxylate benzenesulphonate).

CAS number.

111470-99-6.
Molecular formula: C20H25ClN2O5,C6H6O3S.
Molecular weight: 567.06.

Chemical structure.

Valsartan.


(N-pentanoyl- N-[2'-(1H-tetrazol-5-yl) biphenyl-4ylmethyl]- L-valine).

CAS number.

137862-53-4.
Molecular formula: C24H29N5O3.
Molecular weight: 435.5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes