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.

SUMMARY CMI

EXFORGE®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using EXFORGE?

EXFORGE contains the active ingredients Valsartan and Amlodipine Besilate. EXFORGE is used to control high blood pressure, also called hypertension.

For more information, see Section 1. Why am I using EXFORGE? in the full CMI.

2. What should I know before I use EXFORGE?

Do not use if you have ever had an allergic reaction to EXFORGE or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use EXFORGE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with EXFORGE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use EXFORGE?

  • The usual dose is one tablet a day. Your doctor will tell you how many tablets to take each day. Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.
  • Take this medicine until your doctor tells you to stop even if you feel quite well.

More instructions can be found in Section 4. How do I use EXFORGE? in the full CMI.

5. What should I know while using EXFORGE?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using EXFORGE.
  • If you become pregnant while taking EXFORGE, tell your doctor immediately.
  • Tell your doctor, if for any reason, you have not taken your medicine exactly as prescribed.
  • 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.
Things you should not do
  • Do not stop 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.
Driving or using machines
  • 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.
Looking after your medicine
  • Keep the tablets in the original packet and foils until it is time to take them.
  • Store the tablets in a cool, dark and dry place at room temperature (30°C).

For more information, see Section 5. What should I know while using EXFORGE? in the full CMI.

6. Are there any side effects?

Common side effects: headache, persistent ringing in the ears, dizziness, tiredness, diarrhoea, constipation or gas, muscle or joint pain, abdominal pain, nausea, vomiting, dry cough, sore throat, croaky voice, runny or blocked nose, blistering skin, difficulty sleeping, feeling anxious or sad, tingling or numbness in the hands or feet, problems with sexual function, breast enlargement in men, unusual hair loss or thinning.

Serious side effects: swelling of hands, feet or limbs, feeling of fast or irregular heartbeat, shortness of breath, tiredness, chest pain, severe dizziness, liver disease with nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine, constant "flu-like" symptoms

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

EXFORGE®

Active ingredient(s): Amlodipine besilate/Valsartan

Consumer Medicine Information (CMI)

This leaflet provides important information about using EXFORGE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using EXFORGE.

Where to find information in this leaflet:

1. Why am I using EXFORGE?
2. What should I know before I use EXFORGE?
3. What if I am taking other medicines?
4. How do I use EXFORGE?
5. What should I know while using EXFORGE?
6. Are there any side effects?
7. Product details

1. Why am I using EXFORGE?

EXFORGE contains the active ingredients Valsartan and amlodipine besilate. EXFORGE belongs to a group of medicines called antihypertensives. These medicines help treat high blood pressure. The ingredients in EXFORGE reduce blood pressure in two different ways:

  • 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.
  • Amlodipine besilate 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 control high blood pressure, which is also called hypertension.

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.

2. What should I know before I use EXFORGE?

Warnings

Do not use EXFORGE if:

  • you are allergic to Valsartan or amlodipine besilate, allergic to medicines belonging to a group of chemicals called dihydropyridines, used to treat blood pressure and other heart problems, or allergic to any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
    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
  • you are pregnant or intending to become pregnant.
  • you have severe kidney disease or are having dialysis.
  • you have liver problems caused by a blockage in the bile duct or any other severe liver problems.
  • you have Cholestasis, which is reduced or stopped bile flow.
  • you are also taking other blood pressure lowering medications containing Aliskiren and have type 2 diabetes.
  • it is 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 for disposal.

Check with your doctor if you have any other medical conditions such as:

  • severe kidney problems or received a kidney transplant
  • liver problems
  • heart problems, including obstructed blood flow through the heart from narrowing of valves (stenosis) or enlarged septum of the heart (HOCM)
  • primary hyperaldosteronism (Conn's syndrome), a hormone disorder causing build-up of fluid in the body.
  • 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 allergic to any other medicines, foods, dyes or preservatives.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed. 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.

3. What if I am taking other medicines?

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

Some medicines may interfere with EXFORGE and affect how it works. You may need to take different amounts of your medicines, or you may need to take different medicines.

These medicines 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 (rifamycins), anti-rejection drugs (Cyclosporin), antiretrovirals (Ritonavir) which may increase the effect of EXFORGE
  • potassium supplements, salt substitutes containing potassium, or other drugs that may increase potassium levels
  • 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)
  • anti-inflammatory medicines such as Celebrex, Voltaren and Indocid (NSAIDs) or Selective Cyclooxygenase-2 Inhibitors (Cox-2 inhibitors)
  • intravenous dantrolene used to treat malignant hyperthermia

Your doctor may also check your kidney function.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect EXFORGE.

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

4. How do I use EXFORGE?

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

When to take EXFORGE

  • Take it 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 (i.e. at breakfast time).

How to take EXFORGE

  • 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.

If you forget to take EXFORGE

EXFORGE should be used regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose 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 dose you missed.

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

If you take too much EXFORGE (overdose)

If you think that you have used too much EXFORGE, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should 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, lightheaded 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.

5. What should I know while using EXFORGE?

Things you should do

  • If you become pregnant while taking EXFORGE, tell your doctor immediately. You should not be taking 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 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. 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.

Things to be careful of

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

Call your doctor straight away 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; fever, shortness of breath, wheezing or troubled breathing.

Remind any doctor, dentist or pharmacist you visit that you are using EXFORGE.

Things you should 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how EXFORGE affects you.

EXFORGE may 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.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Keep your tablets in the original container until it is time to take them.

Store it in a cool dry place below 30°C (room temperature) away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • 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 it where young children cannot reach it.

A locked cupboard at least one-and-a-half meters above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • 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
  • upset stomach or indigestion
  • weight gain
  • feeling nervous, depressed or moody
  • change in sense of taste
  • sensitivity to light
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • signs of allergy such as rash, itching or hives on the skin; swelling of the face, lips, tongue or other part of the body; fever, shortness of breath, wheezing or troubled breathing
  • feeling of fast or irregular heart beat (pounding, racing, skipping beats)
  • chest pain
  • shortness of breath not caused by exercise, with swelling of legs and feet
  • tiredness or lack of energy, being short of breath when exercising, dizziness and looking pale
  • bleeding or bruising more easily
  • constant "flu-like" symptoms such as chills, fever, sore throat, aching joints, sores in mouth, swollen glands
  • severe dizziness or fainting
  • stomach pain and signs of liver disease with nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, and dark coloured urine
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

EXFORGE is only available with a doctor's prescription.

What EXFORGE contains

Active ingredient
(main ingredient)		Valsartan and Amlodipine besilate
Other ingredients
(inactive ingredients)		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
Potential allergensNone

Do not take this medicine if you are allergic to any of these ingredients.

What EXFORGE 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.

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)

Who distributes EXFORGE

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
Website: www.novartis.com.au

® = Registered Trademark

This leaflet was prepared in August 2024.

(Internal document code: exf300824c.doc based on PI exf300824i.doc)

Published by MIMS October 2024

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.
Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

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