Consumer medicine information

Amlodipine}Valsartan}HCT Novartis

Amlodipine; Valsartan; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Amlodipine/Valsartan/HCT Novartis

Active ingredient

Amlodipine; Valsartan; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Amlodipine}Valsartan}HCT Novartis.

What is in this leaflet

This leaflet answers some common questions about AMLODIPINE/VALSARTAN/HCT NOVARTIS.

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 AMLODIPINE/VALSARTAN/HCT NOVARTIS is used for

AMLODIPINE/VALSARTAN/HCT NOVARTIS 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.

AMLODIPINE/VALSARTAN/HCT NOVARTIS contains amlodipine besilate, valsartan and hydrochlorothiazide. These medicines reduce blood pressure in three different ways.

  1. 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.
  2. 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.
  3. Hydrochlorothiazide helps reduce the amount of excess fluid in the body by increasing the amount of urine produced. This helps lower your blood pressure.

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 AMLODIPINE/VALSARTAN/HCT NOVARTIS in children.

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

Before you take AMLODIPINE/VALSARTAN/HCT NOVARTIS

When you must not take it

Do not take AMLODIPINE/VALSARTAN/HCT NOVARTIS if you have ever had an allergic reaction after taking:

  • amlodipine besilate, valsartan or hydrochlorothiazide (the active ingredients in AMLODIPINE/VALSARTAN/HCT NOVARTIS
  • medicines belonging to a group of chemicals called dihydropyridines, used to treat blood pressure and other heart problems
  • medicines belonging to a group of chemicals called sulfonamide-derived (such as some antibiotics e.g. Bactrim® trimethoprim and sulfamethoxazole)
  • 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS if you are pregnant or intend to become pregnant. AMLODIPINE/VALSARTAN/HCT NOVARTIS is not recommended for use in pregnancy. Like other similar medicines, it could affect your unborn baby.

Do not take AMLODIPINE/VALSARTAN/HCT NOVARTIS 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
  • Anuria, which is a condition where you are unable to urinate
  • High uric acid levels in the blood, which may cause gout
  • Low level of potassium or sodium, or high level of calcium in your blood.

Check with your doctor if you are unsure if you have any of the above conditions.

Do not take AMLODIPINE/VALSARTAN/HCT NOVARTIS if you are also taking other blood pressure lowering medicines containing aliskiren and have type 2 diabetes.

Do not take AMLODIPINE/VALSARTAN/HCT NOVARTIS 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:

  • kidney problems or received a kidney transplant
  • liver problems
  • systemic lupus erythematosus, a disease affecting the skin, joints and kidneys
  • heart problems, including obstructed blood flow from narrowing of valves (stenosis) or enlarged septum (HOCM)
  • swelling, mainly of the face and throat, while taking other medicines (including an ACE inhibitor or aliskiren)
  • a hormone disorder causing fluid retention known as primary hyperaldosteronism (Conn's syndrome)
  • passing less urine than is normal for you or difficulty passing urine
  • salt restricted diet
  • suffering from several episodes of vomiting or diarrhoea.
  • skin cancer.

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 AMLODIPINE/VALSARTAN/HCT NOVARTIS in this case. Hydrochlorothiazide and amlodipine are known to pass into the breast milk, however it is not known if valsartan, the other active ingredient of AMLODIPINE/VALSARTAN/HCT NOVARTIS, passes into the breast milk and could affect your baby. Therefore, AMLODIPINE/VALSARTAN/HCT NOVARTIS is not recommended if you are breast-feeding.

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 AMLODIPINE/VALSARTAN/HCT NOVARTIS.

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 AMLODIPINE/VALSARTAN/HCT NOVARTIS may interfere with each other. 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS
  • intravenous dantrolene used to treat malignant hyperthermia
  • some antibiotics (rifampicin), anti-rejection drugs (cyclosporin), 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.)
  • non-steroidal anti-inflammatory drugs (NSAIDs) and selective Cyclooxygenase-2 Inhibitors (Cox-2 inhibitors), medicines used to relieve swelling and other symptoms of inflammation, including arthritis (Your doctor may also check your kidney function)
  • medicines or supplements containing calcium
  • vitamin D
  • medicines used to relax muscles before or during surgery
  • steroid medicines such as cortisone, prednisone and ACTH
  • lithium, antidepressants, antipsychotics, medicines used to treat mood swings and some types of depression
  • cyclophosphamide or methotrexate
  • penicillin
  • amphotericin, a medicine used to treat fungal infections
  • insulin and tablets used to treat diabetes
  • medicines used to treat gout
  • cyclosporine
  • carbamazepine, an anticonvulsant and mood stabilising drug used primarily in the treatment of epilepsy and bipolar disorder
  • digoxin or other digitalis glycosides (medicines used to treat heart problems)
  • antiarrhythmics (medicines used to treat heart problems)
  • medicines used for oesophageal ulceration and inflammation
  • amantadine, and anti-Parkinson therapy also used to treat or prevent certain illnesses caused by viruses
  • cytotoxic drugs used in cancer therapy
  • medicine used to treat gastrointestinal cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms, Parkinson's disease and as aid to anaesthesia from a class called anticholinergic agents
  • cholestyramine, colestipol, and other resins (medicines used mainly to treat high levels of lipids in the blood)
  • pressor amines, such as noradrenaline (substances that raise blood pressure)
  • barbiturates, narcotics (medicines with sleep-inducing properties) and alcohol.
  • radioactive iodine, used as a medical tracer or diagnosis.

Your doctor and pharmacist have a more complete list of medicines to be careful of while taking AMLODIPINE/VALSARTAN/HCT NOVARTIS.

How to take AMLODIPINE/VALSARTAN/HCT NOVARTIS

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.

When to take it

Take your AMLODIPINE/VALSARTAN/HCT NOVARTIS 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS.

Do this even if there are no signs of discomfort or poisoning.

Keep the telephone numbers for these places handy.

Too much AMLODIPINE/VALSARTAN/HCT NOVARTIS 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS

Things you must do

If you become pregnant while taking AMLODIPINE/VALSARTAN/HCT NOVARTIS, 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS. AMLODIPINE/VALSARTAN/HCT NOVARTIS 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS.

Tell any other doctor, dentist or pharmacist who treats you that you are taking AMLODIPINE/VALSARTAN/HCT NOVARTIS.

Things you must not do

Do not take AMLODIPINE/VALSARTAN/HCT NOVARTIS 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS 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.

When you are outdoors, wear protective clothing and use at least a factor 30 (or higher), water-resistant sunscreen.

Do not use a sunlamp.

This medicine may cause your skin to be much more sensitive to sunlight than it normally is.

Exposure to sunlight may cause a skin rash, itching, redness or severe sunburn. If your skin does appear to be burning, tell your doctor.

Treatment with AMLODIPINE/VALSARTAN/HCT NOVARTIS, particularly long-term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun exposure and UV rays while taking AMLODIPINE/VALSARTAN/HCT NOVARTIS. Regularly check your skin for any new lesions and promptly report any suspicious skin lesions to your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking AMLODIPINE/VALSARTAN/HCT NOVARTIS, 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
  • indigestion, loss of appetite, stomach upset, pain, diarrhoea, constipation or wind
  • nausea (feeling sick) or vomiting
  • tingling or numbness in hands or feet
  • rash, redness, blistering or peeling of skin, itching
  • appearance of a lump or discoloured patch on the skin
  • lip cancer; the signs and symptoms include:
    - a sore that doesn't heal or comes back after healing
    - pale white or yellow flat areas that look like scars
    - raised and scaly red patches
    - small, smooth and shiny lumps that are pearly white, pink or red
    - a pink growth with raised edges and indents in the centre
    - a growth that has small blood vessels on the surface.
  • excessive sweating
  • feeling anxious or sad
  • problems with sexual function
  • breast enlargement in men
  • unusual hair loss or thinning
  • pain when passing urine, 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
  • unusual tiredness or weakness
  • weight gain
  • feeling nervous, depressed or moody
  • distorted sense of taste
  • sensitivity to light
  • symptoms of sunburn which happens more quickly than normal
  • facial pain.

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
  • signs of a serious skin reaction such as painful red areas, large blisters, peeling of layers of skin, bleeding in the lips, eyes, mouth, nose or genitals. These signs may be accompanied by fever and chills, aching muscles and feeling generally unwell
  • unusual bleeding or bruising under the skin
  • passing less urine than normal
  • decrease in vision or pain in your eyes due to high pressure.

Tell your doctor immediately if you notice any new skin or lip lesions during or after treatment or if an existing lesion changes its appearance.

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 taking AMLODIPINE/VALSARTAN/HCT NOVARTIS

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 AMLODIPINE/VALSARTAN/HCT NOVARTIS or any other medicine in the bathroom or near a sink.
  • Do not leave AMLODIPINE/VALSARTAN/HCT NOVARTIS in the car or on window sills.

Heat and dampness can destroy some medicines. AMLODIPINE/VALSARTAN/HCT NOVARTIS 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 AMLODIPINE/VALSARTAN/HCT NOVARTIS, 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

AMLODIPINE/VALSARTAN/HCT NOVARTIS 5/160/12.5 (5 mg amlodipine, 160 mg valsartan, and 12.5 mg hydrochlorothiazide) tablets are white, ovaloid, biconvex with bevelled edge and imprinted with NVR on one side and VCL on the other. Packs of 7's and 28's#.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/160/12.5 (10 mg amlodipine, 160 mg valsartan, and 12.5 mg hydrochlorothiazide) tablets are pale yellow, ovaloid, biconvex with bevelled edge and imprinted with NVR on one side and VDL on the other. Packs of 7's and 28's.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 5/160/25 (5 mg amlodipine, 160 mg valsartan, and 25 mg hydrochlorothiazide) tablets are yellow, ovaloid, biconvex with bevelled edge and imprinted with NVR on one side and VEL on the other. Packs of 7's and 28's.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/160/25 (10 mg amlodipine, 160 mg valsartan, and 25 mg hydrochlorothiazide) tablets are brown yellow, ovaloid, biconvex with bevelled edge and imprinted with NVR on one side and VHL on the other. Packs of 7's and 28's.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/320/25 (10 mg amlodipine, 320 mg valsartan, and 25 mg hydrochlorothiazide) tablets are brown yellow, ovaloid, biconvex with bevelled edge and imprinted with NVR on one side and VFL on the other. Packs of 7's and 28's.

# marketed pack.

AMLODIPINE/VALSARTAN/HCT NOVARTIS tablets are non-divisible and cannot be divided into equal doses.

Ingredients

AMLODIPINE/VALSARTAN/HCT NOVARTIS tablets contain amlodipine besilate (5 mg or 10 mg), valsartan (160 mg or 320 mg), and hydrochlorothiazide (12.5 mg or 25 mg) as the active ingredients.

The tablets contain the following inactive ingredients:

  • microcrystalline cellulose
  • crospovidone
  • colloidal anhydrous silica
  • magnesium stearate
  • hypromellose
  • macrogol 4000
  • purified talc.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 5/160/12.5 tablets also contain:

  • titanium dioxide.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 5/160/25 also contains:

  • titanium dioxide
  • iron oxide yellow.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/160/12.5 tablets also contains:

  • titanium dioxide
  • iron oxide yellow
  • iron oxide red.

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/160/25 and 10/320/25 tablets also contain:

  • iron oxide yellow.

Sponsor

AMLODIPINE/VALSARTAN/HCT NOVARTIS 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.

Australian Registration Numbers:

AMLODIPINE/VALSARTAN/HCT NOVARTIS 5/160/12.5: AUST R 158161

AMLODIPINE/VALSARTAN/HCT NOVARTIS 5/160/25: AUST R 158163

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/160/12.5: AUST R 158165

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/160/25: AUST R 158167

AMLODIPINE/VALSARTAN/HCT NOVARTIS 10/320/25: AUST R 158169.

This leaflet was prepared in June 2020.

© Copyright 2019.

® = Registered Trademark

Internal document code: vah260620c_V2 based on PI vah260620i_V2

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Amlodipine/Valsartan/HCT Novartis

Active ingredient

Amlodipine; Valsartan; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Amlodipine, valsartan, hydrochlorothiazide.

2 Qualitative and Quantitative Composition

Amlodipine/Valsartan/HCT Novartis 5/160/12.5, Amlodipine/Valsartan/HCT Novartis 5/160/25, Amlodipine/Valsartan/HCT Novartis 10/160/12.5, Amlodipine/Valsartan/HCT Novartis 10/160/25, and Amlodipine/Valsartan/HCT Novartis 10/320/25 are available as film-coated tablets in five strengths containing amlodipine (5 or 10 mg), valsartan (160 or 320 mg) and hydrochlorothiazide (12.5 or 25 mg) as: 5/160/12.5 mg, 5/160/25 mg, 10/160/12.5 mg, 10/160/25 mg and 10/320/25 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Amlodipine/Valsartan/HCT Novartis 5/160/12.5 (5 mg amlodipine, 160 mg valsartan and 12.5 mg hydrochlorothiazide): white, non-scored, ovaloid, biconvex film-coated tablet with bevelled edge, debossed with "NVR" on one side and "VCL" on the other.
Amlodipine/Valsartan/HCT Novartis 10/160/12.5 (10 mg amlodipine, 160 mg valsartan and 12.5 mg hydrochlorothiazide): pale yellow, non-scored, ovaloid, biconvex film-coated tablet with bevelled edge, debossed with "NVR" on one side and "VDL" on the other.
Amlodipine/Valsartan/HCT Novartis 5/160/25 (5 mg amlodipine, 160 mg valsartan and 25 mg hydrochlorothiazide): yellow, non-scored, ovaloid, biconvex film-coated tablet with bevelled edge, debossed with "NVR" on one side and "VEL" on the other.
Amlodipine/Valsartan/HCT Novartis 10/160/25 (10 mg amlodipine, 160 mg valsartan and 25 mg hydrochlorothiazide): brown-yellow, non-scored, ovaloid, biconvex film-coated tablet with bevelled edge, debossed with "NVR" on one side and "VHL" on the other.
Amlodipine/Valsartan/HCT Novartis 10/320/25 (10 mg amlodipine, 320 mg valsartan and 25 mg hydrochlorothiazide): brown-yellow, non-scored, ovaloid, biconvex film-coated tablet with bevelled edge, debossed with "NVR" on one side and "VFL" on the other.
Amlodipine/Valsartan/HCT Novartis tablets are non-divisible and cannot be divided into equal doses.

4 Clinical Particulars

4.1 Therapeutic Indications

Amlodipine/Valsartan/HCT Novartis is indicated only as substitution therapy for the treatment of hypertension in patients whose blood pressure is already adequately controlled on the triple combination of amlodipine, valsartan and hydrochlorothiazide taken either as three single component formulations or as dual component formulation with a single component formulation, all components at the same dose level. Treatment should not be initiated with these fixed dose combinations (see Section 4.2 Dose and Method of Administration).

4.2 Dose and Method of Administration

Amlodipine/Valsartan/HCT Novartis is only indicated as substitution therapy for the treatment of hypertension in patients whose blood pressure is already adequately controlled on the triple combination of amlodipine, valsartan and hydrochlorothiazide taken either as three single component formulations or as dual component formulation with a single component formulation, all components at the same dose level.
Therefore, if blood pressure is not controlled on one of the three possible dual combination therapies, then any third monotherapy must be first added as an individual therapy until dose titration is complete and BP control established before the triple fixed dose combination may be introduced.
Similarly, there can be no direct dose titration within the Amlodipine/Valsartan/HCT Novartis product range. If a patient's blood pressure is uncontrolled at one of the lower dosage of the combination, dose titration must be carried out with the separately administered components.

Children and adolescents.

Amlodipine/Valsartan/HCT Novartis is not recommended for use in patients aged below 18 years due to a lack of safety and efficacy data.

Patients with renal impairment.

Amlodipine/Valsartan/HCT Novartis is contraindicated in severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.3 Contraindications). No dosage adjustment is required for patients with mild to moderate renal impairment (see Section 4.4 Special Warnings and Precautions for Use). Monitoring of creatinine and potassium levels is advised for patients with moderate renal impairment.

Patients with hepatic impairment.

Amlodipine/Valsartan/HCT Novartis is contraindicated in severe hepatic impairment, biliary cirrhosis or cholestasis and in patients undergoing dialysis (see Section 4.3 Contraindications). In patients with mild to moderate hepatic impairment without cholestasis the maximum recommended dose is 80 mg valsartan, and therefore, Amlodipine/Valsartan/HCT Novartis is not suitable in this group of patients (see Section 4.4 Special Warnings and Precautions for Use).

Heart failure and coronary artery disease.

There is limited experience with the use of Amlodipine/Valsartan/HCT Novartis, particularly at the maximum dose, in patients with heart failure and coronary artery disease. Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of Amlodipine/Valsartan/HCT Novartis 10/320/25.

Elderly (age 65 years or over).

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of Amlodipine/Valsartan/HCT Novartis 10/320/25, since available data in this patient population are limited.

Administration.

The recommended dose is one tablet per day. Amlodipine/Valsartan/HCT Novartis can be taken with or without food. It is recommended to take Amlodipine/Valsartan/HCT Novartis with some water.

4.3 Contraindications

Hypersensitivity to the active substances, dihydropyridine derivatives, other sulfonamide derived drugs, or to any of the excipients.
Severe hepatic impairment; biliary cirrhosis and cholestasis.
Severe renal impairment (GFR < 30 mL/min/1.73 m2), anuria and patients undergoing dialysis.
Refractory hypokalaemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia.
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, including orthostatic hypotension was seen in 1.7% of patients treated with the maximum dose of Amlodipine/Valsartan/HCT Novartis (10/320/25 mg) compared to 1.8% of valsartan/hydrochlorothiazide (320/25 mg) patients, 0.4% of amlodipine/valsartan (10/320 mg) patients, and 0.2% of hydrochlorothiazide/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension. In patients with an activated renin angiotensin system, such as volume and/or salt depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. This condition should be corrected prior to administration of Amlodipine/Valsartan/HCT Novartis, or the treatment should start under close medical supervision.
If excessive hypotension occurs with Amlodipine/Valsartan/HCT Novartis, 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.

Renal artery stenosis.

Amlodipine/Valsartan/HCT Novartis 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 Amlodipine/Valsartan/HCT Novartis 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 Amlodipine/Valsartan/HCT Novartis in patients with haemodynamically relevant aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

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. Amlodipine/Valsartan/HCT Novartis should be immediately discontinued in patients who develop angioedema, and Amlodipine/Valsartan/HCT Novartis 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/post-myocardial 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.
In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Association classification) 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.
Caution is advised in patients with heart failure and coronary artery disease, particularly at the maximum dose of Amlodipine/Valsartan/HCT Novartis 10/320/25 mg, since available data in these patient populations is limited (see Section 4.4 Special Warnings and Precautions for Use, Increased angina and/or acute myocardial infarction).

Systemic lupus erythematosus.

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.

Acute angle-closure glaucoma.

Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of a drug initiation. Untreated acute angle closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 Amlodipine/Valsartan/HCT Novartis in these patients is not recommended.

Photosensitivity.

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reaction occurs during treatment with Amlodipine/Valsartan/HCT Novartis, it is recommended to stop the treatment. If a readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

General.

Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. The risk for non-melanoma skin cancer appears to increase with long-term use (see Section 5.1 Pharmacodynamic Properties). Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for non-melanoma skin cancer.
Patients taking hydrochlorothiazide should be informed of the risk of non-melanoma skin cancer and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined, potentially including histological examination of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have previously experienced non-melanoma skin cancer (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in 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, the maximum recommended dose is 80 mg valsartan, and therefore, Amlodipine/Valsartan/HCT Novartis is not suitable in this group of patients. Patients with severe hepatic impairment, biliary cirrhosis or cholestasis should not take Amlodipine/Valsartan/HCT Novartis (see Section 4.3 Contraindications).
Thiazides, like other diuretics, may precipitate electrolyte imbalance, hepatic encephalopathy and hepatorenal syndrome when used to treat cirrhotic ascites.

Use in renal impairment.

No dosage adjustment of Amlodipine/Valsartan/HCT Novartis is required for patients with mild to moderate renal impairment. Renal function has a marked effect on the kinetics of hydrochlorothiazide (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with impaired renal function). Thiazide diuretics may precipitate azotaemia in patients with chronic kidney disease. Amlodipine/Valsartan/HCT Novartis should be used with caution and monitoring of creatinine and potassium levels is advised for patients with moderate renal impairment. Patients with severe renal impairment should not take Amlodipine/Valsartan/HCT Novartis (see Section 4.3 Contraindications).

Use in the elderly (age 65 years or over).

Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of Amlodipine/Valsartan/HCT Novartis 10/320/25 mg, since available data in this patient population are limited.

Paediatric use.

The safety and efficacy of Amlodipine/Valsartan/HCT Novartis in children and adolescents (below the age of 18 years) have not been established.

Effects on laboratory tests.

Serum electrolyte changes.

Amlodipine/valsartan/hydrochlorothiazide.

In the controlled trial of Amlodipine/Valsartan/HCT Novartis, the opposite effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determination of serum electrolytes and potassium in particular should be performed at appropriate intervals to detect possible electrolyte imbalance, especially in patients with other risk factors such as impaired renal function, treatment with other medicinal products or history of prior electrolyte imbalances.
In the controlled trial of Amlodipine/Valsartan/HCT Novartis in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium < 3.5 mEq/L) at any time postbaseline with the maximum dose of Amlodipine/Valsartan/HCT Novartis (10/320/25 mg) was 9.9% compared to 24.5% with hydrochlorothiazide/amlodipine (25/10 mg), 6.6% with valsartan/hydrochlorothiazide (320/25 mg), and 2.7% with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the Amlodipine/Valsartan/HCT Novartis and hydrochlorothiazide/amlodipine groups. The incidence of hyperkalemia (serum potassium > 5.7 mEq/L) was 0.4% with Amlodipine/Valsartan/HCT Novartis compared to 0.2-0.7% with the dual therapies.

Hydrochlorothiazide.

Concomitant use with potassium supplements, potassium sparing diuretics, salt substitutes containing potassium, or other drugs that may increase potassium levels (heparin, etc.) could lead to hyperkalaemia and should be used with caution.
Hypokalaemia has been reported under treatment with thiazide diuretics including hydrochlorothiazide. Frequent monitoring of potassium is recommended. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced potassium loss, for example salt losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If hypokalaemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations), Amlodipine/Valsartan/HCT Novartis should be discontinued. Correction of hypokalaemia and any coexisting hypomagnesaemia is recommended prior to the initiation of thiazides. Potassium and magnesium serum concentrations should be checked periodically. All patients receiving thiazide diuretics should be monitored for imbalances in electrolytes, particularly potassium.
Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatremia and hypochloraemic alkalosis. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been observed in isolated cases. Thiazides, including hydrochlorothiazide increase the urinary excretion of magnesium, which may result in hypomagnesaemia. As for any patient receiving diuretic therapy, periodic determination of serum electrolytes and potassium in particular should be performed at appropriate intervals.

Other metabolic disturbances.

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides, and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.
Hyperuricaemia may occur or gout may be precipitated in certain patients receiving thiazide therapy. Thiazides may reduce urinary calcium excretion and cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Pathological changes in the parathyroid gland of patients with hypercalcaemia and hypophosphataemia have been observed in a few patients on prolonged thiazide therapy.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal interaction studies with other medicinal products were performed with Amlodipine/Valsartan/HCT Novartis. Thus, only information on interactions with other medicinal products that are known for the individual active substances is provided in this section.
However, it is important to take into account that Amlodipine/Valsartan/HCT Novartis may increase the antihypertensive effect of other antihypertensive agents (e.g. alpha blockers, other diuretics) and other medicinal products which may cause hypotensive adverse effects (e.g. tricyclic antidepressants, alpha blockers for treatment of benign prostate hyperplasia). (See Tables 1-3.)

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No specific fertility studies were conducted with the amlodipine/valsartan/hydrochlorothiazide combination.
Testes, ovaries and secondary sex organs were evaluated in other toxicity studies with the amlodipine/valsartan 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.

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.

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.

Hydrochlorothiazide.

The effects of valsartan and hydrochlorothiazide in combination and hydrochlorothiazide alone on fertility have not been investigated.
(Category D)
Amlodipine/Valsartan/HCT Novartis 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 RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. If pregnancy is detected during therapy, Amlodipine/Valsartan/HCT Novartis 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 foetal 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 possible 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. In case of accidental exposure to ARB therapy, appropriate foetal monitoring should be considered. Infants whose mothers have taken ARB therapy should be closely observed for hypotension.
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 Amlodipine/Valsartan/HCT Novartis 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.
No reproductive toxicity studies have been conducted with amlodipine, valsartan and hydrochlorothiazide combination. 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 foetal weights, dilated ureters and delayed/incomplete ossification. The (AUC) exposures at these doses were 3-10x the expected human exposure to amlodipine/valsartan at the maximum proposed clinical dose (10:160 mg/day).
There was no evidence of teratogenicity in mice, rats and rabbits dosed with the valsartan/hydrochlorothiazide combination during organogenesis at up to 600/187.5, 200/62.5 and 10/3.125 mg/kg/day PO, respectively. Foetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan/hydrochlorothiazide doses of 200/62.5 mg/kg/day and 10/3.125 mg/kg/day. Decreased foetal weights, absent renal papillae and delayed ossification were observed in rats and increased late resorptions in rabbits.
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.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with foetal or neonatal thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.
It is not known whether valsartan is excreted in human milk. It is reported that amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide crosses the placenta and is excreted in human milk. It is therefore not advisable for women who are breastfeeding to use Amlodipine/Valsartan/HCT Novartis.

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.
The safety of Amlodipine/Valsartan/HCT Novartis is based on that of Amlodipine/Valsartan/HCT Novartis, amlodipine/valsartan fixed dose combination tablets, and the individual components.

Adverse reactions with suspected relationship to Amlodipine/Valsartan/HCT Novartis.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
In the controlled trial of Amlodipine/Valsartan/HCT Novartis, where only the maximum dose (10/320/25 mg) was evaluated, safety data was obtained in 582 patients with hypertension. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy.
The overall frequency of adverse reactions was not related to gender, age, or race. In the active controlled clinical trial, discontinuation due to side effects occurred in 4.0% of patients treated with Amlodipine/Valsartan/HCT Novartis 10/320/25 mg compared to 2.9% of patients treated with valsartan/hydrochlorothiazide 320/25 mg, 1.6% of patients treated with amlodipine/valsartan 10/320 mg, and 3.4% of patients treated with hydrochlorothiazide/amlodipine 25/10 mg. The most common reasons for discontinuation of therapy with Amlodipine/Valsartan/HCT Novartis were dizziness (1.0%) and hypotension (0.7%).
The adverse reactions that occurred in the active controlled clinical trial in at least 2% of patients treated with Amlodipine/Valsartan/HCT Novartis but at a higher incidence in the triple combination group than in any one of the dual combinations groups are presented in Table 4.

Adverse reactions with suspected relationship to Exforge (amlodipine/valsartan).

The safety of Exforge or Amlodipine/Valsartan Novartis 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 5.

Additional information on individual components.

Adverse reactions previously reported with one of the individual components may occur with Amlodipine/Valsartan/HCT Novartis 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, hypoesthesia, 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.
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.

Valsartan (Diovan).

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, dermatitis bullous, hyponatraemia, 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. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
In rare cases, valsartan may be associated with decreases in haemoglobin and haematocrit. In controlled clinical trials, 0.8% and 0.4% of patients receiving valsartan showed significant decreases (> 20%) in haematocrit and haemoglobin, respectively. In comparison, 0.1% of patients receiving placebo showed significant decreases in both haematocrit and haemoglobin.
Neutropenia was observed in 1.9% of patients treated with valsartan versus 1.6% of patients treated with an ACE inhibitor.
In heart failure patients, greater than 50% increases in creatinine 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 and 3.4% of captopril treated patients.
In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartan treated patients compared to 5.1% of placebo treated patients.
In heart failure patients, greater than 50% increases in BUN were observed in 16.6% of valsartan treated patients compared to 6.3% of placebo treated patients.

Valsartan/hydrochlorothiazide (Co-Diovan).

Other additional adverse experiences reported with valsartan/hydrochlorothiazide combination therapy were as follows: upper respiratory tract infection, abdominal pain upper, arthritis, bronchitis, bronchitis acute, chest pain, dyspnoea, gastroenteritis, hypoesthesia, hypokalaemia, insomnia, muscle strain, nasal congestion, neck pain, otitis media, pain in the extremity, pyrexia, sinus congestion, sinusitis, ligament sprain, urinary tract infection, viral infection, vision blurred, angioedema, serum sickness, vasculitis, renal impairment, myalgia, decrease in serum potassium, elevation in creatinine and blood urea nitrogen. There have also been reported several cases of hydrochlorothiazide induced pulmonary oedema with granulocytic infiltration and IgG deposition in alveolar membranes. Noncardiogenic pulmonary oedema may be an immunologically mediated rare idiosyncratic reaction to hydrochlorothiazide.

Hydrochlorothiazide.

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those contained in Amlodipine/Valsartan/HCT Novartis. The following adverse reactions have been reported in patients treated with thiazide diuretics alone, including hydrochlorothiazide.
Very common: mainly at higher dose, hypokalaemia, blood lipids increased.
Common: hyponatraemia, hypomagnesaemia, hyperuricaemia, urticaria and other forms of rash, loss of appetite, mild nausea and vomiting, postural hypotension, which may be aggravated by alcohol, anaesthetics or sedatives, and impotence (see Section 4.4 Special Warnings and Precautions for Use).
Rare: hypercalcaemia, hyperglycaemia, glycosuria, and worsening of diabetic metabolic state, photosensitisation, abdominal distress, constipation, diarrhoea, and gastrointestinal discomfort, intrahepatic cholestasis or jaundice, cardiac arrhythmias, headache, dizziness or light headedness, sleep disturbances, depression, paraesthesia, disturbances of vision, and thrombocytopenia, sometimes with purpura.
Very rare: hypochloric alkalosis, necrotising vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, pancreatitis, leukopenia, agranulocytosis, bone marrow depression, haemolytic anaemia, hypersensitivity reactions, respiratory distress including pneumonitis and pulmonary oedema.
The following adverse drugs reactions have been identified based on postmarketing experiences. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequencies. Therefore frequency assigned is "not known".
Frequency "not known": acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle closure glaucoma.

With hydrochlorothiazide.

Frequency not known: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma). Based on available data from epidemiological studies, cumulative dose dependent association between hydrochlorothiazide and non-melanoma skin cancer has been observed (also see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Laboratory findings.

Clinical laboratory test findings were obtained in a controlled trial of Amlodipine/Valsartan/HCT Novartis administered at the maximal dose of 10/320/25 mg compared to maximal doses of dual therapies, i.e. valsartan/hydrochlorothiazide 320/25 mg, amlodipine/valsartan 10/320 mg, and hydrochlorothiazide/amlodipine 25/10 mg.

Creatinine.

In hypertensive patients, greater than 50% increases in creatinine occurred in 2.1% of Amlodipine/Valsartan/HCT Novartis patients compared to 2.4% of valsartan/hydrochlorothiazide patients, 0.7% of amlodipine/valsartan patients, and 1.8% of hydrochlorothiazide/amlodipine patients.
In heart failure patients, greater than 50% increases in creatinine 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 and 3.4% of captopril treated patients.

Blood urea nitrogen.

In hypertensive patients, greater than 50% increases in blood urea nitrogen were observed in 29.5% of Amlodipine/Valsartan/HCT Novartis treated patients compared to 29.3% of valsartan/hydrochlorothiazide patients, 15.8% of amlodipine/valsartan patients, and 18.5% of hydrochlorothiazide/amlodipine patients. The majority of blood urea nitrogen values remained within normal limits.
In heart failure patients, greater than 50% increases in blood urea nitrogen were observed in 16.6% of valsartan treated patients compared to 6.3% of placebo treated patients.

Liver function tests.

Occasional elevations (greater than 150%) of liver chemistries occurred in Amlodipine/Valsartan/HCT Novartis treated patients.

Serum potassium.

In hypertensive patients, greater than 20% decreases in serum potassium were observed in 6.5% of Amlodipine/Valsartan/HCT Novartis treated patients compared to 3.3% of valsartan/hydrochlorothiazide patients, 0.4% of amlodipine/valsartan patients, and 19.3% of hydrochlorothiazide/amlodipine patients. Greater than 20% increases in potassium were observed in 3.5% of Amlodipine/Valsartan/HCT Novartis treated patients compared to 2.4% of valsartan/hydrochlorothiazide patients, 6.2% of amlodipine/valsartan patients, and 2.2% of hydrochlorothiazide/amlodipine patients.
In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartan treated patients compared to 5.1% of placebo treated patients.

4.9 Overdose

Symptoms.

There is no experience of overdose with Amlodipine/Valsartan/HCT Novartis. 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. In addition, the following signs and symptoms may occur due to an overdose of the hydrochlorothiazide component: dizziness, nausea, somnolence, hypovolaemia, hypotension and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

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 Amlodipine/Valsartan/HCT Novartis 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 whereas clearance of hydrochlorothiazide will be achieved by dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: dihydropyridine derivatives (amlodipine) combinations with angiotensin II antagonists, plain (valsartan) and thiazide diuretics (hydrochlorothiazide).
Amlodipine/Valsartan/HCT Novartis combines three antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class, valsartan to the angiotensin II (Ang II) antagonist class and hydrochlorothiazide belongs to the thiazide diuretics 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 Amlodipine/Valsartan/HCT Novartis 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.

Hydrochlorothiazide.

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high affinity receptor in the renal cortex with the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter which affects mechanisms of electrolyte reabsorption. Inhibition of the Na+Cl- symporter directly increases excretion of sodium and chloride in approximately equivalent amounts. It also indirectly reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and decreases in serum potassium. The renin aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

Clinical trials.

There have been no long-term, clinical outcome studies using these fixed dose combination tablets.
Amlodipine/Valsartan/HCT Novartis was studied in an 8 week double blind, active controlled study in patients with moderate to severe essential hypertension (mean sitting diastolic blood pressure ≥ 100 mmHg and < 120 mmHg and mean sitting systolic blood pressure ≥ 145 mmHg and < 200 mmHg). Patients with renal or hepatic impairment, type 1 diabetes and uncontrolled type 2 diabetes, and cardiovascular conditions including heart failure requiring treatment, history of myocardial infarction, angina, revascularisation procedure, moderate or malignant retinopathy, hypertensive encephalopathy, cerebrovascular accident or transient ischemic attack were excluded from the study. A total of 2,271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/hydrochlorothiazide 10/320/25 mg, valsartan/hydrochlorothiazide 320/25 mg, amlodipine/valsartan 10/320 mg, or hydrochlorothiazide/amlodipine 25/10 mg. At study initiation patients were assigned lower doses of their treatment combination and were titrated to their full treatment dose by week 2. A total of 55% of patients were male, 14% were 65 years or older, 72% were Caucasian and 17% were Black.
At week 8, the mean reductions in systolic/diastolic blood pressure were 39.7/24.7 mmHg with Amlodipine/Valsartan/HCT Novartis (n = 571), 32.0/19.7 mmHg with valsartan/hydrochlorothiazide (n = 553), 33.5/21.5 mmHg with amlodipine/valsartan (n = 558) and 31.5/19.5 with amlodipine/hydrochlorothiazide (n = 554). The triple combination therapy was statistically superior to each of the three dual combination treatments in reduction of diastolic and systolic blood pressures. The reductions in systolic/diastolic blood pressure with Amlodipine/Valsartan/HCT Novartis were 7.6/5.0 mmHg greater than with valsartan/hydrochlorothiazide, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/hydrochlorothiazide (see Figure 1). The full blood pressure lowering effect was achieved 2 weeks after being on their maximal dose of Amlodipine/Valsartan/HCT Novartis (see Figures 2 and 3). Statistically significant greater proportions of patients achieved BP control (< 140/90 mmHg) with Amlodipine/Valsartan/HCT Novartis (71%) compared to each of the three dual combination therapies (45-54%).
A subgroup of 268 patients was studied with ambulatory blood pressure monitoring. Clinically and statistically superior reductions in 24 hour systolic and diastolic blood pressures with the triple combination compared to valsartan/hydrochlorothiazide, amlodipine/valsartan, and hydrochlorothiazide/amlodipine were observed.
Age, gender, and race did not significantly influence the response to Amlodipine/Valsartan/HCT Novartis.
Similar studies have not been carried out with the lower dose strength Amlodipine/Valsartan/HCT Novartis combinations.
The beneficial effects on mortality and cardiovascular morbidity are unknown.
Withdrawal and rebound effects on efficacy have not been studied.
There have been no sufficient studies carried out to support the use of this product in the context of add on or step up dose titration from the dual combinations (see Section 4.2 Dose and Method of Administration).

Non-melanoma skin cancer.

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer has been observed. One study included a population comprised of 71,553 cases of BCC and of 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥ 50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A clear cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~ 25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~ 100,000 mg). For example: A 100,000 mg cumulative dose corresponds to more than 10 years' daily use with a defined daily dose of 25 mg (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

5.2 Pharmacokinetic Properties

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.
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.

Hydrochlorothiazide.

The absorption of hydrochlorothiazide after an oral dose is rapid (Tmax about 2 hours), with similar absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of hydrochlorothiazide is 60-80% after oral administration.
The increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change in the kinetics of hydrochlorothiazide on repeated administration, and accumulation is minimal when administered once daily.

Amlodipine/valsartan/hydrochlorothiazide.

Following oral administration of Amlodipine/Valsartan/HCT Novartis in normal healthy adults, peak plasma concentrations of amlodipine, valsartan and hydrochlorothiazide are reached in 6-8 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide from Amlodipine/Valsartan/HCT Novartis are the same as when administered as individual dosage forms. The bioavailability of amlodipine, valsartan, and hydrochlorothiazide were not altered when Amlodipine/Valsartan/HCT Novartis was administered with food.

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. Amlodipine crosses the placenta and is excreted into breast milk.

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.

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 percent 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 30 L/h).

Hydrochlorothiazide.

The distribution and elimination kinetics have generally been described by a biexponential decay function, with a terminal half-life of 6-15 hours. Greater than 95% of the absorbed dose is excreted as unchanged compound in the urine.

Pharmacokinetics in children.

No pharmacokinetic data are available in the paediatric population.

Pharmacokinetics in the elderly.

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.
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Since the three components are equally well tolerated in younger and elderly patients, no dosage adjustment of Amlodipine/Valsartan/HCT Novartis is necessary in elderly patients.

Pharmacokinetics 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.
Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the renal tubule. As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Pharmacokinetics 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 AUC. 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).
Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.
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 and hydrochlorothiazide combination. However, amlodipine, valsartan and hydrochlorothiazide have been tested individually for genotoxicity with generally negative results.

Amlodipine.

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).

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.

Hydrochlorothiazide.

Hydrochlorothiazide did not induce gene mutation in bacteria or chromosome damage in mammalian cells in several in vitro and in vivo assays. However positive results were obtained in a mammalian cell assay for gene mutation (mouse lymphoma cell assay) and in two other tests (sister chromatid exchange assay in Chinese hamster ovary cells and nondisjunction assay in Aspergillus nidulans). Hydrochlorothiazide enhanced the UVA-induced formation of pyrimidine dimers in vitro and in the skin of mice following oral treatment. It is therefore concluded that there is no relevant mutagenic potential in vivo, although hydrochlorothiazide could enhance the genotoxic effects of UVA light.

Carcinogenicity.

No carcinogenicity studies have been conducted with the amlodipine, valsartan and hydrochlorothiazide combination. However, amlodipine, valsartan and hydrochlorothiazide have been tested individually for carcinogenicity with generally negative results.

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.

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 (160 mg bid).

Hydrochlorothiazide.

Two year feeding studies in mice and rats showed no evidence of carcinogenic potential in female mice at doses up to approximately 600 mg/kg/day, or in male and female rats at doses up to approximately 100 mg/kg/day. However, there was equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide alone at approximately 600 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline-cellulose, crospovidone, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide, macrogol 4000, purified talc, iron oxide yellow (except 5/160/12.5) and iron oxide red (10/160/12.5 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

Amlodipine/Valsartan/HCT Novartis 5/160/12.5 (5 mg amlodipine, 160 mg valsartan and 12.5 mg hydrochlorothiazide): PA/Al/PVC/Al blister packs of 7, 14, 28, 30 and 56.
Amlodipine/Valsartan/HCT Novartis 10/160/12.5 (10 mg amlodipine, 160 mg valsartan and 12.5 mg hydrochlorothiazide): PA/Al/PVC/Al blister packs of 7, 14, 28, 30 and 56.
Amlodipine/Valsartan/HCT Novartis 5/160/25 (5 mg amlodipine, 160 mg valsartan and 25 mg hydrochlorothiazide): PA/Al/PVC/Al blister packs of 7, 14, 28, 30 and 56.
Amlodipine/Valsartan/HCT Novartis 10/160/25 (10 mg amlodipine, 160 mg valsartan and 25 mg hydrochlorothiazide): PA/Al/PVC/Al blister packs of 7, 14, 28, 30 and 56.
Amlodipine/Valsartan/HCT Novartis 10/320/25 (10 mg amlodipine, 320 mg valsartan and 25 mg hydrochlorothiazide): PA/Al/PVC/Al 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. Hydrochlorothiazide is a white or almost white powder, very slightly soluble in water and freely soluble in dimethylsulfoxide.
Active ingredients (INN): amlodipine besylate, valsartan and hydrochlorothiazide.

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.

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.

Hydrochlorothiazide.

(6-chloro-3,4- dihydro-2H-1,2,4- benzothiadiazine-7-sulfonamide- 1, 1-dioxide).

CAS number.

58-93-5.
Molecular formula: C7H8ClN3O4S2.
Molecular weight: 297.72.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes