Consumer medicine information

Norvasc

Amlodipine

BRAND INFORMATION

Brand name

Norvasc

Active ingredient

Amlodipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Norvasc.

SUMMARY CMI

Norvasc

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 NORVASC?

NORVASC contains the active ingredient amlodipine (as amlodipine besilate). NORVASC is used to lower high blood pressure and treat angina pectoris (chest pain due to the heart not getting enough oxygen).

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

2. What should I know before I use NORVASC?

Do not use if you have ever had an allergic reaction to NORVASC 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 NORVASC? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with NORVASC 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 NORVASC?

  • The usual dose of NORVASC is 5mg each day. Your doctor may increase this to 10mg each day.
  • You must take NORVASC every day. Continue taking it for as long as your doctor tells you.
  • Swallow the tablet whole with a full glass of water.

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

5. What should I know while using NORVASC?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using NORVASC.
  • Keep all your doctor's appointments so that your progress can be checked.
  • Tell your doctor immediately if you become pregnant while taking NORVASC.
Things you should not do
  • Do not take NORVASC to treat any other conditions unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
Things to be careful of
  • Avoid eating large quantities of grapefruit or drinking large quantities of grapefruit juice.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how NORVASC affects you. NORVASC may cause dizziness or drowsiness in some people.
Looking after your medicine
  • Keep your tablets in the pack it is time to take them.
  • Keep NORVASC in a cool dry place, away from moisture, heat, or sunlight where the temperature stays below 25°C.

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

6. Are there any side effects?

Common side effects of NORVASC include headache, dizziness, flushing, tiredness, drowsiness or sleepiness, or stomach pain or nausea. Serious side effects may also occur while taking NORVASC. Serious side effects include fast or irregular heart beats; chest pain (which may or may not be associated with exertion (angina) that lasts longer, is more severe or occurs more often); shortness of breath; symptoms of allergy (such as skin rash and/or itching); and severe upper stomach pain, often with nausea and vomiting.

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

Norvasc

Active ingredient(s): Amlodipine besilate

Consumer Medicine Information (CMI)

This leaflet provides important information about using NORVASC. 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 NORVASC.

Where to find information in this leaflet:

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

1. Why am I using NORVASC?

NORVASC contains the active ingredient amlodipine (as amlodipine besilate). NORVASC belongs to a group of medicines called calcium channel blockers or calcium ion antagonists. They work by widening your blood vessels, making it easier for your heart to pump blood around the body and help increase the supply of blood and oxygen to your heart. Calcium channel blockers do not change the amount of calcium in your blood or bones.

NORVASC is used to:

  • lower high blood pressure (hypertension)
    There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems.
  • treat angina pectoris
    Angina is a pain or uncomfortable feeling in the chest, often spreading to the arms or neck, and sometimes to the shoulders and back. The pain of angina is due to a shortage of oxygen to the heart.
    NORVASC is NOT for the relief of a sudden attack of angina. Your doctor will give you other medication to treat this.

Ask your doctor if you have any questions about why Norvasc has been prescribed for you.

Your doctor may have prescribed it for another reason.

2. What should I know before I use NORVASC?

Warnings

Do not use NORVASC if:

  • You are allergic to amlodipine, other calcium channel blockers (e.g. felodipine, nifedipine or lercanidipine), or any of the ingredients listed at the end of this leaflet.
    - Some symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue, or any other parts of the body; rash, itching or hives on the skin.
    - Always check the ingredients to make sure you can use this medicine. Check with your doctor or pharmacist if you are unsure.
  • The expiry date on the pack has passed, or the package is torn or shows signs of tampering.
    If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Check with your doctor if you:

  • Have any other medical conditions, especially the following:
    - Heart problems, including heart failure
    - Liver problems
  • Take any medicines for any other condition.
  • Have had any allergy to any other medicines, or any other substances, such as foods, preservatives, or dyes.

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

Check with your doctor if you are pregnant or intend to become pregnant.

This medicine may affect your developing baby if you take it during pregnancy. Your doctor can discuss with you the risks and benefits involved.

Do not breast-feed if you are taking this medicine.

The active ingredient in NORVASC passes into breast milk. Your baby may be affected.

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 NORVASC and affect how it works. Tell your doctor if you are taking any of the following:

  • other medicines used to treat angina, such as diltiazem
  • some antibiotics, such as erythromycin, clarithromycin or rifampicin
  • some antifungals, such as ketoconazole or itraconazole
  • anti-proteases, medicines used to treat HIV infection, such as ritonavir
  • simvastatin, a medicine used to lower cholesterol
  • cyclosporin tacrolimus, sirolimus or everolimus, medicines used to suppress the immune system
  • temsirolimus, a medicine used to treat kidney cancer
  • St John's Wort.

You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Your doctor and pharmacist have more information on medicine to be careful with or avoid while taking NORVASC.

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

4. How do I use NORVASC?

Take Norvasc exactly as your doctor has prescribed.

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

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

How much to take

  • The usual dose of NORVASC is 5 mg each day. Your doctor may increase this to 10 mg each day.
  • Your doctor may prescribe another dose depending on your condition your response to this medicine.

When to take NORVASC

  • Take your medicine at about the same time each day, either morning or evening.
  • Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • NORVASC can be taken with or without food.

How to take NORVASC

Swallow the tablet whole with a full glass of water.

How long to take it

You must take NORVASC every day. Continue taking it for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to use NORVASC

If you miss your dose at the usual time, and it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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

Do not take a double dose to make up for the dose you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

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

If you use too much NORVASC

If you think that you have used too much NORVASC, 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.

If you take too many tablets, you may feel dizzy, lightheaded, faint, have breathing difficulty and an irregular heartbeat.

5. What should I know while using NORVASC?

Things you should do

  • If you are about to start any new medicine, tell your doctor or pharmacist that you are taking NORVASC.
  • Keep all your doctor's appointments so that your progress can be checked.
    Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you:

  • Become pregnant while taking NORVASC.

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

Things you should not do

  • Do not take NORVASC to treat any other conditions unless your doctor tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Avoid eating large quantities of grapefruit or drinking large quantities of grapefruit juice.

Grapefruit juice contains one or more components that alter the metabolism of some medicines, including NORVASC.

Drinking very large quantities (over 1.2 litres) of grapefruit juice each day while taking NORVASC may increase the effects of this medicine.

Driving or using machines

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

NORVASC may cause dizziness or drowsiness in some people.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Things that would be helpful for your high blood pressure or angina

Some self-help measures suggested below may assist your condition. Your doctor or pharmacist can give you more information about these measures.

  • Weight: Your doctor may suggest losing some weight. Some people may need a dietician to plan a suitable diet to help with weight loss.
  • Exercise: Regular exercise helps lower blood pressure and strengthen the heart. It is important not to overdo it. Before commencing regular exercise you should consult your doctor who will suggest the most suitable exercise for you. If you feel uncomfortable when exercising or experience symptoms such as chest pain or breathlessness see your doctor.
  • Alcohol: Your doctor may advise you to limit your alcohol intake.
  • Salt: Your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake you should avoid using salt at the table or in cooking.
  • Smoking: Your doctor may advise you to stop smoking or at least cut down.

Looking after your medicine

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack, they may not keep well.

Keep NORVASC in a cool dry place, away from moisture, heat, or sunlight where the temperature stays below 25°C.

  • 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.

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

Keep it where young children cannot reach it.

A locked cupboard at least one and a half metres 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
These are more common side effects of NORVASC.
  • headache
  • dizziness
  • flushing
  • tiredness
  • drowsiness or sleepiness
  • stomach pain or nausea.

These may or may not be due to NORVASC, but you should tell your doctor.

  • indigestion
  • sexual problems
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
  • changes in heart beat either fast or slow
  • swelling of the ankles, feet, face or hands
  • tingling or numbness of the hands or feet
  • dizziness or light-headedness on standing up from a sitting or lying position
  • unusual tiredness or weakness
  • muscle cramps or aches
  • joint pain
  • eye pain or change in vision
  • changes in mood, feeling anxious or nervous
  • symptoms of liver disease such as itching, yellowing of the skin and eyes, and dark coloured urine
  • unusual movements, including trembling and shaking of the hands and fingers, twisting movements of the body, shuffling walk and stiffness of the arms and legs
Call your doctor immediately if you notice any of these serious side effects.
These may be serious side effects that may need urgent medical attention.
Very serious side effectsWhat to do
  • fast or irregular heart beats
  • chest pain
  • chest pain associated with exertion (angina) that lasts longer, is more severe or occurs more often
  • shortness of breath
  • symptoms of allergy such as skin rash and/or itching
  • severe upper stomach pain, often with nausea and vomiting.
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.

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

If you are 65 years or older, you should be especially careful while taking NORVASC. Report any side effects promptly to your doctor.

Some people in this age group may be more likely to experience side effects such as swelling of the feet and ankles, muscle cramps and dizziness.

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

This medicine is only available with a doctor's prescription.

What NORVASC contains

Active ingredient
(main ingredient)		Norvasc 5 mg tablets contain: amlodipine besilate equivalent to amlodipine 5 mg.
Norvasc 10 mg tablets contain: amlodipine besilate equivalent to amlodipine 10 mg.
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • calcium hydrogen phosphate
  • sodium starch glycollate
  • magnesium stearate

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

What NORVASC looks like

NORVASC tablets are available in two strengths:

  • NORVASC 5 mg tablets:
    Emerald-shaped, white to off-white, scored and marked “AML 5” on one side and plain on the other side
    Australian registration number: AUST R 42902
  • NORVASC 10 mg tablets:
    Emerald-shaped, white to off-white, marked “AML-10” on one side and plain on the other side.
    Australian registration number: AUST R 42903

Both the 5 mg tablets and 10 tablets come in packs of 30 tablets.

Who distributes NORVASC

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

This leaflet was prepared in August 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Norvasc

Active ingredient

Amlodipine

Schedule

S4

 

1 Name of Medicine

Amlodipine besilate.

2 Qualitative and Quantitative Composition

Norvasc amlodipine (as besilate) 5 mg and 10 mg tablets.
Each Norvasc 5 mg tablet contains amlodipine besilate equivalent to 5 mg of active amlodipine base.
Each Norvasc 10 mg tablet contains amlodipine besilate equivalent to 10 mg of active amlodipine base.
The tablets contain no excipients with a known effect. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Norvasc is available as "emerald"-shaped, white to off-white tablets.
Norvasc 5 mg tablets are engraved "AML 5" and breaker score on one side and plain on the other side. Norvasc 10 mg tablets are engraved "AML-10" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

1. Hypertension.

Norvasc is indicated for the first line treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately controlled on a single antihypertensive agent may benefit from the addition of Norvasc, which has been used in combination with a thiazide diuretic, beta-adrenoceptor blocking agent or an angiotensin converting enzyme inhibitor.

2. Angina.

Norvasc is indicated for the first line treatment of chronic stable angina. Norvasc may be used alone, as monotherapy or in combination with other antianginal drugs.

4.2 Dose and Method of Administration

Dosage.

For hypertension or angina, the usual initial dose is 2.5 mg to 5 mg once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response.

Method of administration.

Norvasc is for oral administration.

Dosage adjustment.

Small, fragile or elderly individuals, or patients with hepatic insufficiency should be started on 2.5 mg once daily and this dose may be used when adding Norvasc to other antihypertensive therapy.
Dosage should be adjusted according to each patient's need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient's response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently. See Section 4.8 Adverse Effects (Undesirable Effects) for information related to dosage and adverse effects.

Co-administration with other antihypertensive and/or antianginal drugs.

Norvasc has been safely administered with thiazides, ACE inhibitors, beta-blockers, long-acting nitrates, and/or sublingual nitroglycerin.
No dose adjustment of Norvasc is required upon concomitant administration of thiazide diuretics, beta-blockers, long-acting nitrates and ACE inhibitors.

4.3 Contraindications

Norvasc is contraindicated in patients with a known hypersensitivity to amlodipine, other dihydropyridines, or any of the inactive ingredients.

4.4 Special Warnings and Precautions for Use

Increased angina.

Rarely patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Outflow obstruction (aortic stenosis).

Norvasc should be used with caution in the presence of a fixed left ventricular outflow obstruction (aortic stenosis).

Use in patients with congestive heart failure.

In general, calcium channel blockers should be used with caution in patients with heart failure. Norvasc (5 mg to 10 mg per day) has been studied in a placebo controlled trial of 1153 patients with NYHA class III or IV heart failure on stable doses of ACE inhibitor, digoxin and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life threatening arrhythmia, acute myocardial infarction or hospitalisation for worsened heart failure). Norvasc has been compared to placebo in four 8 to 12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.

Beta-blocker withdrawal.

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

Peripheral oedema.

Mild to moderate peripheral oedema was the most common adverse event in the clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). The incidence of peripheral oedema was dose dependent and ranged in frequency from 3.0 to 10.8% in the 5 mg to 10 mg dose range. Care should be taken to differentiate this peripheral oedema from the effects of increasing left ventricular dysfunction.

Use in hepatic impairment.

There are no adequate studies in patients with liver dysfunction and dosage recommendations have not been established. 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. Norvasc should, therefore, be administered with caution in these patients and careful monitoring should be performed. A lower starting dose may be required (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

Amlodipine is extensively metabolised to inactive metabolites with 10% excreted as unchanged drug in the urine. Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment. Norvasc may be used at normal doses in patients with renal failure. Amlodipine is not dialysable.

Use in the elderly.

In elderly patients (≥ 65 years) clearance of amlodipine is decreased with a resulting increase in AUC. In clinical trials the incidence of adverse events in elderly patients was approximately 6% higher than that of younger population (< 65 years). Adverse events include oedema, muscle cramps and dizziness. Norvasc should be used cautiously in elderly patients.

Paediatric use.

Safety and effectiveness have not been established in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Norvasc has been safely administered with thiazide diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, long acting nitrates, sublingual nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycaemic drugs.
Special studies have indicated that the co-administration of Norvasc with digoxin did not change serum digoxin levels or digoxin renal clearance in healthy volunteers, and that co-administration of cimetidine did not alter the pharmacokinetics of amlodipine; and that co-administration with warfarin did not change the warfarin prothrombin response time.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin).

Simvastatin.

Co-administration of multiple doses of amlodipine and simvastatin resulted in an increase in exposure to simvastatin compared to simvastatin alone. The product information for simvastatin should be reviewed for the appropriate dose of simvastatin when the patient is prescribed amlodipine concurrently.

Grapefruit juice.

Grapefruit juice is known to inhibit the cytochrome P450 system, thereby affecting the 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.

CYP3A4 inhibitors.

With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients, the plasma concentration of amlodipine was increased. The clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution when administered with CYP3A4 inhibitors.

Clarithromycin.

Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.

CYP3A4 inducers.

There are no data available regarding the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum (St John's wort)) may decrease the plasma concentrations of amlodipine. Amlodipine should be used with caution when administered with CYP3A4 inducers.

Aluminium/ magnesium (antacid).

Co-administration of an aluminium/magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

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.

Atorvastatin.

Co-administration of multiple 10 mg doses of amlodipine with 80 mg atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Ethanol (alcohol).

Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Ciclosporin.

No drug interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients. Various studies in renal transplant patients report that co-administration of amlodipine with ciclosporin affects the trough concentrations of ciclosporin, and consideration should be given for monitoring ciclosporin levels in renal transplant patients on amlodipine.

Tacrolimus.

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Mechanistic target of rapamycin (mTOR) inhibitors.

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use of mTOR inhibitors and amlodipine may increase exposure of mTOR inhibitors.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In animal studies, amlodipine did not affect fertility in rats at oral doses up to 18 mg/kg (base) and had no teratogenic effects in rats (18 mg/kg) or rabbits (10 mg/kg).
(Category C)
Calcium channel blockers carry the potential to produce fetal hypoxia associated with maternal hypotension. Accordingly they should not be used in pregnant women unless the potential benefit outweighs the risk to the fetus.
The safety of Norvasc in human pregnancy or lactation has not been established. Amlodipine (10 mg/kg as besilate salt, 7 mg/kg base), administered orally to rats at or near parturition induced a prolongation of gestation time, an increase in the number of stillbirths and a decreased postnatal survival.
 Experience in humans indicates that amlodipine is transferred into human breast milk. The median amlodipine concentration ratio of milk/plasma in 31 lactating women with pregnancy-induced hypertension was 0.85 following amlodipine administration at an initial dose of 5 mg once daily which was adjusted as needed (mean daily dose and body weight adjusted daily dose: 6 mg and 98.7 microgram/kg, respectively). The estimated daily dose of amlodipine in the infant via breast milk was 4.17 microgram/kg.
Breast-feeding should be discontinued during treatment with Norvasc.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Norvasc has been evaluated for safety in more than 11,000 patients in clinical trials worldwide.
In general, treatment with Norvasc was well tolerated at doses up to 10 mg daily. Most adverse events reported during therapy with Norvasc were of mild or moderate severity. In controlled clinical trials directly comparing Norvasc (N = 1730) in doses up to 10 mg to placebo (N = 1250), discontinuation of Norvasc due to adverse events was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). Norvasc therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, creatinine or liver function tests.
The most common side effects are headache and oedema. The incidence (%) of side effects which occurred in a dose related manner is as follows. See Table 1.
Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo controlled clinical trials include the following. See Table 2.
The following events occurred in ≤ 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Blood and lymphatic system disorders.

Leucopenia, thrombocytopenia.

Cardiac disorders.

Tachycardia.

Ear and labyrinth disorders.

Tinnitus, vertigo.

Eye disorders.

Abnormal vision, conjunctivitis, diplopia, eye pain.

Gastrointestinal disorders.

Altered bowel habits, constipation, diarrhoea, dry mouth, dyspepsia*, dysphagia, flatulence, gingival hyperplasia, pancreatitis, vomiting.

General disorders and administration site conditions.

Asthenia*, malaise, pain, rigors, thirst.

Immune system disorders.

Allergic reactions.

Investigations.

Weight gain.

Metabolism and nutrition disorders.

Anorexia, hyperglycaemia.

Musculoskeletal and connective tissue disorders.

Arthralgia, arthrosis, back pain, muscle cramps*, myalgia.

Nervous system disorders.

Hypoesthesia, paresthesia, peripheral neuropathy, postural dizziness, syncope, tremor.

Psychiatric disorders.

Abnormal dreams, anxiety, depersonalisation, depression, insomnia, mood changes, nervousness.

Renal and urinary disorders.

Micturition disorder, micturition frequency, nocturia.

Reproductive system and breast disorders.

Gynaecomastia, sexual dysfunction (male* and female).

Respiratory, thoracic and mediastinal disorders.

Dyspnoea*, epistaxis.

Skin and subcutaneous tissue disorders.

Alopecia, angioedema, pruritus*, purpura, rash*, rash erythematous, rash maculopapular, sweating increased.

Vascular disorders.

Hot flushes, hypotension, peripheral ischaemia, postural hypotension, vasculitis.
* These events occurred in less than 1% of patients in placebo controlled trials, but the incidence of these adverse effects was between 1% and 2% in all multiple dose studies.
The following events occurred in ≤ 0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discolouration, urticaria, skin dryness, dermatitis, erythema multiforme, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, 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, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.

Postmarketing experience.

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.
There have been postmarketing reports of extrapyramidal disorder in association with use of amlodipine.
Norvasc has been used safely in patients with chronic obstructive pulmonary disease, well compensated congestive heart failure, peripheral vascular disease, diabetes mellitus and abnormal lipid profiles.

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.

4.9 Overdose

Signs and symptoms.

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.
Available data suggest that overdose might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. Dysrhythmias may occur following overdose with any calcium antagonist. Hypotension and bradycardia are usually seen within 1 to 5 hours following overdose. Hypotension can persist for longer than 24 hours despite treatment. Cardiac rhythm disturbances have been noted to persist for up to 7 days. Marked and probably prolonged systemic hypotension, up to and including shock with fatal outcome, have been reported.
Reports of intentional overdose include a patient who ingested 250 mg and was asymptomatic and was not hospitalised; another (120 mg) was hospitalised, underwent gastric lavage and remained normotensive; a third one (105 mg) was hospitalised and had hypotension (90/50 mmHg) which normalised following plasma expansion. Death resulted from a mixed overdose of 140 mg and 10 mefenamic acid capsules in a 15 year old girl, and from a mixed overdose of amlodipine 70 mg and an unknown quantity of oxazepam in a 63 year old woman. A case of accidental drug overdose has been documented in a 19 month old male who ingested 30 mg Norvasc (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm.

Recommended treatment.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support, including elevation of the extremities, and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine), should be considered with attention to circulating volume and urine output. Intravenous calcium may help to reverse the effects of calcium entry blockade. Administration of activated charcoal to healthy volunteers immediately or up to 2 hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected. Ipecac emesis is not recommended since haemodynamic instability and CNS depression may rapidly develop. Since amlodipine is highly protein bound, dialysis is not likely to be of benefit.
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.

Amlodipine is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
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. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionised compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterised by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. The precise mechanism by which amlodipine relieves angina has not been fully determined, but amlodipine reduces the total ischaemic burden by the following two actions.
1. Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
2. Amlodipine has been shown to block constriction in main coronary arteries and coronary arterioles, induced by calcium, potassium, adrenaline, serotonin and thromboxane A2 analogue both in normal and in ischaemic regions.

Haemodynamics.

Following administration of therapeutic doses to patients with hypertension, Norvasc 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. Although the acute intravenous administration of amlodipine decreased arterial blood pressure and increased heart rate in haemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients.
The magnitude of reduction in blood pressure with Norvasc is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
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 Norvasc 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, Norvasc has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well compensated patients with heart failure with agents possessing significant negative inotropic effects.
In hypertensive patients with normal renal function, therapeutic doses of Norvasc 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.

Clinical trials.

Studies in patients with congestive heart failure.

Norvasc has been compared to placebo in four 8 to 12 week studies of patients with New York Heart Association (NYHA) class II/III heart failure, involving a total of 697 patients. Although efficacy in regard to the primary and secondary endpoints was not demonstrated, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms or LVEF. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo controlled mortality/ morbidity study of Norvasc 5-10 mg in 1153 patients with NYHA classes III (n = 931) or IV (n = 222) heart failure on stable doses of diuretics, digoxin and ACE inhibitors, Norvasc had no effect on the primary endpoint of the study which was the combined endpoint of all cause mortality and cardiac morbidity (as defined by life threatening arrhythmia, acute myocardial infarction or hospitalisation for worsened heart failure), or on NYHA classification or symptoms of heart failure. Total combined all cause mortality and cardiac morbidity events were 222/571 (39%) for patients on Norvasc and 246/583 (42%) for patients on placebo: the cardiac morbid events represented about 25% of the endpoints in the study.
In this study, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure compared to placebo.

Electrophysiologic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg of amlodipine and a further 10 mg of amlodipine after a 30 minute interval produced peripheral vasodilation and afterload reduction, but did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving Norvasc and concomitant beta-blockers. In clinical studies in which Norvasc was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse events on electrocardiographic parameters were observed. In clinical trials with angina patients alone, Norvasc therapy did not alter electrocardiographic intervals or produce higher degrees of A-V blocks.

Effects in hypertension.

In patients with hypertension once daily dosing provides clinically significant reductions in blood pressure in both the supine and standing positions throughout the 24 hour interval postdose. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration. The blood pressure effect is maintained over the 24 hour dosing interval, with little difference in peak and trough effect. Tolerance has not been demonstrated in patients studied for up to 1 year. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure.

Effects in chronic stable angina.

In patients with angina, once daily administration of amlodipine increases total exercise time to angina onset and total work time to 1 mm ST segment depression and decreases both angina attack frequency and nitroglycerin tablet consumption. The sustained efficacy of Norvasc in angina patients has been demonstrated over long-term dosing. In patients with angina there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

Other.

In clinical trials amlodipine has shown no harmful effect on lipid levels. Dihydropyridine calcium channel blockers have not been associated with any adverse metabolic effects and are suitable for use in patients with asthma, diabetes and gout.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6 and 12 hours postdose. This may reflect significant initial uptake by the liver, followed by a phase of redistribution. This interval is shorter (2 to 8 hours) in patients with hepatic insufficiency.

Distribution.

Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food. The volume of distribution is approximately 20 L/kg.
In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism/excretion.

The terminal plasma elimination half-life is about 35 to 50 hours and is consistent with once daily dosing. Steady-state plasma levels are reached after 7 to 8 days of consecutive dosing.
Amlodipine is extensively metabolised by the liver to inactive metabolites, with 10% of the parent compound and 60% of metabolites excreted in the urine.

Special populations.

Elderly (≥ 65 years).

In elderly hypertensive patients (mean age 69 years) there was a decrease in clearance of amlodipine from plasma as compared to young volunteers (mean age 36 years) with a resulting increase in the area under the curve (AUC) of about 60%.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

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

Microcrystalline cellulose, calcium hydrogen phosphate, sodium starch glycollate, magnesium stearate.

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 25°C.

6.5 Nature and Contents of Container

Norvasc are supplied in PVC/PVDC/Aluminium foil blister packs within cardboard cartons. The 5 mg tablets are supplied in packs of 7, 10 and 30 tablets±, and the 10 mg tablets are supplied in packs of 30 tablets.
± Not all presentations are available.

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 besilate is a white crystalline powder and is slightly soluble in water and sparingly soluble in ethanol.

Chemical structure.

Amlodipine besilate is a dihydropyridine derivative and has the following structural formula:
Chemical name: 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)- 4-(2-chlorophenyl)- 1,4-dihydro-6-methyl- 3,5-pyridinedicarboxylate benzene sulphonate.
Molecular formula: C20H25ClN2O5.C6H6O3S.
Molecular weight: 567.1 (free base 408.9).

CAS number.

CAS registry numbers: amlodipine 88150-42-9; amlodipine besilate 111470-99-6.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes