Consumer medicine information

Amlo

Amlodipine

BRAND INFORMATION

Brand name

Amlo

Active ingredient

Amlodipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Amlo.

SUMMARY CMI

AMLO Tablets

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 AMLO?

AMLO contains the active ingredient amlodipine (besilate).

AMLO is used to lower high blood pressure (hypertension) and treat angina pectoris.

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

2. What should I know before I use AMLO?

Do not use if you have ever had an allergic reaction to amlodipine, other calcium channel blockers, or any of the ingredients listed at the end of the CMI.

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

3. What if I am taking other medicines?

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

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 AMLO?

  • Take your tablet at about the same time each day.
  • AMLO can be taken with or without food.
  • Take AMLO exactly as your doctor has prescribed.
  • More instructions can be found in Section 4. How do I use AMLO? in the full CMI.

5. What should I know while using AMLO?

Things you should do
  • Tell any doctors, dentists and pharmacists who are treating you that you are taking AMLO.
  • Tell your doctor if you become pregnant while taking AMLO.
Things you should not do
  • Do not take AMLO to treat any other conditions unless your doctor says so.
  • Do not give this medicine to anyone else, even if their symptoms are similar to yours.
  • Avoid eating large quantities of grapefruit or drinking large quantities of grapefruit juice.
Driving or using machines
  • AMLO may cause dizziness or drowsiness in some people and affect alertness. If affected, do not drive or operate machinery.
Looking after your medicine
  • Keep AMLO Tablets in a cool dry place where the temperature is below 30°C. Protect from light.

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

6. Are there any side effects?

There are a number of side effects associated with this medicine. It is important to be aware of them so that you can identify any symptoms if they occur (see the full CMI for more details). The serious side effects are: signs of allergy; fast or irregular heart beats; chest pain; shortness of breath; severe upper stomach pain, often with nausea and vomiting. The common side effects are headache; dizziness; flushing; tiredness; drowsiness or sleepiness; stomach pain or nausea.

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

AMLO Tablets

Active ingredient(s): amlodipine (besilate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using AMLO tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you taking AMLO against the benefits this medicine is expected to have for you.

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 AMLO.

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

Where to find information in this leaflet:

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

1. Why am I using AMLO?

AMLO 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.

AMLO is not for the relief of a sudden attack of angina. Your doctor will give you other medication to treat this.

How it works:

AMLO 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.

Your doctor may have prescribed AMLO for another reason.

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

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

Use in Children

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

2. What should I know before I use AMLO?

Warnings

Do not use AMLO if:

  • you have ever had an allergic reaction to amlodipine (including Norvasc) or other calcium channel blockers. These medicines include felodipine (Plendil ER, Agon SR, Felodur ER), nifedipine (Adalat, Adalat Oros, Nifecard, Nifedipine-BC, Nifehexal, Nyefax, SBPA Nifedipine) or lercanidipine (Zanidip) (Not all brands are given). Check with your doctor or pharmacist if you are unsure. Some of the symptoms of an allergic reaction to amlodipine may include a skin rash similar to hives, itchiness, shortness of breath, Wheezing or difficulty breathing, swelling of the face, lips or tongue or other parts of the body.
  • you are allergic to any of the ingredients listed at the end of this leaflet.

If you are not sure whether you should be taking AMLO, talk to your doctor.

Do not use AMLO if the packaging is torn or shows signs of tampering. Do not use AMLO beyond the expiry date printed on the pack.

Check with your doctor or pharmacist if you:

  • have allergies to any other medicines, foods, preservatives or dyes.
  • have or have had any of the following medical conditions:
    - heart problems, including heart failure
    - liver problems.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking or are given AMLO.

Your doctor will advise you whether or not to take AMLO or if you need to adjust the dose or adapt your treatment.

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

Tell your doctor if you are pregnant or plan 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.

It is not known if the active ingredient in AMLO passes into breast milk or if your baby may be affected.

If you have not told your doctor about any of the above, tell him/her before you start taking AMLO.

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 be affected by AMLO or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor will advise you.

In particular, you should tell your doctor if you are taking or have recently taken medicines like:

  • 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
  • ciclosporin or tacrolimus, sirolimus or everolimus, medicines used to suppress the immune system
  • temsirolimus, a medicine used to treat kidney cancer
  • St John's Wort.

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

4. How do I use AMLO?

Take Amlodipine tablets exactly as your doctor has prescribed.

Follow all directions given to you by your doctor or pharmacist. 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 AMLO is one 5 mg tablet each day, although a 2.5 mg dose may be prescribed in some cases.

Your doctor may increase this to one 10 mg tablet each day.

Your doctor may prescribe another dose of AMLO depending on your condition and how you respond to this medicine.

When to take / use AMLO

Take your tablet at about the same time each day, either morning or evening.

Taking your tablet at the same time each day will have the best effect. It will also help you to remember when to take it.

You must take AMLO every day. Continue taking your medicine 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.

How to take AMLO?

  • Swallow the tablet whole with a full glass of water.
  • AMLO 5 mg tablets can be divided in half along the scoreline if your doctor has prescribed a 2.5 mg dose.
  • AMLO can be taken with or without food.
  • If you accidentally take a larger dose than recommended, tell your doctor immediately.
  • If you do not understand the instructions provided with this medicine, ask your doctor or pharmacist for help.

If you forget to use AMLO

If you miss a dose and it is less than 12 hours from when you should take it, take it straight away, then continue as normal the next day. Otherwise, skip that day's dose but be sure to take the next day's dose when it is due.

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

This may increase the chance of 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 AMLO

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

You may need urgent medical attention.

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

5. What should I know while using AMLO?

Things you should do

Tell any other doctors, dentists and pharmacists who are treating you that you are taking AMLO.

If you are about to start any new medicine, tell your doctor or pharmacist that you are taking AMLO.

If you become pregnant while taking AMLO tell your doctor immediately.

Keep all of 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.

Things you should not do

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

Driving or using machines

Be careful driving or operating machinery until you know how AMLO affects you.

Amlodipine may cause dizziness or drowsiness in some people and affect alertness.

If this occurs, do not drive, operate machinery or do things that could be dangerous if you are not alert.

Effects of food

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 AMLO.

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

Drinking alcohol

Tell your doctor if you drink alcohol.

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

  • 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 unusual 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 AMLO tablets in the original pack until it is time to take them.
  • Keep AMLO tablets in a cool dry place where the temperature is below 30°C. Protect from light.

Do not store AMLO, or any other medicine, in the bathroom or near a sink.

Do not leave medicines in the car or on window sills. Heat and dampness can destroy some medicines.

Keep your medicines where children cannot reach them. A locked cupboard at least one-and-a-half metres (1.5 m) 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.

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.

Less serious side effects

Less serious side effectsWhat to do
  • headache
  • dizziness
  • flushing
  • tiredness
  • drowsiness or sleepiness
  • stomach pain or nausea.
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.
  • indigestion
  • sexual problems.
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.
These may or may not be due to AMLO but you should tell your doctor.

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 straight away if you notice any of these serious side effects.
These may be serious side effects that may need urgent medical attention
  • 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.
Tell your doctor immediately or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

If you are 65 years or older, you should be especially careful while taking AMLO. 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 available with a doctor's prescription.

What AMLO contains

Active ingredient
(main ingredient)		amlodipine besilate
Other ingredients
(inactive ingredients)

AMLO tablets contain:

  • microcrystalline cellulose
  • mannitol
  • sodium starch glycollate
  • colloidal anhydrous silica
  • magnesium stearate
Potential allergensNone

AMLO does not contain gluten, sugar or lactose.

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

What AMLO looks like

AMLO is available in two strengths.

AMLO 5 tablets - White to off-white, octagonal shaped, uncoated tablets debossed with “AM 5” on one side and scoreline on the other side (Aust R 201371)

The tablets are available in blister pack of 30's.

AMLO 10 tablets - White to off-white, octagonal shaped, uncoated tablets debossed with “AM 10” on one side and plain on the other side. (Aust R 201372).

The tablets are available in blister pack of 30's.

Who distributes AMLO

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in August 2024

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Amlo

Active ingredient

Amlodipine

Schedule

S4

 

1 Name of Medicine

Amlodipine besilate.

2 Qualitative and Quantitative Composition

Amlo contains the active ingredient amlodipine besilate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Amlo tablets are available in two strengths.

5 mg tablets.

White to off-white, octagonal shaped, uncoated tablets, debossed with "AM 5" on one side and scoreline on the other side containing 5 mg of amlodipine (as besilate).

10 mg tablets.

White to off-white, octagonal shaped uncoated tablets, debossed with "AM 10" on one side and plain on the other side containing 10 mg of amlodipine (as besilate).

4 Clinical Particulars

4.1 Therapeutic Indications

1. Hypertension.

Amlo tablets are 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 amlodipine, which has been used in combination with a thiazide diuretic, beta adrenoceptor blocking agent or an angiotensin converting enzyme inhibitor.

2. Angina.

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

4.2 Dose and Method of Administration

For hypertension or angina the usual initial dose is 2.5 to 5 mg once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response.
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 amlodipine tablets to other antihypertensive therapy.
Amlo 5 mg tablets can be divided in half along the scoreline if your doctor has prescribed a 2.5 mg dose.
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 side effects.

Coadministration with other antihypertensive and/or antianginal drugs.

Amlodipine tablets have been safely administered with thiazides, ACE inhibitors, beta-blockers, long acting nitrates and/or sublingual nitroglycerin.
No dose adjustment of amlodipine tablets is required upon concomitant administration of thiazide diuretics, beta-blockers, long acting nitrates and angiotensin-converting enzyme inhibitors.

4.3 Contraindications

Amlo tablets are contraindicated in patients with a known hypersensitivity to amlodipine, 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).

Amlo tablets 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. Amlodipine tablets (5-10 mg per day) have 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). Amlodipine tablets have been compared to placebo in four 8-12 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.

Amlodipine 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 5 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. Amlo tablets 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 degree of renal impairment. Amlo tablets may be used in such patients at normal doses. 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 reactions in elderly patients was approximately 6% higher than that of younger population (< 65 years). Adverse reactions include oedema, muscle cramps and dizziness. Amlo tablets 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

Amlodipine tablets have been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerine, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycaemic drugs.
Special studies have indicated that the coadministration of amlodipine tablets with digoxin did not change serum digoxin levels or digoxin renal clearance in healthy volunteers, and that coadministration of cimetidine did not alter the pharmacokinetics of amlodipine; and that coadministration 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.

Coadministration 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 coadministered 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).

Coadministration 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.

Coadministration of multiple 10 mg doses of amlodipine with 80 mg of 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.

Cyclosporin.

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

Tacrolimus.

There is a risk of increased tacrolimus blood levels when coadministered 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 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.
Safety of amlodipine tablets 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.
Breastfeeding should be discontinued during treatment with Amlo tablets.

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)

Amlodipine tablets have been evaluated for safety in more than 11,000 patients in clinical trials worldwide.
In general, treatment with amlodipine tablets was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine tablets were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine tablets (N = 1730) in doses up to 10 mg to placebo (N = 1250), discontinuation of amlodipine tablets due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). Amlodipine tablets 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 or 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 are shown in 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 are included in 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.

Constipation, dyspepsia*, dysphagia, diarrhoea, flatulence, vomiting, altered bowel habits, pancreatitis, gingival hyperplasia.

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 frequency, micturition disorder, nocturia.

Reproductive system and breast disorders.

Gynaecomastia, sexual dysfunction (male* and female).

Respiratory, thoracic and mediastinal disorders.

Dyspnoea*, epistaxis.

Skin and subcutaneous tissues disorders.

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

Autonomic nervous system.

Dry mouth.

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 side 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.
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.
Amlodipine tablets have 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

Reports of intentional overdosage 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 amlodipine 30 mg (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.
Available data suggest that overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a 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 probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
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 (e.g. 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 two 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 central nervous system (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 Poison Information Centre on 131126 (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 ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized 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, 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. 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 amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 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 amlodipine tablets 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 tablets have not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when coadministered with beta-blockers to man. Similar findings, however, have been observed in normals or well compensated patients with heart failure with agents possessing significant negative inotropic effects.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine tablets 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.

Amlodipine tablets have been compared to placebo in four 8-12 weeks studies of patients with 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 amlodipine tablets 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, amlodipine tablets 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 hospitalization 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 amlodipine tablets 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 as 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 amlodipine tablets and concomitant beta-blockers. In clinical studies in which amlodipine tablets were administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine tablet 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 of 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 nitroglycerine tablet consumption. The sustained efficacy of amlodipine tablets 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 6-12 hours postdose. This may reflect significant initial uptake by the liver, followed by a phase of redistribution. This interval is shorter (2-8 hours) in patients with hepatic insufficiency. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.

Distribution.

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.

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Steady-state plasma levels are reached after 7-8 days of consecutive dosing.

Excretion.

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.

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

In addition to amlodipine besilate, each Amlo tablet contains the following inactive ingredients: mannitol, microcrystalline cellulose, colloidal anhydrous silica, 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

Amlo tablets should be stored below 30°C in the original packaging. Protect from light.

6.5 Nature and Contents of Container

Amlo tablets are supplied in PVC/PVDC/Al blister packs in cartons of 30 tablets.

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 name: 3-ethyl 5-methyl-(4RS)-2-(2-(aminoethoxy)methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzene sulphonate.

Chemical structure.

Amlodipine besilate is a dihydropyridine derivative and has the following structural formula.
Molecular formula: C20H25ClN2O5.C6H6O3S.
Molecular weight: 567.1 (free base 408.9).

CAS number.

111470-99-6.

7 Medicine Schedule (Poisons Standard)

S4: Prescription Only Medicine.

Summary Table of Changes