Consumer medicine information

Auro-Amlodipine Tablets

Amlodipine

BRAND INFORMATION

Brand name

Auro-Amlodipine Tablets

Active ingredient

Amlodipine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Auro-Amlodipine Tablets.

What is in this leaflet

This leaflet answers some common questions people ask about AURO-AMLODIPINE.

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 AURO-AMLODIPINE against the benefits they expect it will have for you.

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

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

What AURO-AMLODIPINE is used for

AURO-AMLODIPINE 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.

AURO-AMLODIPINE is also used to 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.

AURO-AMLODIPINE is not for the relief of a sudden attack of angina. Your doctor may have given you other medication to treat this.

AURO-AMLODIPINE 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 AURO-AMLODIPINE for another purpose.

Always ask your doctor if you need more information.

AURO-AMLODIPINE is available only with a doctor's prescription.

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

Before you take it

Tell your doctor if you have any of the following conditions or if you have ever experienced any of these conditions.

When you must not take it

Do not take AURO-AMLODIPINE if:

  • You have ever had an allergic reaction to amlodipine or other calcium channel-blockers.
    These medicines include felodipine, nifedipine or lercanidipine.

Check with your doctor or pharmacist if you are unsure.

You are allergic to any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction to AURO-AMLODIPINE may include rash, itching or hived on the skin, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

Do not take AURO-AMLODIPINE after the use by (expiry) date printed on the pack has passed.

It may have no effect at all or an unexpected effect if you take it after the expiry date.

Do not take AURO-AMLODIPINE if the packaging is torn or shows signs of tampering..

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

Before you start to take it

You must tell your doctor if:

  • You are pregnant or intend to become pregnant while taking AURO-AMLODIPINE.
    Medicines like AURO-AMLODIPINE may affect the developing baby if you take it during pregnancy. Your doctor will discuss the possible risks and benefits involved.
  • You are allergic to any other medicines, foods, dyes, or preservatives.
  • You have any medical problems, including:
    - heart disease, including heart failure; or
    - liver problems.

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

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

If you have not told your doctor about any of the above, tell them before you start taking AURO-AMLODIPINE.

Taking other medicines

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

Some medicines and AURO-AMLODIPINE may interfere with each other.

Tell your doctor or pharmacist 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 or tacrolimus, medicines used to suppress the immune system; or
  • St John's Wort.

Your doctor or pharmacist have more information on medicines to be careful with or avoid while taking AURO-AMLODIPINE.

Your doctor or pharmacist can tell you what to do if you are taking any of these medicines.

How to take it

Take AURO-AMLODIPINE exactly as your doctor has prescribed.

Follow all directions given to you by your doctor.

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 AURO-AMLODIPINE is 5 mg each day. Your doctor may increase this to 10 mg each day.

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

As the 5 mg AURO-AMLODIPINE tablets do not have a breakline, alternative amlodipine besilate products should be used if a 2.5 mg dose is required. The 5 mg AURO-AMLODIPINE tablets must not be broken in half to give a 2.5 mg dose.

How and when to take it:

Your AURO-AMLODIPINE should be swallowed with a drink of water.

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.

AURO-AMLODIPINE can be taken with or without food.

How long to take it:

You must take AURO-AMLODIPINE every day.

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it:

If you miss a dose and it is less than 12 hours from when you should take it, take it straight away, and 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 take too much (overdose):

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26 for Australia, 0800 POISON or 0800 764 766 for New Zealand) for advice, or go to Accident and Emergency at nearest hospital if you think you or anyone else may have taken too much AURO-AMLODIPINE. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include dizziness, lightheadedness or fainting and an irregular heart-beat.

While you are taking it

Things you must do:

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking AURO-AMLODIPINE.

Tell any other doctors, dentists and pharmacists who are treating you that you are taking AURO-AMLODIPINE.

If you become pregnant while taking AURO-AMLODIPINE, 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.

If you are not sure whether you should be taking AURO-AMLODIPINE, talk to your doctor.

Things you must not do:

Do not stop taking AURO-AMLODIPINE, or lower the dose, without checking with your doctor.

Do not use AURO-AMLODIPINE to treat any other conditions unless your doctor tells you to.

Do not give this AURO-AMLODIPINE 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 AURO-AMLODIPINE.

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

Be careful driving or operating machinery until you know how AURO-AMLODIPINE affects you.

AURO-AMLODIPINE may cause dizziness or drowsiness in some people and affect alertness.

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 strengthens 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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking AURO-AMLODIPINE.

AURO-AMLODIPINE helps most people but it may have some unwanted side effects in a few people.

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

It can be difficult to tell whether side effects are the result of taking AURO-AMLODIPINE, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

Do not be alarmed by the list of possible side effects.

You may not experience any of them.

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

Tell your doctor if you experience any of the following and they worry you:

  • headache;
  • dizziness;
  • flushing;
  • palpitations;
  • tiredness;
  • drowsiness or sleepiness; or
  • stomach pain or nausea.

These are the more common side effects of AURO-AMLODIPINE. All side effects should be reported to a health professional.

Tell your doctor if you experience any of the following and they worry you:

  • indigestion; or
  • sexual problems.

These may or may not be due to AURO-AMLODIPINE but you should tell your doctor.

Tell your doctor immediately if you notice any of the following:

  • 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 lightheadedness 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;
  • shortness of breath;
  • symptoms of liver disease such as itching, yellowing of the skin and eyes, and dark coloured urine, or
  • 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.

These may be serious side effects that may need urgent medical attention.

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

  • 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 or;
  • severe upper stomach pain, often with nausea and vomiting.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell.

Other side effects not listed above may also occur in some patients.

If you are 65 years or older, you should be especially careful while taking AURO-AMLODIPINE. 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.

After taking it

Storage:

Keep AURO-AMLODIPINE where children cannot reach it.

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

Keep your tablets in the blister pack until it is time to take them.

If you take your tablets out of the blister pack they will not keep as well.

Keep your tablets in a cool dry place where temperatures stay below 30°C.

Do not store AURO-AMLODIPINE or any other medicine in the bathroom or near a sink.

Do not leave AURO-AMLODIPINE on a window sill or in the car.

Heat and dampness can destroy some medicines.

Disposal:

If your doctor tells you to stop taking AURO-AMLODIPINE, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What AURO-AMLODIPINE looks like

AURO-AMLODIPINE 5 and 10 (5 and 10 mg amlodipine (as besilate)) are presented in a blister pack, size of 30 tablets.

AURO-AMLODIPINE 5
White to off white, flat, bevel edged barrel shaped uncoated tablets, debossed with ‘C’ on one side and ‘58’ on the other side.

AURO-AMLODIPINE 10
White to off white, flat, bevel edged round shaped uncoated tablets, debossed with ‘C’ on one side and ‘59’ on the other side.

Ingredients

Active ingredient
Amlodipine (as besilate).

Other ingredients

  • microcrystalline cellulose-;
  • calcium hydrogen phosphate anhydrous;
  • sodium starch glycolate; and
  • magnesium stearate.

AURO-AMLODIPINE does not contain gluten, sugar or lactose.

BRAND INFORMATION

Brand name

Auro-Amlodipine Tablets

Active ingredient

Amlodipine

Schedule

S4

 

Name of the medicine

Amlodipine besilate.

Excipients.

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

Description

Chemical name: 3-ethyl 5-methyl (4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate. Molecular formula: C26H31ClN2O8S. MW: 567.1. CAS: 111740-99-6. Amlodipine besilate is a white or almost white powder and is slightly soluble in water, freely soluble in methanol, sparingly soluble in anhydrous ethanol and slightly soluble in 2-propanol.

Pharmacology

Pharmacodynamics.

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:
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.
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 have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and 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 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.

Pharmacokinetics.

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. 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.

Biotransformation/ elimination.

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. 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%.
A bioavailability study comparing Auro-Amlodipine 10 tablets with the originator product gave mean Cmax, for amlodipine of 5.45 nanogram/mL and 4.99 nanogram/mL, respectively. The Cmax point estimate was 107.8 and the 90% confidence interval was between 100.1 and 116.0. The mean AUC0-∞ for amlodipine were 380.95 nanogram.h/mL and 348.62 nanogram.h/mL, respectively. The AUC0-∞ point estimate was 109.1 and the 90% confidence interval was between 103.2 and 115.4.

Clinical Trials

Studies in patients with congestive heart failure.

Amlodipine has been compared to placebo in four 8-12 weeks 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 amlodipine 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 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 amlodipine 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 and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of atrioventricular 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 post dose. 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 (glyceryl trinitrate) tablet consumption. The sustained efficacy of amlodipine 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 beats per minute (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.

Indications

Hypertension.

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

Angina.

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

Contraindications

Amlodipine is contraindicated in patients with a known sensitivity to amlodipine, dihydropyridines, or any of the inactive ingredients.

Precautions

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).

Amlodipine 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 (5-10 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). Amlodipine has 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.

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. Amlodipine should, therefore, be administered with caution in these patients and careful monitoring should be performed. A lower starting dose may be required (see Dosage and 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. Amlodipine may be used at normal doses in patients with renal failure. Amlodipine is not dialysable.

Peripheral oedema.

Mild to moderate peripheral oedema was the most common adverse event in the clinical trials (see Adverse 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 pregnancy.

(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 in human pregnancy or lactation has not been established. 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). 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.

Use in lactation.

It is not known whether amlodipine is excreted in human milk. In the absence of this information, breastfeeding should be discontinued during treatment with amlodipine.

Paediatric use.

Safety and effectiveness have not been established in children.

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. Amlodipine should be used cautiously in elderly patients.

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.

Interactions

Amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, long acting nitrates, sublingual nitroglycerine, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycaemic drugs.
Special studies have indicated that the coadministration of amlodipine 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.

Adverse Effects

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

Cardiovascular 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 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.

Dosage and Administration

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.
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 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 Adverse Effects section for information related to dosage and side effects.

Coadministration with other antihypertensive and/or antianginal drugs.

Amlodipine has been safely administered with thiazides, ACE inhibitors, beta-blockers, long acting nitrates, and/or sublingual nitroglycerin.
No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta-blockers, long acting nitrates and ACE inhibitors.
Since there is no lower dose (2.5 mg) of Auro-Amlodipine available, if a 2.5 mg dose of amlodipine besilate is required, an alternative product must be used.
As the Auro-Amlodipine 5 mg tablets do not have a breakline, alternative amlodipine besilate products should be used if a 2.5 mg dose is required. The Auro-Amlodipine 5 mg tablets must not be broken in half to give a 2.5 mg dose.

Overdosage

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 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 amlodipine (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.

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 an overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Tablets (white to off white, flat, bevel edged, uncoated, marked C on one side), 5 mg (barrel shaped, marked 58 on reverse, AUST R 151427), 10 mg (round, marked 59 on reverse, AUST R 151430): 30’s (blister pack).

Storage

Store below 30°C.

Poison Schedule

S4.