Consumer medicine information

APO-Amlodipine/Atorvastatin 10/40 Tablets

Amlodipine; Atorvastatin

BRAND INFORMATION

Brand name

APO-Amlodipine/Atorvastatin 10/40 Tablets

Active ingredient

Amlodipine; Atorvastatin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Amlodipine/Atorvastatin 10/40 Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about amlodipine and atorvastatin combination tablets. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up-to-date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is APO-Amlodipine/Atorvastatin, Tablets. It contains the active ingredients amlodipine besylate and atorvastatin calcium propylene glycol solvate.

It is used to:

  • treat high blood pressure
  • treat high cholesterol
  • treat angina (type of chest pain)
  • reduce the risk of heart attack or stroke in patients with high blood pressure who have coronary heart disease (CHD) or multiple risk factors for CHD.

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

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

How it works

This medicine contains a combination of amlodipine and atorvastatin.

Amlodipine belongs to a group of medicines called calcium channel blockers. They work by relaxing 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.

Atorvastatin belongs to a group of medicines called HMG-CoA reductase inhibitors. It works by reducing the amount of cholesterol made by the liver. It reduces the 'bad' cholesterol and can raise the 'good' cholesterol. Atorvastatin also helps to protect you from having a heart attack or stroke.

There is no evidence that this medicine is addictive.

Use in children

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

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have active liver disease or your liver function test results are persistently elevated (check with your doctor).
  • You are taking the antibiotic fusidic acid which is used to treat infections.
  • You are pregnant or are a female of childbearing age and are not using effective contraception.
    Amlodipine and atorvastatin combination tablets may affect your developing baby if it is taken during pregnancy.
  • You are breastfeeding.
    Amlodipine and atorvastatin combination tablets may pass into human breast milk.
  • You are hypersensitive to, or have had an allergic reaction to, amlodipine or atorvastatin or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  2. You have or have had any medical conditions, especially the following:
    - heart problems, including heart failure
    - stroke or transient ischaemic attack (known as 'mini stroke') in the last 6 months
    - low blood pressure
    - liver problems
    - kidney problems
    - muscle pain, tenderness or weakness when taking medicines used to treat high cholesterol or triglycerides
    - breathing problems when taking medicines used to treat high cholesterol or triglycerides.
  3. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant.
  4. You are currently breastfeeding or you plan to breastfeed. Do not take this medicine whilst breastfeeding.
  5. You are planning to have surgery or an anaesthetic.
  6. You are currently receiving or are planning to receive dental treatment.
  7. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with amlodipine/atorvastatin. These include:

  • other medicines used to treat high cholesterol or triglycerides, such as colestipol
  • other medicines used to treat high blood pressure
  • digoxin, a medicine to treat heart problems
  • some antibiotics such as erythromycin, clarithromycin, rifampicin and fusidic acid
  • phenytoin, a medicine used to treat epilepsy (seizures)
  • oral contraceptives
  • cyclosporine, a medicine used to suppress the immune system
  • some medicines used to treat fungal infections, such as ketoconazole and itraconazole
  • efavirenz and protease inhibitors such as ritonavir, tipranavir and telaprevir, for the treatment of HIV infection and/or hepatitis C
  • diltiazem, a medicines used to treat angina
  • cimetidine and antacids, medicines used to treat reflux or ulcers
  • spironolactone, a medicine used to treat high blood pressure and certain types of swelling
  • colchicine, a medicine used to treat a disease with painful swollen joints caused by uric acid crystals
  • vitamin B3
  • St John's Wort
  • grapefruit juice.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with amlodipine and/or atorvastatin.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Amlodipine and atorvastatin combination tablet is taken once a day. Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow the tablet(s) whole with a full glass of water.

Do not chew or crush tablets.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

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

It is important to keep taking your medicine even if you feel well. If you stop taking amlodipine/atorvastatin your blood pressure and cholesterol levels may rise again.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is less than 12 hours before your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

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

This may increase the chance of you experiencing side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

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

Avoid drinking large quantities of alcohol, as this may increase the chance of you experiencing liver problems.

Avoid eating large quantities of grapefruit or drinking large quantities of grapefruit juice, as this may increase the chance of you experiencing side effects.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking amlodipine and atorvastatin combination tablets or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not. Tell your doctor if you notice any of the following:

  • swelling of the ankles, feet, face or hands
  • muscle and joint pain, muscle weakness
  • headache
  • flushing
  • fast or irregular heart beats
  • dizziness
  • tiredness or weakness
  • drowsiness or sleepiness
  • stomach pain or nausea
  • constipation, diarrhoea, wind
  • heartburn, indigestion or wind
  • urine infection or other infections
  • stuffy or runny nose
  • nose bleeds
  • rash.

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • symptoms of liver disease such as itching, yellowing of the skin and eyes and dark coloured urine
  • feeling weak and tired, excessively thirsty and passing more urine
  • dizziness or lightheadedness on standing up from a sitting or lying position
  • problems with breathing, including shortness of breath, persistent cough and fever
  • eye pain or change in vision
  • changes in mood, feeling anxious or nervous
  • chest pain associated with exertion (angina) that lasts longer, is more severe or occurs more often
  • chest pain.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • unexpected muscle pain, tenderness or weakness not caused by exercise
  • tingling in the hands or feet
  • changes in heart beat either fast or slow
  • sudden severe headache, which may be accompanied by nausea, vomiting, loss of sensation, tingling in any part of the body or ringing in the ears
  • severe blisters and bleeding of the lips, eyes, mouth, nose or genitals
  • severe upper stomach pain, often with nausea and vomiting.

If you are 65 years old or over, you may be more likely to experience side effects such as swelling of the feet and ankles, muscle cramps and dizziness.

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

Allergic reactions

If you think you are having an allergic reaction to amlodipine and atorvastatin combination tablets, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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.

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Amlodipine/Atorvastatin Tablets looks like

  • 5/10mg tablets
    White to off-white, oval, biconvex, coated tablet. Engraved "5/10" on one side, "APO" on the other side.
  • 5/20mg tablets
    White to off-white, oval, biconvex, coated tablet. Engraved "5/20" on one side, "APO" on the other side.
  • 5/40mg tablets
    White to off-white, oval, biconvex, coated tablet. Engraved "5/40" on one side, "APO" on the other side.
  • 5/80mg tablets
    White to off-white, oval, biconvex, coated tablet. Engraved "5/80" on one side, "APO" on the other side.
  • 10/10mg tablets
    Light blue, oval, biconvex, coated tablet. Engraved "10/10" on one side, "APO" on the other side.
  • 10/20mg tablets
    Light blue, oval, biconvex, coated tablet. Engraved "10/20" on one side, "APO" on the other side.
  • 10/40mg tablets
    Light blue, oval, biconvex, coated tablet. Engraved "10/40" on one side, "APO" on the other side.
  • 10/80mg tablets
    Light blue, oval, biconvex, coated tablet. Engraved "10/80" on one side, "APO" on the other side.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 5mg or 10mg of amlodipine (as besylate) and 10mg, 20mg, 40mg or 80mg of atorvastatin (as calcium propylene glycol solvate) as the active ingredients.

It also contains the following inactive ingredients:

  • croscarmellose sodium
  • microcrystalline cellulose
  • iron oxide yellow
  • magnesium stearate
  • colloidal anhydrous silica
  • calcium acetate
  • blue colourant (ARTG #10379) (10mg/10mg, 10mg/20mg, 10mg/40mg and 10mg/80mg strengths only)
  • white colourant (ARTG #108944) (5mg/10mg, 5mg/20mg, 5mg/40mg and 5mg/80mg strengths only).

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

  • APO-Amlodipine/Atorvastatin 5/10 tablets (blister pack 30):
    AUST R 214378.
  • APO-Amlodipine/Atorvastatin 5/20 tablets (blister pack 30):
    AUST R 214385.
  • APO-Amlodipine/Atorvastatin 5/40 tablets (blister pack 30):
    AUST R 214375.
  • APO-Amlodipine/Atorvastatin 5/80 tablets (blister pack 30):
    AUST R 214386.
  • APO-Amlodipine/Atorvastatin 10/10 tablets (blister pack 30):
    AUST R 214409.
  • APO-Amlodipine/Atorvastatin 10/20 tablets (blister pack 30):
    AUST R 214360.
  • APO-Amlodipine/Atorvastatin 10/40 tablets (blister pack 30):
    AUST R 214345.
  • APO-Amlodipine/Atorvastatin 10/80 tablets (blister pack 30):
    AUST R 214359.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in July 2014.

BRAND INFORMATION

Brand name

APO-Amlodipine/Atorvastatin 10/40 Tablets

Active ingredient

Amlodipine; Atorvastatin

Schedule

S4

 

Name of the medicine

Amlodipine (besylate) and atorvastatin (calcium propylene glycol solvate).

Excipients.

Croscarmellose sodium, microcrystalline cellulose, iron oxide yellow, magnesium stearate, anhydrous colloidal silica, calcium acetate, Opadry II complete film coating system 85F10919 blue (ARTG #10379) (10 mg/10 mg, 10 mg/20 mg, 10 mg/40 mg and 10 mg/80 mg strengths only) and Opadry II complete film coating system white 85F180001 (ARTG #108944) (5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg and 5 mg/80 mg strengths only).

Description

Amlodipine besylate.

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: C20H25CIN2O.C6H5SO3H. MW: 567.05. CAS: 111470-99-6. Amlodipine besylate is a white or almost white powder that is slightly soluble in water and sparingly soluble in ethanol.

Atorvastatin (as calcium propylene glycol solvate).

Chemical name: calcium bis((3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4- phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate) propylene glycol solvate. Molecular formula: C66H68CaF2N4O10.C3H8O2. MW: 1231.46. CAS: 134523-03-8 (atorvastatin calcium). Atorvastatin calcium propylene glycol solvate is a white to off white crystalline powder that is sparingly soluble in methanol, practically insoluble in ethanol and very slightly soluble in acetonitrile.

Pharmacology

Pharmacological actions.

Amlodipine and atorvastatin combination tablets have a dual mechanism of action consisting of the dihydropyridine calcium ion antagonist, amlodipine and the HMG-CoA reductase inhibitor, atorvastatin.
Studies have been conducted in which placebo, amlodipine alone, atorvastatin alone, and the eight dose combinations of amlodipine and atorvastatin have been administered once daily, in patients with comorbid hyperlipidaemia and hypertension. Analyses of changes in systolic blood pressure demonstrated that there was no overall modification of amlodipine's effect on systolic blood pressure when the drug was taken in combination with atorvastatin compared to amlodipine alone. Analyses of changes in low density lipoprotein cholesterol (LDL-C) demonstrated that there was no overall modification of atorvastatin's effect on LDL-C when the drug was taken in combination with amlodipine compared with atorvastatin alone (see Clinical Trials).

Antihypertensive/ antianginal action of amlodipine.

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

Haemodynamics.

Following administration of therapeutic doses to patients with hypertension, 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 normal or well compensated patients with heart failure with agents possessing significant negative inotropic effects.
In hypertensive patients with normal renal function, therapeutic doses of 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.

The dyslipidaemic action of atorvastatin.

Atorvastatin is an inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated into very low density lipoprotein (VLDL) and released into the plasma for delivery to peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolised primarily through the high affinity LDL receptor.
Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL. Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a marked and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles.
A variety of clinical and pathologic studies have demonstrated that elevated cholesterol and lipoprotein levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.
The atorvastatin component reduces total-C, LDL-C, and apo B in both normal volunteers and in patients with homozygous and heterozygous forms of familial hypercholesterolaemia (FH), nonfamilial forms of hypercholesterolaemia, and mixed dyslipidaemia. Atorvastatin also reduces very low density lipoprotein cholesterol (VLDL-C) and TG and produces variable increases in HDL-C and apolipoprotein A1 (apo A1). Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B and TG, and increases HDL-C in patients with isolated hypertriglyceridaemia. Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinaemia. In animal models, atorvastatin limits the development of lipid enriched atherosclerotic lesions and promotes the regression of pre-established atheroma.
Atorvastatin and its metabolites are responsible for pharmacological activity in humans. The liver is its primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dose rather than systemic drug concentration correlates better with LDL-C reduction. Individualisation of drug dose should be based on therapeutic response (see Dosage and Administration).

Pharmacokinetics.

Absorption.

Tablets.

Following oral administration of amlodipine and atorvastatin combination tablets, peak plasma concentrations are observed within 1 to 2 hours for atorvastatin and between 6 and 12 hours for amlodipine. The rate and extent of absorption (bioavailability) of amlodipine and atorvastatin from amlodipine and atorvastatin combination tablets are not significantly different from the bioavailability of amlodipine and atorvastatin from coadministration of amlodipine and atorvastatin tablets as assessed by Cmax and AUC for the amlodipine component and Cmax and AUC for the atorvastatin component in healthy volunteers.
The bioavailability of amlodipine from amlodipine and atorvastatin combination tablets was not affected by food as assessed by Cmax: 105% (90% CI: 99, 111) and AUC: 101% (90% CI: 97, 105). Although food decreases the rate and extent of absorption of atorvastatin from the tablets by approximately 32% and 11% respectively, as assessed by Cmax: 68% (90% CI 60, 79) and AUC: 89% (90% CI 83, 95), similar reductions in plasma concentrations in the fed state have been seen with atorvastatin without a reduction in LDL-C effect.
Coadministration of multiple 10 mg doses of amlodipine with 80 mg atorvastatin in healthy subjects resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin compared to when the two drugs were given independently.
The individual pharmacokinetic profile of amlodipine and atorvastatin are outlined below.

Amlodipine.

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. 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 in healthy volunteers.
Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Atorvastatin.

Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. A constant proportion of atorvastatin is absorbed intact. The absolute bioavailability is 14%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9% respectively as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration (see Dosage and Administration).
The mean volume of distribution of atorvastatin is about 400 litres. Atorvastatin is ≥ 98% bound to plasma proteins. A red blood cell/ plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin is likely to be secreted in human milk (see Precautions, Use in lactation).
In humans, atorvastatin is extensively metabolised to orthohydroxylated and parahydroxylated derivatives. In vitro inhibition of HMG-CoA reductase by orthohydroxylated and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme (see Precautions). In animals, the orthohydroxy metabolite undergoes further glucuronidation.
Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.

Special populations.

No studies have been conducted with amlodipine and atorvastatin combination tablets in special populations. Information is provided below on the individual components of amlodipine and atorvastatin combination tablets.

Elderly (≥ 65 years).

Amlodipine.

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%.

Atorvastatin.

Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥ 65 years) than in young adults. Lipid effects are comparable to that seen in younger patient populations given equal doses of atorvastatin.

Gender.

Atorvastatin.

Plasma concentrations of atorvastatin in women differ (approximately 20% higher for Cmax and 10% lower for AUC) from those in men; however, there is no clinically significant difference in lipid effects with atorvastatin between men and women.

Renal impairment.

Amlodipine.

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. Amlodipine may be used in such patients at normal doses. Amlodipine is not dialysable.

Atorvastatin.

Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary. While studies have not been conducted in patients with endstage renal disease, haemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.

Hepatic impairment.

See Dosage and Administration, Precautions and Contraindications.

Clinical Trials

Amlodipine and atorvastatin combination.

Studies in patients with hypertension and dyslipidaemia.

In the RESPOND double blind, placebo controlled study, a total of 1,660 patients with comorbid hypertension and dyslipidaemia received once daily treatment with eight dose combinations of amlodipine and atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80, 10/80 mg), amlodipine alone (5 mg and 10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, 80 mg) or placebo. At 8 weeks, all eight combination treatment groups of amlodipine and atorvastatin demonstrated statistically significant dose related reductions in systolic blood pressure (SBP) and LDL-C compared to placebo, with no overall modification of effect of either component on SBP and LDL-C (see Table 1).
In the AVALON double blind, placebo controlled study, a total of 847 patients with comorbid hypertension and dyslipidaemia received once daily placebo, 5 mg amlodipine, 10 mg of atorvastatin or the combination of 5 mg amlodipine and 10 mg atorvastatin. The primary objective of the study was the percentage of patients on the combination of amlodipine and atorvastatin reaching JNC VI and NCEP III goals compared to atorvastatin, amlodipine and placebo alone. The results following 8 weeks of treatment are summarised in Table 2. Significantly more patients treated with the combination (45.5%) reached both their blood pressure (BP) and LDL-C goals compared to amlodipine or atorvastatin alone. Amlodipine and atorvastatin combination tablets was not studied in patients with decompensated chronic cardiac failure or postmyocardial infarction (within 3 to 6 months).

Amlodipine component.

Studies in patients with congestive heart failure.

Amlodipine has been compared to placebo in four 8-12 week studies of male and female patients with NYHA class II-IV heart failure, involving a total of 697 patients. Primary endpoints for these studies were: symptom limiting exercise time, pulmonary capillary wedge pressure (PCWP) and cardiac index (CI). Secondary endpoints varied from study to study and included functional status (NYHA classification), cardiopulmonary exam (including symptomatic status), left ventricular ejection fraction (LVEF), and gas exchange measurement.
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. (See Table 3.)
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 AV 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 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.

Atorvastatin component.

In a multicentre, placebo controlled, double blind dose response study in patients with hypercholesterolaemia, atorvastatin was given as a single daily dose over 6 weeks. Atorvastatin (10-80 mg) reduced total-C (30%-46%), LDL-C (41%-61%), apolipoprotein B (34%-50%) and triglycerides (14%-33%) while producing variable increases in HDL-C and apolipoprotein A (see Table 4). A therapeutic response was seen within 2 weeks, and maximum response achieved within 4 weeks.
In three further trials, 1,148 patients with either heterozygous familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia, or mixed dyslipidaemia were treated with atorvastatin for one year. The results were consistent with those of the dose response study and were maintained for the duration of therapy.
In patients with primary hypercholesterolaemia and mixed dyslipidaemia (Fredrickson types IIa and IIb), data pooled from 24 controlled trials demonstrated that the adjusted mean percent increases from baseline in HDL-C for atorvastatin (10-80 mg) were 5.0 to 7.8% in a nondose related manner.
Clinical studies demonstrate that a dose of 10 mg atorvastatin is more effective than simvastatin 10 mg and pravastatin 20 mg in reducing LDL-C, total-C, triglycerides and apo B. In several multicentre, double blind studies in patients with hypercholesterolaemia, atorvastatin was compared to other HMG-CoA reductase inhibitors. After randomisation, patients were treated with atorvastatin 10 mg per day or the recommended starting dose of the comparative agent. At week 16 a greater proportion of atorvastatin treated patients than those treated with simvastatin (46% vs. 27%) or pravastatin (65% vs. 19%) reached their target LDL-C levels. Increasing the dosage of atorvastatin resulted in more patients reaching target LDL-C goals.

Prevention of cardiovascular disease.

In the lipid lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on the composite endpoint of fatal coronary heart disease and nonfatal myocardial infarction (MI) was assessed in 10,305 hypertensive patients, 40-79 years of age, without a history of symptomatic coronary heart disease and with total-C levels ≤ 6.5 mmol/L. Additionally patients were at moderate risk of coronary heart disease, having at least 3 of the predefined cardiovascular risk factors [male gender (81%), age ≥ 55 years (84%), smoking (33%), noninsulin dependent diabetes mellitus (25%), history of CHD in a first degree relative (26%), plasma total-C to HDL-C ratio ≥ 6 (14%), peripheral vascular disease (5%), left ventricular hypertrophy on echocardiography (14%), past history of cerebrovascular event (10%), specific ECG abnormality (14%), proteinuria/ albuminuria (62%)]. Patients with a history of previous myocardial infarction or angina were excluded.
In this randomised, double blind, placebo controlled study, patients were treated with antihypertensive therapy (goal BP < 140/90 mmHg for nondiabetic patients, < 130/80 mmHg for diabetic patients) and either atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137) and followed for a median duration of 3.3 years. At baseline, in the atorvastatin group, 38 patients (0.7%) had total-C levels less than 3.5 mmol/L; 2,340 patients (45.3%) had total-C levels greater than or equal to 3.5 mmol/L and less than 5.5 mmol/L; 2,304 patients (44.6%) had total-C levels greater than or equal to 5.5 mmol/L and less than 6.5 mmol/L; and 486 patients (9.4%) had total-C levels greater than or equal to 6.5 mmol/L. At baseline, 457 patients (9.8%) in the atorvastatin group had LDL-C levels less than or equal to 2.5 mmol/L; 1,731 patients (37%) had LDL-C levels greater than 2.5 mmol/L and less than 3.4 mmol/L; and 2,495 patients (53.3%) had LDL-C levels greater than or equal to 3.4 mmol/L. Median (25th and 75th percentile) changes from baseline after 1 year of atorvastatin treatment in total-C, LDL-C, TG and HDL-C were -1.40 mmol/L (-1.80, -0.90), -1.27 mmol/L (-1.66, -0.84), -0.20 mmol/L (-0.60, 0.10) and 0.00 mmol/L (-0.10, 0.10). Blood pressure control throughout the trial was similar in patients assigned to atorvastatin and placebo. (See Table 5.)
The primary endpoint examined in ASCOT was the rate of fatal coronary heart disease or nonfatal myocardial infarction over 3.3 years. These coronary events occurred in 1.9% of atorvastatin treated patients compared to 3% of placebo treated patients, a relative risk reduction of 36% (p = 0.0005) (see Table 5). Although this difference was statistically significant for the whole trial population, this difference was not statistically significant in specified subgroups such as diabetes, patients with left ventricular hypertrophy (LVH), previous vascular disease or metabolic syndrome.
There was no statistically significant reduction in the rate of total mortality, cardiovascular mortality or heart failure in the atorvastatin treated group compared to placebo.

Noninsulin dependent diabetes mellitus (NIDDM).

A 26 week randomised, double blind, comparator study in NIDDM subjects showed that atorvastatin is effective in dyslipidaemic patients with NIDDM. A 10 mg dose of atorvastatin produced a 34% reduction in LDL-C, a 27% reduction in total-C, a 24% reduction in TG and a 12% rise in HDL-C.

Homozygous familial hypercholesterolaemia.

Atorvastatin has also been shown to reduce LDL-C in patients with homozygous familial hypercholesterolaemia (FH), a population that has not usually responded to other lipid lowering medication. In an uncontrolled compassionate use study, 29 patients aged 6 to 37 years with homozygous FH received maximum daily doses of 20 mg to 80 mg of atorvastatin. The mean LDL reduction in this study was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range 7%-53%, median 24%). Five of the 29 patients had absent LDL receptor function, 3 of whom responded to atorvastatin with a mean LDL-C reduction of 22%. Experience in paediatric patients has been limited to patients with homozygous FH.

Hypertriglyceridaemia.

In patients with hypertriglyceridaemia (baseline TG ≥ 2.26 mmol/L and LDL-C < 4.14 mmol/L) atorvastatin (10 to 80 mg) reduced serum triglycerides by 31% to 40%.
In patients with severe hypertriglyceridaemia (baseline TG > 5.7 mmol/L), atorvastatin (10 to 80 mg) reduced serum triglycerides by 30% to 56%.
In a randomised, placebo controlled, double blind, multicentre study in patients with hypertriglyceridaemia (TG ≥ 3.95 mmol/L, LDL-C ≤ 4.1 mmol/L), atorvastatin 20 mg/day and 80 mg/day produced significantly greater reductions in TG levels than placebo (see Table 6).

Dysbetalipoproteinaemia.

In patients with dysbetalipoproteinaemia, atorvastatin (10 to 80 mg) reduced intermediate density lipoprotein (IDL-C) (range 28% to 52%) and IDL-C + VLDL-C (range 34% to 58%).
In an open label, randomised, crossover study in patients with dysbetalipoproteinaemia, treatment with atorvastatin 80 mg/day resulted in significantly greater mean percent decreases in IDL-C + VLDL-C, IDL-C, total-C, VLDL-C and Apo B than either simvastatin 40 mg/day or gemfibrozil 1200 mg/day and significantly greater mean percent decreases in triglycerides than simvastatin 40 mg/day (see Table 7).

Indications

Amlodipine and atorvastatin combination tablets are indicated for patients in whom treatment with amlodipine and atorvastatin is appropriate at the doses presented.

The indications for amlodipine are the following.


1. 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.
2. 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.

The indications for atorvastatin are the following.


1. Atorvastatin is indicated as an adjunct to diet for the treatment of patients with hypercholesterolaemia. Prior to initiating therapy with atorvastatin, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, and alcoholism) should be identified and treated.
2. Atorvastatin is indicated in hypertensive patients with multiple risk factors for coronary heart disease (CHD) which may include diabetes, history of stroke or other cerebrovascular disease, peripheral vascular disease or existing asymptomatic CHD (see Clinical Trials, Prevention of cardiovascular disease) to reduce the risk of nonfatal myocardial infarction and nonfatal stroke.
These effects do not replace the need to independently control known causes of cardiovascular mortality and morbidity such as hypertension, diabetes and smoking.

Contraindications

Amlodipine and atorvastatin combination tablets are contraindicated in patients with a known hypersensitivity to any component of this medication.
Amlodipine and atorvastatin combination tablets contain atorvastatin calcium and is, therefore, contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases (see Precautions, Liver dysfunction).
Amlodipine and atorvastatin combination tablets are contraindicated during pregnancy, while breastfeeding and in women of childbearing potential, unless on an effective contraceptive and highly unlikely to conceive (see Precautions, Use in pregnancy and Use in lactation).
Concomitant use with fusidic acid is also contraindicated due to the atorvastatin component (see Precautions and Interactions with Other Medicines).

Precautions

The tablet is a combination of atorvastatin, a HMG-CoA reductase inhibitor (statin) and amlodipine, a calcium channel blocker (CCB). Adverse events may result from either component of this medicine.
As the tablet contains amlodipine and atorvastatin, the precautions applying to both of these medicines are applicable and are detailed below.

Precautions relating to the amlodipine component of the tablets.

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 (see Clinical Trials).

Hypotension.

The use of amlodipine in patients where there is a risk of hypotension (e.g. in normotensive, small, elderly or fragile patients) is not recommended unless titration to 5 mg amlodipine has been achieved (see Dosage and Administration).

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 patients with impaired hepatic function.

See Pharmacology, Pharmacokinetics, Special populations.

Use in renal failure.

See Pharmacology, Pharmacokinetics, Special populations.

Peripheral oedema.

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

Precautions relating to the atorvastatin component of the tablets.

Liver dysfunction.

Amlodipine and atorvastatin combination tablets should be administered with caution in patients with impaired liver function. Following therapy with other lipid lowering agents of the same class as atorvastatin, moderate (> 3 x upper limit of normal [ULN]) elevations of serum transaminases have been reported.
Persistent increases in serum transaminases > 3 x ULN occurred in 0.7% of patients who received atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6% and 2.3% for 10, 20, 40 and 80 mg respectively. Increases were generally not associated with jaundice or other clinical signs or symptoms. When the dosage of atorvastatin was reduced, or drug treatment interrupted or discontinued, transaminase levels returned to pretreatment levels. Most patients continued treatment on a reduced dose of atorvastatin without sequelae.
Liver function tests should be performed before the initiation of treatment and periodically thereafter. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of > 3 x ULN persist, reduction of dose or withdrawal of atorvastatin is recommended.
Atorvastatin should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin (see Contraindications).

Skeletal muscle.

Uncomplicated myalgia has been reported in atorvastatin treated patients (see Adverse Effects). Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine kinase (CK) values > 10 x ULN, should be considered in any patient with diffuse myalgias, muscle tenderness or weakness and/or marked elevation of CK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. Atorvastatin therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with other drugs in this class is increased with concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, niacin, azole antifungals, colchicine, telaprevir or the combination of tipranavir/ ritonavir (see Interactions with Other Medicines). Physicians considering combined therapy with atorvastatin and fibric acid derivatives, erythromycin, immunosuppressive drugs, azole antifungals, or lipid lowering doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Therefore, lower starting and maintenance doses of atorvastatin should also be considered when taken concomitantly with the aforementioned drugs (see Dosage and Administration, Concomitant medications).
There have been reports of rhabdomyolysis (including some fatalities) in patients receiving concomitant fusidic acid and statins (see Contraindications and Interactions with Other Medicines). In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of the fusidic acid treatment. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be reintroduced seven days after the last dose of fusidic acid.
Periodic creatine kinase (CK) determinations may be considered in such situations, although there is no assurance that such monitoring will prevent the occurrence of severe myopathy (see Precautions, Effects on laboratory tests).
As with other drugs in this class, rhabdomyolysis with acute renal failure has been reported. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, (e.g. severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Haemorrhagic stroke.

A post hoc analysis of a clinical study (SPARCL) in patients without known coronary heart disease who had a recent stroke or TIA, showed a higher incidence of haemorrhagic stroke in patients on atorvastatin 80 mg (55/2365, 2.3%) compared to placebo (33/2366, 1.4%), (p = 0.02). Throughout the study, all cause mortality was numerically higher in the atorvastatin arm than the placebo arm. At study end all cause mortality was 9.1% on atorvastatin vs. 8.9% on placebo.
The increased risk of haemorrhagic stroke was observed in patients who entered the study with prior haemorrhagic stroke (15.6% for atorvastatin vs. 4.2 % for placebo, HR 4.06; 95% CI 0.84-19.57) or prior lacunar infarct (2.8% for atorvastatin vs. 0.6% for placebo, HR 4.99; 95% CI 1.71-14.61). All cause mortality was also increased in these patients with prior haemorrhagic stroke (15.6% for atorvastatin vs. 10.4% for placebo) or prior lacunar infarct (10.9% for atorvastatin vs. 9.1% for placebo). The potential risk of haemorrhagic stroke should be carefully considered before initiating treatment with atorvastatin in patients with recent (1-6 months) stroke or TIA.
In 68% of patients who entered the study with neither a haemorrhagic stroke nor lacunar infarct, the risk of haemorrhagic stroke on atorvastatin vs. placebo was 2% vs. 1.8 % (large vessel), 1.7% vs. 1.6 % (TIA),1.6% vs. 1.7 % (unknown cause).

Endocrine function.

HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically may blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin does not reduce basal plasma cortisol concentration nor impair adrenal reserve. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary gonadal axis in premenopausal women are unknown. Caution should be exercised if an HMG-CoA reductase inhibitor is administered concomitantly with other drugs that may decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone and cimetidine.
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin.

Effect on ubiquinone levels (COQ10).

Significant decreases in circulating ubiquinone levels in patients treated with atorvastatin and other statins have been observed. The clinical significance of a potential long-term, statin induced deficiency of ubiquinone has not been established.

Effect on lipoprotein (a).

Like other HMG-CoA reductase inhibitors, atorvastatin has variable effects on lipoprotein(a) (Lp(a)). It is unclear whether the beneficial effects of lowering LDL-C and total cholesterol in some patients may be blunted by raised Lp(a) levels.

Interstitial lung disease.

Exceptional cases of interstitial lung disease have been reported with some statins, especially with long-term therapy (see Adverse Effects). Presenting features can include dyspnoea, nonproductive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected a patient has developed interstitial lung disease, statin therapy should be discontinued.

Use in pregnancy.

(Category D)
Amlodipine and atorvastatin combination tablets are contraindicated in pregnancy due to the atorvastatin component (see Contraindications).

Atorvastatin.

Atherosclerosis is a chronic process and discontinuation of lipid lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary dyslipidaemia. Cholesterol and other products of cholesterol biosynthesis are essential components for foetal development (including synthesis of steroids and cell membranes). Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause foetal harm when administered to pregnant women. Amlodipine and atorvastatin combination tablets should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential. If the patient becomes pregnant while taking this drug, therapy should be discontinued and the patient apprised of the potential hazard to the foetus (see Contraindications).
Atorvastatin crosses the rat placenta and reaches a level in foetal liver equivalent to that in maternal plasma. Animal reproduction studies showed no evidence of teratogenic activity in rats or rabbits at oral doses up to 300 mg/kg/day and 100 mg/kg/day respectively. Increased postimplantation foetal loss, decreased foetal weight and increased skeletal variations were observed in rats dosed at 100-300 mg/kg/day and rabbits dosed at 50-100 mg/kg/day. In a perinatal/ postnatal study, rats dosed at 225 mg/kg/day showed an increased incidence of stillbirths, decreases in birthweight, an increased incidence of dilated renal pelvis, increased postnatal mortality, suppression of pup growth, retardation of physical development and abnormal behavioural development; some of these effects were also observed at the nonmaternotoxic dose of 100 mg/kg/day; the plasma AUC for HMG-CoA reductase inhibitory activity at the no effect dose level of 20 mg/kg/day was similar to that in humans dosed at 80 mg/day.
HMG-CoA reductase inhibitors are contraindicated in pregnancy. The risk of foetal injury outweighs the benefits of HMG-CoA reductase inhibitor therapy during pregnancy.
In two series of 178 and 143 cases where pregnant women took HMG-CoA reductase inhibitor (statin) during the first trimester of pregnancy, serious foetal abnormalities occurred in several cases. These included limb and neurological defects, spontaneous abortions and foetal deaths. The exact risk of injury to the foetus occurring after a pregnant woman exposed to HMG-CoA reductase inhibitor has not been determined. The current data do not indicate that the risk of foetal injury in women exposed to HMG-CoA inhibitors is high. If a pregnant woman is exposed to a HMG-CoA reductase inhibitor she should be informed of the possibility of foetal injury and discuss the implications with her pregnancy specialist.

Amlodipine.

Amlodipine and atorvastatin combination tablets contains amlodipine, a calcium channel blocker. This class of medicines carry the potential to produce foetal hypoxia associated with maternal hypotension. Amlodipine was not teratogenic in rats (18 mg/kg/day) or rabbits (10 mg/kg/day). Oral doses of amlodipine (7 mg/kg/day) given to rats at or near parturition induced a prolongation of gestation time, an increase in the number of stillbirths and a decrease in postnatal survival.

Use in lactation.

It is not known whether amlodipine and atorvastatin are excreted in human milk. In rats, plasma concentrations of atorvastatin are similar to those in milk. Because of the potential for adverse reactions in nursing infants due to the atorvastatin component, women taking amlodipine and atorvastatin combination tablets should not breastfeed (see Contraindications).

Paediatric use.

There have been no studies conducted on the safety and efficacy of amlodipine and atorvastatin combination tablets in paediatric populations.

Use in the elderly.

Amlodipine.

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 events include oedema, muscle cramps and dizziness. Amlodipine should be used with caution in the elderly.

Atorvastatin.

The safety and efficacy of atorvastatin in patients ≥ 70 years of age were similar to those of patients < 70 years of age.

Effects on fertility.

The potential effect of the amlodipine and atorvastatin combination on fertility has not been evaluated in animal studies.

Amlodipine.

There was no effect on fertility of rats treated with amlodipine at oral doses up to 18 mg/kg/day.

Atorvastatin.

The effects of atorvastatin on spermatogenesis and human fertility have not been investigated in clinical studies. Dietary administration of 100 mg atorvastatin/kg/day to rats caused a decrease in spermatid concentration in the testes, a decrease in sperm motility and an increase in sperm abnormalities. Similar effects, however, were not observed in male rats dosed by gavage to 175 mg/kg/day (plasma AUC for HMG-CoA reductase inhibitory activity 14 times higher than in humans dosed at 80 mg/day) and male fertility was not affected in either study. No adverse effects on fertility or reproduction were observed in female rats given doses up to 225 mg/kg/day (plasma AUC for enzyme inhibitory activity 56 times higher than in humans dosed at 80 mg/day). Atorvastatin caused no adverse effects on sperm or semen parameters, or on reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg/day for 2 years (plasma AUC for enzyme inhibitory activity 13 times higher than in humans).

Genotoxicity.

There are no genotoxicity studies with the amlodipine and atorvastatin combination.

Amlodipine.

Amlodipine did not induce gene mutation in bacteria and mouse lymphoma cells; nor did it induce chromosome aberrations in human lymphocytes or Chinese hamster V79 fibroblast cells (in vitro) and in mouse bone marrow cells (in vivo).

Atorvastatin.

Atorvastatin did not demonstrate mutagenic or clastogenic potential in an appropriate battery of assays. It was negative in the Ames test with Salmonella typhimurium and Escherichia coli, and in the in vitro HGPRT forward mutation assay in Chinese hamster lung cells. Atorvastatin did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay and was negative in the in vivo mouse micronucleus test.

Carcinogenicity, mutagenicity, impairment of fertility.

There are no carcinogenicity studies with the amlodipine and atorvastatin combination.

Amlodipine.

The carcinogenic potential of amlodipine has not been fully elucidated. Amlodipine did not induce any tumours when tested in mice or rats at oral doses up to 2.5 mg/kg. This dose gave rise to plasma levels that are similar to or below those achieved clinically.

Atorvastatin.

In a 2 year study in rats given 10, 30 or 100 mg/kg/day, the incidence of hepatocellular adenoma was marginally, although not significantly, increased in females at 100 mg/kg/day. The maximum dose used was 11 times higher than the highest human dose (80 mg/day) based on AUC(0-24) values. In a 2 year study in mice given 100, 200 or 400 mg/kg, incidences of hepatocellular adenoma in males and hepatocellular carcinoma in females were increased at 400 mg/kg/day. The maximum dose used was 14 times higher than the highest human dose (80 mg/day) based on AUC(0-24) values. Other HMG-CoA reductase inhibitors have been reported to induce hepatocellular tumours in mice and rats.

Effect on laboratory tests.

The atorvastatin component of amlodipine and atorvastatin combination tablets can cause elevations in ALT/AST, alkaline phosphatase, GGT, bilirubin and creatine kinase.

Interactions

There have been two studies (one single and one multiple dose) to examine possible pharmacokinetic interaction between amlodipine and atorvastatin in healthy volunteers.
The single dose study was a randomised, open label, 3 treatment, 3 period, crossover study in 27 healthy male volunteers (only 24 could be evaluated due to drop out of 3 subjects). Study treatments included atorvastatin 80 mg alone, amlodipine 10 mg alone, or both treatments coadministered, with a 2 week washout period between each dose. In this study, the geometric mean of the atorvastatin AUC was 18% greater when amlodipine was coadministered; however, this was not accompanied by any statistically significant increase in Cmax. An analysis using an estimation approach based on the point estimate and the 90% confidence interval indicated no clinically significant pharmacokinetic interaction.
The multiple dose study was a randomised, open label, crossover study in 16 healthy male volunteers. Study treatments included atorvastatin 80 mg alone, amlodipine 10 mg alone, or both treatments coadministered, with a 2 week washout period between each 7 day dosing period. In this study, the geometric mean AUC of atorvastatin was 16% greater when amlodipine was coadministered. Also in this study, an analysis using an estimation approach based on the point estimate and the 95% confidence interval failed to show a clinically significant pharmacokinetic interaction.
Medicines affected by or affecting the individual components are outlined below followed by those where no interaction has been observed with either amlodipine or atorvastatin and other medicines.

Atorvastatin.

Atorvastatin is metabolised by cytochrome P450 3A4.
Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depends on the variability of effect on cytochrome P450 3A4. Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have been noted with HIV protease inhibitors (fosamprenavir and combinations of lopinavir/ ritonavir, saquinavir/ ritonavir, darunavir/ ritonavir, fosamprenavir/ ritonavir), hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole. Based on experience with other HMG-CoA reductase inhibitors, caution should be exercised when atorvastatin is administered with inhibitors of cytochrome P450 3A4 (e.g. cyclosporin, macrolide antibiotics including erythromycin and azole antifungals including itraconazole). The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporin, fibric acid derivatives, erythromycin, azole antifungals or niacin (see Precautions, Precautions relating to the atorvastatin component of the tablets, Skeletal muscle and Dosage and Administration, Concomitant medications).
Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin, phenytoin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampicin (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter (OATP1B1)), simultaneous coadministration of atorvastatin with rifampicin is recommended, as delayed administration of atorvastatin after administration of rifampicin has been associated with a significant reduction on atorvastatin plasma concentrations.

Fusidic acid.

The risk of myopathy including rhabdomyolysis may be increased by the concomitant administration of systemic fusidic acid with statins. Coadministration of this combination may cause increased plasma concentrations of both agents. The mechanism of this interaction (whether it is pharmacodynamics or pharmacokinetic, or both) is yet unknown.
Although interaction studies with atorvastatin and fusidic acid have not been conducted, there have been reports of rhabdomyolysis (including some fatalities) in patients receiving this combination. If treatment with fusidic acid is necessary, statin treatment should be discontinued throughout the duration of the fusidic acid treatment (see Contraindications and Precautions, Precautions relating to the atorvastatin component of the tablets, Skeletal muscle).

Colchicine.

Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing atorvastatin with colchicine (see Precautions, Precautions relating to the atorvastatin component of the tablets, Skeletal muscle).

Effects of other medicines on atorvastatin.

The following drugs have been shown to have an effect on the pharmacokinetics or pharmacodynamics of atorvastatin.

Antacid.

Coadministration of an oral antacid suspension containing magnesium and aluminium hydroxides with atorvastatin decreased atorvastatin plasma concentrations approximately 35%; however, LDL-C reduction was not altered.

Colestipol.

Plasma concentrations of atorvastatin were lower (approximately 25%) when colestipol and atorvastatin were coadministered. However, LDL-C reduction was greater when atorvastatin and colestipol were coadministered than when either drug was given alone.

Transporter inhibitors.

Atorvastatin and atorvastatin metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporin) can increase the bioavailability of atorvastatin. Concomitant administration of atorvastatin 10 mg and cyclosporin 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin (see Dosage and Administration).

Erythromycin/ clarithromycin.

In healthy individuals, coadministration of atorvastatin (10 mg once daily) and erythromycin (500 mg four times a day), or clarithromycin (500 mg twice daily), known inhibitors of cytochrome P450 3A4, was associated with higher plasma concentrations of atorvastatin (see Precautions, Precautions relating to the atorvastatin component of the tablets, Skeletal muscle).

Protease inhibitors.

Coadministration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin.

Diltiazem hydrochloride.

Coadministration of atorvastatin (40 mg) with diltiazem (240 mg) was associated with higher plasma concentrations of atorvastatin (see Precautions, Precautions relating to the atorvastatin component of the tablets, Skeletal muscle).

Itraconazole.

Concomitant administration of atorvastatin (20 to 40 mg) and itraconazole (200 mg) was associated with an increase in atorvastatin AUC.

Grapefruit juice.

Contains one or more components that inhibit cytochrome P450 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (> 1.2 L per day).

Effects of atorvastatin on other medicines.

The following medicines have been shown to have their pharmacokinetics or pharmacodynamics affected by atorvastatin.

Digoxin.

When multiple doses of digoxin (0.25 mg once daily) and 10 mg atorvastatin were coadministered, steady-state plasma digoxin concentrations were unaffected. However, steady-state plasma digoxin concentrations increased by approximately 20% following administration of digoxin with 80 mg atorvastatin daily. Patients taking digoxin should be monitored appropriately.

Oral contraceptives.

Coadministration with an oral contraceptive containing norethisterone and ethinyl oestradiol increased AUC values for norethisterone and ethinyl oestradiol by approximately 30% and 20%. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin.

Medicines shown not to interact with atorvastatin.

Cimetidine.

Atorvastatin plasma concentrations and LDL-C reduction were not altered by coadministration of cimetidine.

Warfarin.

Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Azithromycin.

Coadministration of atorvastatin 10 mg daily and azithromycin (500 mg once daily) did not alter the plasma concentrations of atorvastatin.

Other concomitant therapy.

In clinical studies, atorvastatin was used concomitantly with antihypertensive agents and oestrogen replacement therapy without evidence of clinically significant adverse interactions. Interaction studies with all specific agents have not been conducted.

Amlodipine.

Amlodipine has 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 with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers, 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).

Grapefruit juice.

Grapefruit juice is known to inhibit the cytochrome P450 system in the gastrointestinal mucosa, 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 together with CYP3A4 inhibitors.

CYP3A4 inducers.

There are no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum (St John's Wort)) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together 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.

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 amlodipine coadministration with cyclosporin affect trough concentrations of cyclosporin and consideration should be given for monitoring cyclosporin levels in renal transplant patients on amlodipine.

Adverse Effects

Amlodipine and atorvastatin combination tablets has been evaluated in 1092 patients in double blind, placebo controlled studies who were treated for concomitant hypertension and dyslipidaemia. In clinical trials with amlodipine and atorvastatin combination tablets, no adverse events peculiar to this combination have been observed.
In general, treatment with amlodipine and atorvastatin tablets was well tolerated and adverse events were mild to moderate in severity. In controlled clinical trials, discontinuation of therapy due to adverse events or laboratory abnormalities was 5.1% of patients treated with the amlodipine and atorvastatin component versus 4% in the placebo treated patients.
Adverse events reported in more than 1% of patients who took concomitant amlodipine and atorvastatin in the AVALON and RESPOND studies are provided in Table 8.
The safety profile of the combination product is consistent with the adverse events previously reported for amlodipine and/or atorvastatin that are detailed below.

Amlodipine.

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 most common adverse events are headache and oedema. The incidence (%) of adverse events that occurred in a dose related manner are provided in Table 9.
Other adverse events which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo controlled clinical trials are provided in Table 10.
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.

Cardiovascular.

Hypotension, peripheral ischaemia, syncope, tachycardia, postural dizziness, postural hypotension, angioedema.

Central and peripheral nervous system.

Hypoaesthesia, paresthesia, tremor, vertigo, peripheral neuropathy.

Gastrointestinal.

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

General.

Allergic reactions, asthenia*, back pain, hot flushes, malaise, pain, rigors, weight gain.

Musculoskeletal system.

Arthralgia, arthrosis, muscle cramps*, myalgia.

Psychiatric.

Sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalisation, mood changes.

Respiratory system.

Dyspnoea*, epistaxis.

Skin and appendages.

Alopecia, pruritus*, rash*, rash erythematous, rash maculopapular, vasculitis.

Special senses.

Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary system.

Micturition frequency, micturition disorder, nocturia.

Autonomic nervous system.

Dry mouth, sweating increased.

Metabolic and nutritional.

Thirst, hyperglycaemia.

Haemopoietic.

Purpura, leucopenia, thrombocytopenia.

Endocrine.

Gynaecomastia.
*These events occurred in less than 1% in placebo controlled trials, but the incidence of these adverse events 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.
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.

Atorvastatin.

Atorvastatin is generally well tolerated. Adverse events have usually been mild and transient.

Clinical adverse events.

In the atorvastatin placebo controlled clinical trial database of 16,066 patients (8,755 atorvastatin; 7,311 placebo), treated for a median period of 53 weeks, 5.2% of patients on atorvastatin discontinued due to adverse reactions compared to 4.0% of the patients on placebo.
The most frequent (≥ 1%) adverse events that may be associated with atorvastatin therapy, reported in patients participating in placebo controlled clinical studies include the following.

Gastrointestinal disorders.

Dyspepsia, nausea, flatulence, diarrhoea.

Infections and infestations.

Nasopharyngitis.

Investigations.

Liver function test abnormal1, blood creatine phosphokinase increased.

Metabolism and nutrition disorders.

Hyperglycaemia.

Musculoskeletal and connective tissue disorders.

Myalgia, arthralgia, pain in extremity, musculoskeletal pain, muscle spasms, joint swelling.

Respiratory, thoracic and mediastinal disorders.

Pharyngolaryngeal pain, epistaxis.
1Refers to the following preferred terms: hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, liver function test abnormal and transaminases increased.

Additional adverse events.

The following have been reported in clinical trials of atorvastatin, however, not all the events listed have been causally associated with atorvastatin therapy.

Common (≥ 1% and < 10%).

Gastrointestinal disorders: constipation.
Infections and infestations: urinary tract infection.
Nervous system disorders: headache.

Uncommon (≥ 0.1% and < 1 %).

Ear and labyrinth disorders: deafness.
Eye disorders: vision blurred.
Gastrointestinal disorders: abdominal discomfort, abdominal pain, vomiting.
General disorders and administration site conditions: asthenia, malaise.
Infections and infestations: infection, influenza.
Metabolism and nutrition disorders: anorexia.
Musculoskeletal and connective tissue disorders: back pain, neck pain.
Nervous system disorders: paraesthesia.
Psychiatric disorders: insomnia, nightmare.
Reproductive system and breast disorders: erectile dysfunction.
Respiratory, thoracic and mediastinal disorders: asthma.
Skin and subcutaneous tissue disorders: rash, pruritus, urticaria.

Rare (≥ 0.01% and < 0.1%).

Ear and labyrinth disorders: tinnitus.
Gastrointestinal disorders: pancreatitis, eructation.
General disorders and administration site conditions: pyrexia.
Hepatobiliary disorders: hepatitis, cholestasis.
Immune system disorders: hypersensitivity (including anaphylaxis).
Infections and infestations: sinusitis, pharyngitis.
Injury, poisoning and procedural complications: injury.
Investigations: white blood cells urine positive.
Metabolism and nutrition disorders: hypoglycaemia.
Musculoskeletal and connective tissue disorders: myositis, myopathy, muscle fatigue.
Nervous system disorders: peripheral neuropathy.
Skin and subcutaneous tissue disorders: angioedema, alopecia.
A post hoc analysis of a clinical study (SPARCL) in patients without known coronary heart disease who had a recent stroke or TIA, showed an increased risk of haemorrhagic stroke in patients with prior haemorrhagic stroke or prior lacunar infarct (see Precautions).
In ASCOT (see Clinical Trials, Prevention of cardiovascular disease) involving 10,305 participants treated with atorvastatin 10 mg daily (n = 5,168) or placebo (n = 5,137), the safety and tolerability profile of the group treated with atorvastatin was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.

Postmarketing experience.

Rare adverse events that have been reported postmarketing which are not listed above, regardless of causality, include the following.

Blood and lymphatic system disorders.

Thrombocytopenia.

General disorders and administration site conditions.

Chest pain, fatigue, peripheral oedema.

Hepatobiliary disorders.

Hepatic failure.

Injury, poisoning and procedural complications.

Tendon rupture.

Investigations.

Weight increased.

Musculoskeletal and connective tissue disorders.

Immune mediated necrotising myopathy, rhabdomyolysis which may be fatal2 (see Contraindications, Precautions and Interactions with Other Medicines).

Nervous system disorders.

Hypoaesthesia, dizziness, amnesia, dysgeusia.

Reproductive system and breast disorders.

Gynaecomastia.

Skin and subcutaneous tissue disorders.

Bullous rashes (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis).
The following adverse events have been reported with some statins: exceptional cases of interstitial lung disease, especially with long-term therapy (see Precautions).
2Examples of signs and symptoms are muscle weakness, muscle swelling, muscle pain, dark urine, myoglobinuria, elevated serum creatine kinase, acute renal failure and cardiac arrhythmia.

Dosage and Administration

Amlodipine and atorvastatin combination tablets are a combination product targeting two distinct cardiovascular risk factors, hypertension and dyslipidaemia.
The starting dose and maintenance doses of amlodipine and atorvastatin combination tablets should be individualised according to goals consistent with current treatment guidelines and patient response.
Amlodipine and atorvastatin tablets are available in eight strengths ranging from 5 mg/10 mg to 10 mg/80 mg of amlodipine (as besylate) and atorvastatin (as calcium propylene glycol solvate) respectively to allow the physician maximum flexibility in titrating patients to treatment targets.
Amlodipine and atorvastatin tablets are to be taken once daily and may be taken at any time of the day with or without food.
After initiation of amlodipine and atorvastatin combination tablets, lipid levels should be analysed and blood pressure measured after approximately 4-6 weeks, and dosage adjusted accordingly. Titration for blood pressure response may proceed more rapidly if clinically warranted.
In patients requiring additional blood pressure lowering and/or angina treatment, amlodipine and atorvastatin combination tablets may be added to existing therapies.

Special patient populations.

Small, fragile or elderly.

Amlodipine and atorvastatin combination tablets can be used in this patient population provided titration to 5 mg of amlodipine has been achieved (see Precautions).

Children.

There are no studies to date to determine the safety or efficacy of amlodipine and atorvastatin combination tablets in children.

Use in renal impairment.

No dosage adjustment is necessary in patients taking amlodipine and atorvastatin combination tablets (see Precautions).

Use in hepatic impairment.

Plasma concentrations of atorvastatin are markedly increased in patients with chronic alcoholic liver disease (Child-Pugh B). The half-life of amlodipine is prolonged in patients with impaired liver function and dosage recommendations have not been established. Therefore, amlodipine and atorvastatin combination tablets should be administered with caution in patients with impaired liver function or history of liver disease, and in patients who consume substantial quantities of alcohol (see Precautions, Precautions relating to the atorvastatin component of the tablets, Liver dysfunction).

Concomitant medications.

The amlodipine component of amlodipine and atorvastatin tablets has been safely administered with thiazides, ACE inhibitors, beta-blockers, long acting nitrates, and/or sublingual nitroglycerine. No dose adjustment of amlodipine is required.
The atorvastatin component of amlodipine and atorvastatin combination tablets was used concomitantly with antihypertensive agents in clinical studies without evidence of clinically significant adverse interactions. Interaction studies with all specific agents have not been conducted.
The atorvastatin component of amlodipine and atorvastatin combination tablets may be used in combination with a bile acid binding resin for additive effect. The combination of HMG-CoA reductase inhibitors and fibrates should generally be avoided (see Precautions, Precautions relating to the atorvastatin component of the tablets, Skeletal muscle). For other interactions, see Interactions with Other Medicines.
In cases where coadministration of atorvastatin with cyclosporin, telaprevir or the combination of tipranavir/ ritonavir is necessary, the dose of atorvastatin should not exceed 10 mg. Caution should be used when coprescribing atorvastatin with medicinal compounds that result in an increase in systemic concentrations of atorvastatin and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin is employed (see Precautions, Precautions relating to the atorvastatin component of the tablets, Skeletal muscle and Interactions with Other Medicines).

Overdosage

There is no information on overdosage with amlodipine and atorvastatin tablets.
Available data suggest that amlodipine and atorvastatin combination tablets overdosage, due to its CCB component, might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. Dysrhythmias may occur following overdose with any calcium antagonist. Hypotension and bradycardia are usually seen within 1 to 5 hours following amlodipine 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.
If massive amlodipine and atorvastatin combination tablets 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 should be considered with attention to circulating volume and urine output. Intravenous calcium may help to reverse the effects of calcium entry blockade. In symptomatic patients, monitor serum creatinine, BUN, creatinine kinase, urine myoglobin for indications of renal impairment secondary to rhabdomyolysis and liver function tests.
If there has been significant ingestion, consider administration of activated charcoal. 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 CNS depression may rapidly develop. As both amlodipine and atorvastatin are highly protein bound, dialysis is not likely to be of benefit. For atorvastatin induced rhabdomyolysis, administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Diuretics may be necessary to maintain urine output. Urinary alkalinisation is not routinely recommended.
For information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia).

Presentation

Tablets (oval, biconvex, coated, marked APO on reverse), amlodipine 5 mg/ atorvastatin 10 mg (white to off white, marked 5/10, AUST R 214378); amlodipine 5 mg/ atorvastatin 20 mg (white to off white, marked 5/20, AUST R 214385); amlodipine 5 mg/ atorvastatin 40 mg (white to off white, marked 5/40, AUST R 214375); amlodipine 5 mg/ atorvastatin 80 mg (white to off white, marked 5/80, AUST R 214386); amlodipine 10 mg/ atorvastatin 10 mg (light blue, marked 10/10, AUST R 214409); amlodipine 10 mg/ atorvastatin 20 mg (light blue, marked 10/20, AUST R 214360); amlodipine 10 mg/ atorvastatin 40 mg (light blue, marked 10/40, AUST R 214345); amlodipine 10 mg/ atorvastatin 80 mg (light blue, marked 10/80, AUST R 214359): 30's (aluminium/ aluminium silver foil blister pack).
APO-Amlodipine/Atorvastatin 5/10, 5/20, 5/40, 5/80, 10/10, 10/20, 10/40, 10/80 tablets are intended for oral administration.

Storage

Store below 25°C. Protect from moisture.

Poison Schedule

S4.