Consumer medicine information

Actos

Pioglitazone

BRAND INFORMATION

Brand name

Actos

Active ingredient

Pioglitazone

Schedule

What is in this leaflet

This leaflet answers some common questions about ACTOS. It does not contain all the available information and does not take the place of talking with your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available. You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on this medicine.

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

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

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

What ACTOS is used for

ACTOS is a tablet that is used to improve the action of the body's naturally produced insulin. ACTOS is used in the management of type 2 diabetes not controlled by diet. ACTOS helps to control the level of glucose in your blood when you have type 2 diabetes. This is the 'adult onset' type of diabetes and is controlled by diet, certain oral medications and occasionally insulin.

This medicine is also called pioglitazone hydrochloride and belongs to a group of medicines called glitazones. Glitazones decrease insulin resistance.

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

ACTOS can be used alone (when diet and exercise is not enough to treat your diabetes) or together with other anti-diabetic medicines.

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

The use of ACTOS has not been studied in children.

Before you take ACTOS

When you must not take it

Do not take ACTOS if:

you have heart failure requiring treatment. Talk to your doctor if you have heart failure
you have type 1 diabetes or diabetic ketoacidosis) often caused by very high blood glucose levels)
you have an allergy to any medicine containing pioglitazone hydrochloride or any of the ingredients listed at the end of this leaflet (see 'Product Description').

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

Do not take this medicine after the date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

heart disease with shortness of breath after minimal physical activity
heart disease with severe symptoms at rest
swelling of hands, ankles or feet
bladder cancer or symptoms associated with bladder cancer such as blood in the urine (hematuria) often accompanied by pain and burning or, sudden urges to urinate
problems with your liver
problems with your kidneys that requires dialysis. ACTOS is not recommended for use if you are on dialysis
some women who do not have monthly periods and have not been through menopause may restart their periods when taking ACTOS. These women may be at increased risk of pregnancy
bone fractures, usually in the hand, upper arm or foot, have been seen in some women when taking ACTOS. Talk to your doctor for advice on how to keep your bones healthy.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Like most medicines, ACTOS is not recommended for use during pregnancy. If there is a need to consider ACTOS during your pregnancy, your doctor will discuss with you the benefits and risks of taking ACTOS. It is recommended that you do not breast-feed while taking ACTOS, as it is not known whether ACTOS passes into breast milk.

Tell your doctor if you are using another medicine for diabetes. ACTOS can enhance the action of other medicines. You may be at risk of low blood sugar (hypoglycaemia). If this happens, your doctor may need to adjust the dose of your other medicines.

Tell your doctor if you suffer from lactose intolerance (because ACTOS tablets contain lactose).

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

Taking other medicines

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

Some medicines and ACTOS may interfere with each other. These include:

chlorpropamide
gemfibrozil
glibenclamide
gliclazide
insulin
oral contraceptives
rifampicin
tolbutamide

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

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking this medicine.

How to take ACTOS

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

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

How much to take

Your doctor will tell you how many ACTOS tablets you should take. The dose your doctor will prescribe for you will usually be in the range of 15 mg to 45 mg per day.

ACTOS tablets should be taken once a day as advised by your doctor.

Your doctor may increase or decrease your dose in order to find the appropriate dose for your condition.

How to take it

ACTOS tablets should be swallowed whole with a glass of water.

When to take it

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

It does not matter if you take this medicine before or after food.

How long to take it

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

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

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

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

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

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

If you take too much (Overdose)

Immediately telephone your doctor or the Australian Poisons Information Centre (13 11 26) or the New Zealand National Poisons Centre (0800 POISON or 0800 764 766), or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much ACTOS. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking ACTOS

Things you must do

It is important that you remember to take ACTOS daily and at the dose prescribed by your doctor.

Tell any other doctors, dentists and pharmacists who treat you that you are taking ACTOS.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking ACTOS.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Tell your doctor if you have gained weight since taking ACTOS. Weight gain can be associated with improved blood sugar control however; it may also be a symptom of heart failure.

Things you must not do

Do not take ACTOS to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if their symptoms seem similar to yours or they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

ACTOS alone is unlikely to affect your ability to drive or operate machinery. However, be careful whilst driving or operating machinery if using ACTOS combination with other diabetes medicines.

If your blood glucose level becomes too low, you may feel dizzy, lightheaded, weak or tired and your reaction time may be slower than usual.

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

Side effects

Tell your doctor or pharmacist as soon as possible if you experience any undesirable effect or feel unwell while you are taking ACTOS.

This medicine helps most people with type 2 diabetes not controlled by diet, but it may have unwanted side effects in some people.

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

Some side effects may be related to the dose of ACTOS. Accordingly, it is important that you tell your doctor as soon as possible about any unwanted effects. Your doctor may then decide to adjust the dose of ACTOS you are taking.

Do not be alarmed by the following list of side effects. You may not experience any of them.

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

A few patients have experienced the following side effects whilst taking ACTOS:

a small increase in weight
low blood sugar levels (hypoglycaemia). This occurs more often when ACTOS is taken with a sulfonylurea or insulin
heart failure which may show as localised swelling of the ankles, feet and hands (oedema) and/or fluid in the lungs (pulmonary oedema). This has been reported in clinical trials mainly in patients who are taking ACTOS in combination with insulin
increased risk of bone fracture in women
macular oedema (an eye disorder that can affect vision)
altered or impaired liver function.

Tell your doctor if you notice any of the following side effects:

weight gain
signs of hypoglycaemia which may include weakness, trembling or shaking, sweating, light-headedness, headache, dizziness, lack of concentration, tearfulness or crying, irritability, hunger, numbness around the lips and fingers
eye problems including blurred or double vision.

The above list includes the more common side effects of your medicine.

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

dark urine or pale stools, yellowing of the skin or eyes, severe cramps of the stomach, nausea or vomiting, loss of weight, tiredness
shortness of breath when at rest or after minimal physical activity with swelling of legs, feet and hands, rapid increase in weight
blood in the urine often accompanied by pain and burning, these can be symptoms of bladder cancer.

The above list includes serious side effects, which may require medical attention. Serious side effects are rare.

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

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

After using ACTOS

Storage

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

Keep your tablets in a cool, dry place where the temperature stays below 25°C.

Do not store ACTOS 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 it 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 ACTOS or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product Description

What it looks like

15 mg ACTOS tablets are white to off white, round, convex tablets, marked with a "15" on one face and "ACTOS" on the other.

30 mg ACTOS tablets are white to off white, round flat tablets, marked with a "30" on one face and "ACTOS" on the other.

45 mg ACTOS tablets are white to off white, round flat tablets, marked with a "45" on one face and "ACTOS" on the other.

ACTOS is presented in aluminium blister packs containing 28 tablets.

Ingredients

ACTOS contains 15mg, 30mg or 45mg of pioglitazone (as hydrochloride) as the active ingredient. It also contains:

lactose
hyprolose
carmellose calcium
magnesium stearate

Contains sugars as lactose. This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Actos is supplied in Australia by:

Celltrion Healthcare Australia Pty Ltd.
Suite 13.03, 31 Market Street,
Sydney 2000
Australia
Phone: 1800 325 228
www.celltrionhealthcare.com/au

Australian Registration Numbers:

15 mg tablet - AUST R 76462

30 mg tablet - AUST R 76463

45 mg tablet - AUST R 76464

This leaflet was revised in July 2021

ACTOS® is a registered trademark of Celltrion Asia Pacific Pte. Ltd.

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Actos

Active ingredient

Pioglitazone

Schedule

1 Name of Medicine

Pioglitazone hydrochloride.

2 Qualitative and Quantitative Composition

Each tablet contains 15 mg, 30 mg or 45 mg of pioglitazone (as the hydrochloride). Excipient with known effect; contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

15 mg Actos tablets are white to off-white, round, convex tablets, embossed 15 on one face, Actos on the other.
30 mg Actos tablets are white to off-white, round-flat tablets, embossed 30 on one face, Actos on the other.
45 mg Actos tablets are white to off-white, round-flat tablets, embossed 45 on one face, Actos on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of type 2 diabetes mellitus inadequately controlled by diet and exercise:
as monotherapy;
as dual therapy to improve glycaemic control in combination with metformin or sulfonylurea or in combination with insulin;
as triple therapy to improve glycaemic control, in combination with metformin and sulfonylurea.

4.2 Dose and Method of Administration

Actos should be taken once daily with or without food.
After initiation of Actos or with dose increase, patients should be carefully monitored for adverse events related to fluid retention, see Section 4.4 Special Warnings and Precautions for Use, Oedema.

Female patients.

Oedema has been reported more often in women. Dosage should start at 15 mg and be increased cautiously, paying attention to the development of oedema.

Monotherapy.

The recommended dose of Actos is 15 mg or 30 mg once daily, increasing after four weeks, if greater therapeutic effect is needed, to 45 mg once daily.

Dual therapy.

The recommended dose of Actos is 30 mg once daily in combination with sulfonylureas, insulin or metformin. It may be possible to achieve metabolic control at a reduced dose of the sulfonylurea, insulin or metformin. If there is a particular risk of hypoglycaemia, pioglitazone can be introduced at a dose of 15 mg. For patients already on insulin, pioglitazone should be introduced at a dose of 15 mg once daily. Dosage can then be increased cautiously.

Triple therapy.

The recommended dose of Actos is 30 mg once daily in combination with sulfonylurea and metformin. It may be possible to achieve metabolic control at a reduced dose of the sulfonylurea or metformin. If there is a particular risk of hypoglycaemia, pioglitazone can be introduced at a dose of 15 mg. If greater therapeutic effect is needed, the dose may be increased to a maximum of 45 mg once daily.

Patients with renal insufficiency.

Dose adjustment in patients with renal insufficiency is not recommended, see Section 5.2 Pharmacokinetic Properties, Special populations, Renal insufficiency. No information is available for patients on dialysis therefore Actos should not be used in such patients.

Patients with hepatic impairment.

The intrinsic clearance of pioglitazone may be reduced in patients with hepatic disease. Dosage should start at 15 mg and be increased cautiously. Actos therapy should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 times the upper limit of normal).

Maximum recommended dose.

The dose of Actos should not exceed 45 mg/day since doses higher than 45 mg/day have not been studied in clinical trials.

4.3 Contraindications

Actos is contraindicated in patients with known hypersensitivity or allergy to pioglitazone or any of the excipients.
Actos is not recommended in patients with symptomatic heart failure. Initiation of Actos (like other thiazolidinediones) is contraindicated in patients with NYHA class II, III or IV heart failure, see Section 4.4 Special Warnings and Precautions for Use, Cardiac.
Because of its mechanism of action, Actos is only active in the presence of insulin. Therefore, Actos should not be used in type 1 diabetes or for the treatment of diabetic ketoacidosis.

4.4 Special Warnings and Precautions for Use

Hypoglycaemia.

Patients receiving Actos in combination with insulin or oral hypoglycaemic agents may be at risk for hypoglycaemia. A reduction in the dose of the concomitant agent may be necessary.

Cardiac.

Actos should not be prescribed to lower the risk of cardiovascular disease such as myocardial infarction and stroke or to lower cardiovascular mortality.
Actos, like other thiazolidinediones, can cause or exacerbate congestive heart failure (CHF) in some patients. In postmarketing experience with pioglitazone, CHF has been reported in patients both with and without pre-existing cardiac disease. After initiation of Actos and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnoea, and/or oedema). If these signs and symptoms develop, Actos should be discontinued. The patient's heart failure should be evaluated and managed according to the current standards of care.
Patients with New York Heart Association (NYHA) class III and IV cardiac status were excluded from initial clinical trials. Therefore, Actos is not indicated in patients with NYHA class III or IV cardiac status.
Actos should be initiated at the lowest approved dose in patients with type 2 diabetes and systolic heart failure (NYHA class I). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, oedema or congestive heart failure exacerbation.
In one 16 week U.S. double blind, placebo controlled clinical trial involving 566 patients with type 2 diabetes, Actos at doses of 15 mg and 30 mg in combination with insulin were compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischaemic attack (4.1%), and congestive heart failure (2.3%).
In this study two of the 191 patients receiving 15 mg Actos plus insulin (1.1%) and two of the 188 patients receiving 30 mg Actos plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures and myocardial infarction. Analysis of data from this study did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin.
A 24 week postmarketing safety study was performed to compare Actos (n = 262) to glibenclamide (n = 256) in uncontrolled diabetic patients (mean HbA_1c 8.8% at baseline) with NYHA class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Overnight hospitalisation for congestive heart failure was reported in 9.9% of patients on Actos compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with Actos was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed.
A cardiovascular outcome study of Actos has been performed in patients with type 2 diabetes mellitus and pre-existing major macrovascular disease (PROactive). Actos or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed the expected increase in reports of serious heart failure (an average of 16 per 1000 treated patients); however, this did not lead to an increase in mortality in this study.

Oedema.

As thiazolidinediones can cause fluid retention, Actos should be used with caution in patients with oedema. In placebo controlled clinical trials oedema was reported more frequently in patients treated with Actos than in placebo treated patients.

Weight gain.

Dose related weight gain was seen with Actos alone and in combination with other hypoglycaemic agents (see Table 1). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Bladder cancer.

Pioglitazone should not be used in patients with bladder cancer or a history of bladder cancer. The risk of bladder cancer should be considered in the care of all patients treated with pioglitazone. Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents, e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as urinary urgency develop during treatment.
Some epidemiological studies suggested a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, although other large, long-term observational studies did not.
An increased incidence of bladder cancer was observed in subjects receiving pioglitazone in the PROactive study. In the pioglitazone arm there were 14 cases (0.5%) and in the placebo arm there were 5 cases (0.2%); the point estimate for the hazard ratio (HR) was 2.7 (95% confidence interval [CI] 0.99-7.6). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.2%) cases in the pioglitazone arm and two (0.1%) cases in the placebo arm.

Bone fracture.

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse event reports of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator (excluding thiazolidinediones) treated patients, on treatment for up to 3.5 years. Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%). The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is, therefore, 0.8 fractures per 100 patient years of use.
In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. This difference was noted after the first year of treatment and remained during the course of the study. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).
The risk of fractures should be considered in the long-term care of women treated with pioglitazone.

Ovulation.

In premenopausal anovulatory patients with insulin resistance, treatment with thiazolidinediones, including Actos, may result in resumption of ovulation. These patients may be at risk of pregnancy.
Patients with polycystic ovarian syndrome may resume ovulation after pioglitazone treatment, as a consequence of enhanced insulin action. Patients should therefore be aware of the risk of pregnancy; if the patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued.

Use in hepatic impairment.

In clinical trials worldwide, over 4500 patients have been treated with Actos. There was no evidence of drug induced hepatotoxicity.
Therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or increased transaminase levels (ALT > 2.5 times the upper limit of normal) at the start of therapy. Existing Actos therapy should be discontinued if ALT levels are persistently higher than 3 x the upper limit of normal, and symptoms suggesting hepatic dysfunction should cause the liver enzymes to be checked. Pending the results of laboratory investigations, the decision as to whether pioglitazone therapy should continue must be based on clinical judgement; in the presence of jaundice, drug therapy should be discontinued.
Liver function tests should be performed at baseline and every two months for the first twelve months and periodically thereafter, and if a patient develops symptoms suggestive of hepatic dysfunction, liver enzyme levels should be checked.

Use in the elderly.

Approximately 500 patients in placebo-controlled clinical trials of Actos were 65 and over. No significant differences in safety and efficacy were observed between these patients and younger patients.

Paediatric use.

Safety and effectiveness in paediatric patients have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The cytochrome P450 isoforms CYP2C8 and CYP3A4 are partially responsible for the metabolism of pioglitazone. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporine, calcium channel blockers and HMG-CoA reductase inhibitors, are not to be expected. Inhibitors of CYP2C8 (such as gemfibrozil) may increase the AUC of pioglitazone, a decrease in the AUC of pioglitazone may occur when administered in combination with CYP2C8 inducers (such as rifampicin).

Gemfibrozil.

Coadministration of Actos and gemfibrozil is reported to result in a 3-fold increase in the AUC of pioglitazone. Since there is a potential for dose related adverse events with pioglitazone, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered.

Rifampicin.

Coadministration of Actos and rifampicin is reported to result in a 54% decrease in the AUC of pioglitazone. The dose of Actos may need to be increased based on clinical response when rifampicin is concomitantly administered.

Oral contraceptives.

Administration of a similar thiazolidinedione with an oral contraceptive containing ethinylestradiol and norethisterone reduced the plasma concentrations of both hormones by approximately 30%. This could result in loss of contraception. Therefore, a higher dose of oral contraceptive or an alternative method of contraception should be considered.

Glipizide.

Coadministration of Actos and glipizide does not alter the steady-state pharmacokinetics of glipizide.

Digoxin.

Coadministration of Actos with digoxin does not alter the steady-state pharmacokinetics of digoxin.

Warfarin.

Coadministration of Actos with warfarin does not alter the steady-state pharmacokinetics of warfarin. In addition, Actos has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.

Metformin.

Coadministration of Actos with metformin does not alter the steady-state pharmacokinetics of metformin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats at oral doses up to 40 mg/kg/day. Systemic exposure (plasma AUC_0-24h) to total active compounds at the highest dose was about 7 times greater than that in humans at the maximum recommended dose. See Section 4.4 Special Warnings and Precautions for Use, Ovulation.
(Category B3)
A study in pregnant rats showed that pioglitazone and its metabolites cross the placenta. Pioglitazone was not teratogenic in rats or rabbits at oral doses up to 80 and 160 mg/kg/day respectively. Systemic exposure (plasma AUC_(0-24h)) to total active compounds at the highest dose was about 12 times (rats) and 7 times (rabbits) greater than that in humans at the maximum recommended dose. Embryotoxicity (increased postimplantation loss) was observed in both animal species, and foetotoxic effects (reduced foetal weight and retarded development) were seen in rats. Administration of pioglitazone during the period of organogenesis also caused suppression of postnatal growth in rats. Administration of pioglitazone to rats throughout gestation and lactation caused retardation in postnatal growth and development, and impaired fertility of the offspring. The no effect dose for retardation of postnatal growth and development in rats was 3 mg/kg/day and systemic exposure to total active compounds at this dose was similar to that in humans. There are no adequate and well controlled studies in pregnant women. Actos should be used during pregnancy only if the potential benefits justify the potential risk to the foetus.
Pioglitazone is secreted in the milk of lactating rats. It is not known whether Actos is secreted in human milk. In reproductive studies in rats, oral administration of pioglitazone during late gestation and lactation caused adverse effects on postnatal survival, growth, development and fertility of the offspring. The no effect dose on retardation of postnatal growth and development was 3 mg/kg/day and systemic exposure to total active compounds at this dose was similar to that in humans. Actos should not be administered to lactating women. Breastfeeding should be discontinued if the use of this product is considered essential.

4.7 Effects on Ability to Drive and Use Machines

The effect of Actos on the ability to drive and use machinery has not been studied but based on its pharmacodynamic properties, Actos monotherapy is unlikely to affect this ability. When driving vehicles or operating machinery it should be taken into account that the hypoglycaemic effects of sulfonylureas and insulin may be exacerbated upon combination therapy with Actos.

4.8 Adverse Effects (Undesirable Effects)

Adverse events identified from clinical trials.

The overall incidence and types of adverse events reported in placebo controlled clinical trials of Actos monotherapy are shown in Table 2. In pooled, double blind, placebo controlled trials in 862 patients taking pioglitazone and 431 patients taking placebo, withdrawal due to adverse events occurred in 3.6% of pioglitazone patients and in 4.6% of patients on placebo. Table 2 shows the 12 week cumulative incidence at > 2% of patients with pioglitazone when this was in excess of placebo.

See Tables 3 and 4.

In the PROactive study, which involved a high risk population of patients with pre-existing macrovascular disease, treatment emergent adverse events that occurred more often in the Actos group compared to placebo group were oedema (26.4% and 15.1% respectively), hypoglycaemia (27.2% and 18.8% respectively) and cardiac failure, including serious and nonserious cases (12.6% and 8.7% respectively).

Cardiovascular system.

In insulin combination studies a small number of patients with previously existing cardiac disease developed congestive heart failure when treated with pioglitazone. The incidence of congestive heart failure is increased in patients with uncontrolled diabetes, NYHA class II or III cardiac status and ejection fraction less than 40% when treated with pioglitazone, see Section 4.4 Special Warnings and Precautions for Use, Cardiac.
In one 16 week clinical trial of insulin plus Actos combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone, see Section 4.4 Special Warnings and Precautions for Use, Cardiac.
In the PROactive study, the rate of serious heart failure was higher for patients treated with Actos (5.7%) than for patients treated with placebo (4.1%) and the incidence of death subsequent to a report of serious heart failure was 1.5% in patients treated with Actos and 1.4% in placebo treated patients. In patients treated with an insulin containing regimen at baseline, the incidence of serious heart failure was 6.3% with Actos and 5.2% with placebo. For those patients treated with a sulfonylurea containing regimen at baseline, the incidence of serious heart failure was 5.8% with Actos and 4.4% with placebo.

Hypoglycaemia.

Although pioglitazone does not change the safety profile of sulfonylureas and insulin, the combination may increase the risk of developing hypoglycaemic symptoms.

Oedema.

In combination therapy studies, oedema was reported for 7.2% of patients treated with Actos and sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, oedema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, oedema was reported in 15.8% of patients on combination therapy compared to 7.8% of patients on insulin alone (see Section 4.4 Special Warnings and Precautions for Use, Oedema). Most of these events were considered mild or moderate in intensity. In a study of triple combination therapy with Actos, metformin and sulfonylurea, peripheral oedema was reported in 3.45% of pioglitazone treated patients compared to 3.25% receiving placebo.

Weight gain.

In all clinical trials, weight increased proportionately as the HbA_1c decreased, suggesting that weight gain was associated with improved glycaemic control. Occasional transient increases in creatine phosphokinase were noticed in patients taking pioglitazone.

Bladder cancer.

An increased incidence of bladder cancer was observed in subjects receiving pioglitazone in the PROactive study. In the pioglitazone arm there were 14 cases (0.5%) and in the placebo arm there were 5 cases (0.2%); the point estimate for the HR was 2.7 (95% CI 0.99-7.6). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.2%) cases in the pioglitazone arm and two (0.1%) cases in the placebo arm (see Section 4.4 Special Warnings and Precautions for Use, Bladder cancer).

Bone fracture.

A pooled analysis was conducted of adverse event reports of bone fractures from randomised, comparator controlled (excluding thiazolidinediones), double blind clinical trials in over 8100 patients in the pioglitazone treated groups and 7400 in the comparator treated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%), see Section 4.4 Special Warnings and Precautions for Use, Bone fracture.
In the 3.5 year PROactive study, 44/870 (5.1%) of pioglitazone treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

Laboratory test abnormalities.

Haematologic.

Actos may cause decreases in haemoglobin and haematocrit. Across all clinical studies, mean haemoglobin values declined by 2% to 4% in patients treated with Actos. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with Actos therapy and have not been associated with any significant haematologic clinical effects.

Serum transaminase levels.

During placebo controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with Actos and 2 of 793 (0.25%) placebo treated patients had ALT values ≥ 3 times the upper limit of normal. During all clinical studies in the U.S., 11 of 2561 (0.43%) patients treated with Actos had ALT values ≥ 3 times the upper limit of normal. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with Actos, mean values for bilirubin, AST, ALT, alkaline phosphatase and GGT were decreased at the final visit compared with baseline. Fewer than 0.12% of patients treated with Actos were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In preapproval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure, see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment.

CPK levels.

During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. A single, isolated elevation to greater than 10 times the upper limit of normal (values of 2150 to 8610 IU/L) was noted in 7 patients. Five of these patients continued to receive Actos and the other two patients had completed receiving study medication at the time of the elevated value. These elevations resolved without any apparent clinical sequelae. The relationship of these events to Actos therapy is unknown.

Adverse events identified from spontaneous postmarketing surveillance.

Cardiovascular system.

Cardiac failure. In postmarketing experience with pioglitazone, congestive heart failure has been reported very rarely (0.9/10,000 patient years) in patients both with and without pre-existing cardiac disease. In clinical trials, heart failure was reported more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure, see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Cardiac.

Hepatic system.

Hepatocellular dysfunction. In postmarketing experience with pioglitazone, reports of hepatitis and hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these have involved hepatic failure with and without fatal outcome, although causality has not been established.

Eye disorders.

Very rarely, postmarketing reports of new onset or worsening (diabetic) macular oedema with decreased visual acuity have been reported with the use of thiazolidinediones, including pioglitazone. It is unknown whether or not there is a causal relationship between pioglitazone and macular oedema. Physicians should consider the possibility of macular oedema if a patient reports decreased visual acuity.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

During clinical trials, one case of overdose with Actos was reported. A patient took 120 mg/day for four days, then 180 mg/day for seven days. The patient did not report any clinical symptoms.
Hypoglycaemia would not be expected with Actos alone but may occur in combination with sulfonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Actos is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its unique mechanism of action. Actos decreases insulin resistance in the periphery and in the liver resulting in increased insulin dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator activated receptor gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver.
Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, pioglitazone reduces the hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia characteristic of insulin resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin dependent tissues and are observed in numerous animal models of insulin resistance.
Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Clinical trials.

Clinical studies demonstrate that Actos improves insulin sensitivity in insulin resistant patients. Actos enhances cellular responsiveness to insulin, increases insulin dependent glucose disposal, improves hepatic sensitivity to glucose and thus improves dysfunctional glucose homeostasis.