Consumer medicine information

ARX-Pioglitazone (was APOTEX-Pioglitazone)

Pioglitazone

BRAND INFORMATION

Brand name

ARX-Pioglitazone (was APOTEX-Pioglitazone)

Active ingredient

Pioglitazone

Schedule

SUMMARY CMI

ARX-PIOGLITAZONE

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking ARX-PIOGLITAZONE?

ARX-PIOGLITAZONE contains the active ingredient pioglitazone hydrochloride. ARX-PIOGLITAZONE is used to treat type 2 diabetes not controlled by diet and exercise. It helps to improve the action of insulin produced by your body.

For more information, see Section 1. Why am I taking ARX-PIOGLITAZONE? in the full CMI.

2. What should I know before I take ARX-PIOGLITAZONE?

Do not use if you have ever had an allergic reaction to ARX-PIOGLITAZONE or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take ARX-PIOGLITAZONE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ARX-PIOGLITAZONE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take ARX-PIOGLITAZONE?

Your doctor will tell you how many tablets you will need to take. This depends on your condition and whether you are taking any other medicines. ARX-Pioglitazone tablets should be taken once a day.
Follow the directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

More instructions can be found in Section 4. How do I take ARX-PIOGLITAZONE? in the full CMI.

5. What should I know while taking ARX-PIOGLITAZONE?

Things you should do	Remind any doctor, dentist, pharmacist, surgeon or anaesthetist you visit that you are taking ARX-PIOGLITAZONE. If you become pregnant while taking ARX-PIOGLITAZONE, tell your doctor immediately.
Things you should not do	Do not stop taking ARX-PIOGLITAZONE or change the dosage without first checking with your doctor
Driving or using machines	Be careful before you drive or use any machines or tools until you know how ARX-PIOGLITAZONE affects you.
Looking after your medicine	Keep your medicine in a cool dry place where the temperature stays below 30°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.

For more information, see Section 5. What should I know while taking ARX-PIOGLITAZONE? in the full CMI.

6. Are there any side effects?

Less serious side effects: a small increase in weight, signs of low blood sugar levels (hypoglycaemia) such as weakness, trembling or shaking, sweating, light-headedness, headache, dizziness, lack of concentration, tearfulness or crying, irritability, hunger, numbness around the lips and finger, blood in the urine, often accompanied by pain and burning eye problems, including blurred or double vision, macular oedema (an eye disorder that can affect vision). Serious side effects: dark urine or pale stools, yellowing of the skin or eyes, severe cramps of the stomach, nausea or vomiting, loss of weight, tiredness (altered or impaired liver function) heart failure, which may show as 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 pioglitazone in combination with insulin shortness of breath when at rest or after minimal physical activity with swelling of legs, feet and hands or rapid increase in weight, bone fracture.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

ARX-PIOGLITAZONE

Active ingredient(s): pioglitazone hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about taking ARX-PIOGLITAZONE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking ARX-PIOGLITAZONE.

Where to find information in this leaflet:

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

1. Why am I taking ARX-PIOGLITAZONE?

ARX-PIOGLITAZONE contains the active ingredient pioglitazone hydrochloride.

ARX-PIOGLITAZONE belongs to a group of medicines called glitazones.

Glitazones decrease insulin resistance and help 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 usually controlled by diet, certain oral medications and occasionally insulin.

ARX-PIOGLITAZONE is used to treat type 2 diabetes not controlled by diet and exercise. It helps to improve the action of insulin produced by your body.

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

ARX-PIOGLITAZONE is only available with a doctor's prescription. ARX-PIOGLITAZONE is not addictive.

2. What should I know before I take ARX-PIOGLITAZONE?

Warnings

Do not use ARX-PIOGLITAZONE if:

you are allergic to pioglitazone hydrochloride, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
Symptoms of allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of face, lips, tongue or other parts of the body.

Check with 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
- liver problems
- kidney problems requiring dialysis
- bone fractures, usually in the hand, upper arm or foot
- bladder cancer, or symptoms such as blood in the urine, often accompanied by pain, burning or sudden urges to urinate
Do not take this medicine if you have or have had any of the following medical conditions:
- heart failure
- type 1 diabetes mellitus
- diabetic ketoacidosis
you are taking other medicines for diabetes. Pioglitazone can enhance the action of other medicines, causing an increased risk of low blood sugar (hypoglycaemia). Your doctor may adjust the dose of your medicines.
suffer from lactose intolerance. ARX-PIOGLITAZONE tablets contain lactose.
are pregnant or if you plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.
take any medicines for any other condition.

Some premenopausal women who do not have monthly periods may restart their periods when taking pioglitazone. These women may have an increased risk of pregnancy. Your doctor will discuss with you the risks and benefits involved.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

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

Pioglitazone is not recommended for use during pregnancy and breastfeeding. It is not known whether pioglitazone passes into breast milk.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

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

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

gemfibrozil
medicines to treat diabetes (e.g. glibenclamide, gliclazide, insulin, metformin, chlorpropamide or tolbutamide)
oral contraceptives
rifampicin

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

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

4. How do I take ARX-PIOGLITAZONE?

How much to take

Your doctor will tell you how many tablets you will need to take. This depends on your condition and whether you are taking any other medicines.
ARX-Pioglitazone tablets should be taken once a day.
Follow the directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

When to use ARX-PIOGLITAZONE

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 to take ARX-PIOGLITAZONE

Swallow the tablets whole with a full glass of water

How long take ARX-PIOGLITAZONE

Follow the instructions provided and use ARX-PIOGLITAZONE 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. Make sure you have enough to last over weekends and holidays.

If you forget to take ARX-PIOGLITAZONE

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 you missed.

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

If you use too much ARX-PIOGLITAZONE

If you think that you have used too much ARX-PIOGLITAZONE, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking ARX-PIOGLITAZONE?

Things you should do

If you are about to start any new medicines, tell your doctor and pharmacist that you are taking ARX-PIOGLITAZONE.

Remind any doctor, dentist, or pharmacist you visit that you are taking ARX-PIOGLITAZONE.

If you are going to have a surgery, tell the surgeon or anaesthetist that you are taking ARX-PIOGLITAZONE. It may affect other medicines used during surgery.

Call your doctor straight away if you:

become pregnant while taking ARX-PIOGLITAZONE.
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.
have gained weight since taking pioglitazone. Weight gain can be associated with improved blood sugar control; however, it may also be a symptom of heart failure.

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

Things you should not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.
Do not give your medicine to anyone else, even if 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

Be careful to avoid low blood sugar levels (hypoglycaemia) whilst driving or operating machinery, especially if using pioglitazone in 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, operate machinery or do anything else that could be dangerous.

If you are travelling, it is a good idea to:

wear some form of identification showing you have diabetes
carry some form of sugar to treat hypoglycaemia if it occurs, e.g. sugar sachets or jellybeans
carry emergency food rations in case of a delay, e.g. dried fruit, biscuits or muesli bars

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ARX-PIOGLITAZONE affects you.

Looking after your medicine

Keep the tablets in the pack until it is time to take them. If you take the tablets out of the pack, they may not keep well.
Keep your medicine in a cool dry place where the temperature stays below 30°C.

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

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

This medicine helps most people with type 2 diabetes mellitus, but it may have unwanted side effects in a few people.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

a small increase in weight
signs of low blood sugar levels (hypoglycaemia) such as weakness, trembling or shaking, sweating, light-headedness, headache, dizziness, lack of concentration, tearfulness or crying, irritability, hunger, numbness around the lips and finger.

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

blood in the urine, often accompanied by pain and burning
eye problems, including blurred or double vision
macular oedema (an eye disorder that can affect vision)

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

dark urine or pale stools, yellowing of the skin or eyes, severe cramps of the stomach, nausea or vomiting, loss of weight, tiredness (altered or impaired liver function)
heart failure, which may show as 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 pioglitazone in combination with insulin
shortness of breath when at rest or after minimal physical activity with swelling of legs, feet and hands or rapid increase in weight
bone fracture

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

These side effects are very rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What ARX-PIOGLITAZONE contains

Active ingredient (main ingredient)	15 mg, 30 mg or 45 mg of pioglitazone hydrochloride
Other ingredients (inactive ingredients)	lactose monohydrate carmellose calcium hyprolose magnesium stearate
Potential allergens	Contains sugars as lactose

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

What ARX-PIOGLITAZONE looks like

ARX-PIOGLITAZONE 15mg tablets - White to off-white, round, biconvex, uncoated tablet embossed "15" on one side and plain on the other side. (Aust R 166911).

ARX-PIOGLITAZONE 30mg tablets - White to off-white, round, flat, bevelled edged, uncoated tablets embossed "30" on one side and plain on the other side. (Aust R 166914).

ARX-PIOGLITAZONE 45mg tablets - White to off-white, round, flat, bevelled edged, uncoated tablet embossed "45" on one side and plain on the other side. (Aust R 166913).

Available in blister packs of 7, 28, 50 or 98 tablets.

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

Who distributes ARX-PIOGLITAZONE

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

This leaflet was prepared in September 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

ARX-Pioglitazone (was APOTEX-Pioglitazone)

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 hydrochloride) as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

15 mg tablets.

White to off-white, round, biconvex, uncoated tablet embossed "15" on one side and plain on the other side.

30 mg tablets.

White to off-white, round, flat, bevelled edged, uncoated tablets embossed "30" on one side and plain on the other side.

45 mg tablets.

White to off-white, round, flat, bevelled edged, uncoated tablet embossed "45" on one side and plain on the other side.

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, in combination with insulin; as triple therapy to improve glycaemic control in combination with metformin and sulfonylurea.

4.2 Dose and Method of Administration

Pioglitazone should be taken once daily with or without food.
After initiation of pioglitazone 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).

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 pioglitazone 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 pioglitazone 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 pioglitazone 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.

Maximum recommended dose.

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

Renal impairment.

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

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. Pioglitazone therapy should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 x the upper limit of normal).

4.3 Contraindications

Pioglitazone is contraindicated in patients with known hypersensitivity or allergy to pioglitazone or any of the excipients in the tablets.
Pioglitazone is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone (like other thiazolidinediones) is contraindicated in patients with New York Heart Association (NYHA) class II, III or IV heart failure (see Section 4.4 Special Warnings and Precautions for Use).
Because of its mechanism of action, pioglitazone is only active in the presence of insulin. Therefore, pioglitazone 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 pioglitazone 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.

Pioglitazone should not be prescribed to lower the risk of cardiovascular disease such as myocardial infarction and stroke or to lower cardiovascular mortality.
Pioglitazone, 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 pioglitazone, 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, pioglitazone should be discontinued. The patient's heart failure should be evaluated and managed according to the current standards of care.
Patients with NYHA class III and IV cardiac status were excluded from initial clinical trials. Therefore, pioglitazone is not indicated in patients with NYHA class III or IV cardiac status.
Pioglitazone 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, pioglitazone 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 pioglitazone plus insulin (1.1%) and two of the 188 patients receiving 30 mg pioglitazone 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 pioglitazone (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 hospitalization for congestive heart failure was reported in 9.9% of patients on pioglitazone compared to 4.7% of patients on glibenclamide with a treatment difference observed from 6 weeks. This adverse event associated with pioglitazone 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 pioglitazone has been performed in patients with type 2 diabetes mellitus and pre-existing major macro vascular disease (PROactive). Pioglitazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3½ 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, pioglitazone should be used with caution in patients with oedema. In placebo controlled clinical trials, oedema was reported more frequently in patients treated with pioglitazone than in placebo treated patients.

Weight gain.

Dose related weight gain was seen with pioglitazone alone and in combination with other hypoglycaemic agents (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 assessed 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.
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 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.
A five year interim analysis of a cohort of 193,099 diabetic patients ≥ 40 years of age drawn from the Kaiser Permanente Northern California (KPNC) health plan found that, after adjusting for age, sex, use of tobacco products, use of other diabetic medications, and other risk factors, the hazard ratio for bladder cancer in patients exposed to pioglitazone compared to other patients was 1.2 (95% CI 0.9-1.5). The risk of bladder cancer increased with increasing cumulative dose and duration of pioglitazone use. The HR for bladder cancer in subjects with 12-24 months of pioglitazone use (compared to subjects never exposed to pioglitazone was 1.4 (95% CI 0.9-2.1). The HR after 24 months of pioglitazone use was 1.4 (95% CI 1.03-2.0).
Based on epidemiological data, treatment with pioglitazone for longer than 12 months may be associated with 27.5 excess cases of bladder cancer per 100,000 person years follow-up, compared to never use of pioglitazone and this risk may increase with further duration of therapy. These conclusions have not been tested in a purposefully designed prospective study.
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.

Bone fracture.

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse event reports of bone fracture from randomized, controlled, double blind clinical trials in over 8,100 pioglitazone and 7,400 comparator (excluding thiazolidinediones) treated patients, on treatment for up to 3½ 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 3½ 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 pioglitazone, 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 4,500 patients have been treated with pioglitazone. 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 x the upper limit of normal) at the start of therapy. Existing pioglitazone 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 renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

Approximately 500 patients in placebo controlled clinical trials of pioglitazone 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.

See Section 4.8 Adverse Effects (Undesirable Effects).

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 pioglitazone 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 pioglitazone and rifampicin is reported to result in a 54% decrease in the AUC of pioglitazone. The dose of pioglitazone 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 ethinyloestradiol and norethindrone 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 pioglitazone and glipizide does not alter the steady-state pharmacokinetics of glipizide.

Digoxin.

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

Warfarin.

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

Metformin.

Coadministration of pioglitazone 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 x greater than that in humans at the maximum recommended dose.
(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 x (rats) and 7 x (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. Pioglitazone 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 pioglitazone 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. Pioglitazone should not be administered to lactating women.

4.7 Effects on Ability to Drive and Use Machines

The effect of pioglitazone on the ability to drive and use machinery has not been studied, but based on its pharmacodynamic properties, pioglitazone 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 pioglitazone.

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 pioglitazone 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 2, 3 and 4.

In the PROactive study, which involved a high risk population of patients with pre-existing macro vascular disease, treatment emergent adverse events that occurred more often in the pioglitazone 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 pioglitazone 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 pioglitazone (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 pioglitazone and 1.4% in placebo treated patients. In patients treated with insulin containing regimen at baseline, the incidence of serious heart failure was 6.3% with pioglitazone 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 pioglitazone 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 pioglitazone 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 pioglitazone, 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.

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

Serum transaminase levels.

During placebo controlled clinical trials in the U.S., a total of 4 of 1,526 (0.26%) patients treated with pioglitazone and 2 of 793 (0.25%) placebo treated patients had ALT values ≥ 3 x the upper limit of normal. During all clinical studies in the U.S., 11 of 2,561 (0.43%) patients treated with pioglitazone had ALT values ≥ 3 x the upper limit of normal. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, 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 pioglitazone 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 x the upper limit of normal (values of 2,150-8,610 IU/L) was noted in 7 patients. Five of these patients continued to receive pioglitazone 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 pioglitazone 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).
Digestive 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

During clinical trials, one case of overdose with pioglitazone 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 pioglitazone alone but may occur in combination with sulfonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.
Contact the Poisons Information Centre on 13 11 26 (Australia) for advice on the management of overdosage.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pioglitazone is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycaemic control while reducing circulating insulin levels.
Fasting and postprandial glycaemic control are improved in patients with type 2 diabetes mellitus. The decreased insulin resistance produced by pioglitazone results in lower blood glucose concentrations, lower plasma insulin levels and lower haemoglobin A_1c (HbA_1c) values.

Mechanism of action.

Pioglitazone is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its unique mechanism of action. Pioglitazone 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 pioglitazone improves insulin sensitivity in insulin resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin dependent glucose disposal, improves hepatic sensitivity to glucose and thus improves dysfunctional glucose homeostasis.

Monotherapy.

Three randomized, double blind, placebo controlled trials of 16-26 weeks were conducted to study the use of pioglitazone as monotherapy in patients with type 2 diabetes. These studies examined pioglitazone doses from 7.5-45 mg/day in 865 patients.
In a 26 week dose ranging study, 408 patients with type 2 diabetes were randomized to receive 7.5, 15, 30 or 45 mg pioglitazone, or placebo. Compared with placebo, treatment with 15-45 mg pioglitazone resulted in significant improvements in HbA_1c and fasting blood glucose (FBG) (Figure 1).

The study population included patients not previously treated with antidiabetic medication (naive; 31%) and patients who were receiving antidiabetic medication at the time of study enrolment (previously treated; 69%). The data for the naive and previously treated patient subsets are shown in Table 5. This run in period was associated with little change in HbA_1c and FBG values from screening to baseline for the naive patients. However, for the previously treated group, washout from previous antidiabetic medication resulted in deterioration of glycaemic control and increase in HbA_1c and FBG. With pioglitazone, while most patients in the previously treated group had a decrease from baseline in HbA_1c and FBG, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to pioglitazone from another antidiabetic agent.

Pioglitazone has been shown to reduce total plasma triglycerides and free fatty acids and to increase HDL cholesterol levels. LDL cholesterol levels remain unchanged. In a 26 week, placebo controlled, dose ranging study, mean triglyceride levels decreased in the 15 mg, 30 mg and 45 mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL levels increased to a greater extent in the pioglitazone treated patients than in the placebo treated patients. There were no consistent differences for LDL and total cholesterol in pioglitazone treated patients compared with placebo (Table 6).

In a separate 24 week study, 260 patients with type 2 diabetes were randomized to one of two forced titration pioglitazone treatment arms (final doses 30 or 45 mg) or a mock titration placebo arm. In one pioglitazone treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second pioglitazone treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with pioglitazone, as described, produced statistically significant improvements in HbA_1c and FBG at endpoint compared with placebo (Table 7).

For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 10.1% for HbA_1c and 13.22 mmol/L for FBG. At baseline, mean HbA_1c was 10.2% and mean FBG was 13.5 mmol/L. Compared with placebo, treatment with mean HbA_1c of 2.3% and 2.6% and mean FBG of 3.5 mmol/L and 5.28 mmol/L, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA_1c and 12 mmol/L for FBG. At baseline, mean HbA_1c was 10.7% and mean FBG was 16.11 mmol/L. Compared with placebo, treatment with pioglitazone titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA_1c of 1.3% and 1.4% and mean FBG of 3.06 mmol/L and 3.33 mmol/L, respectively. For many previously treated patients, HbA_1c and FBG had not returned to screening levels by the end of the study.
In a 16 week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg pioglitazone or placebo once daily. Compared with placebo, treatment with pioglitazone resulted in significant reduction in HbA_1c and FBG (Table 8).

For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA_1c and 13.33 mmol/L for FBG. At baseline, mean HbA_1c was 10.4% and mean FBG was 14.11 mmol/L. Compared with placebo, treatment with pioglitazone 30 mg resulted in reductions from baseline in mean HbA_1c of 1.0% and mean FBG of 3.44 mmol/L. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA_1c and 12 mmol/L for FBG. At baseline, mean HbA_1c was 10.6% and mean FBG was 15.94 mmol/L. Compared with placebo, treatment with pioglitazone 30 mg resulted in reductions from baseline in mean HbA_1c of 1.3% and mean FBG of 2.56 mmol/L. For many previously treated patients, HbA_1c and FBG had not returned to screening levels by the end of the study.

Dual therapy.

Three 16 week, randomized, double blind, placebo controlled clinical studies were conducted to evaluate the effects of pioglitazone on glycaemic control in patients with type 2 diabetes who were inadequately controlled (HbA_1c ≥ 8%) despite sulfonylurea, metformin or insulin therapy. Previous diabetes treatment may have been monotherapy or combination therapy.
In one combination study, 560 patients on a sulfonylurea, either alone or combined with another antidiabetic agent, were randomized to receive pioglitazone 15 mg, pioglitazone 30 mg or placebo in addition to their sulfonylurea regimen. Any other antidiabetic agent was withdrawn. Compared with placebo, the addition of pioglitazone to the sulfonylurea significantly reduced the mean HbA_1c 0.9% and 1.3% for the 15 and 30 mg doses, respectively. In addition, compared with placebo, pioglitazone decreased FBG by 2.17 mmol/L (15 mg dose) and 3.22 mmol/L (30 mg dose). The therapeutic effect of pioglitazone in combination with a sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium or high doses of sulfonylurea (< 50%, 50%, or > 50% of the recommended maximum daily dose).
In a second combination study, 328 patients with type 2 diabetes on metformin, either alone or combined with another antidiabetic agent, were randomized to receive either pioglitazone 30 mg or placebo in addition to their metformin. Any other antidiabetic agent was withdrawn. Compared with placebo, the addition of pioglitazone to metformin significantly reduced the mean HbA_1c 0.8% and FBG 2.11 mmol/L. The therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin (< 2000 mg per day or ≥ 2000 mg per day).
In a third combination study, 566 patients with type 2 diabetes receiving a median of 60.5 units/day insulin, either alone or combined with another antidiabetic agent, were randomized to receive either pioglitazone 15 mg, pioglitazone 30 mg or placebo in addition to their insulin. Any other antidiabetic agent was discontinued. Compared with treatment with placebo, treatment with pioglitazone in addition to insulin significantly reduced both HbA_1c 0.7% (15 mg dose) and 1.0% (30 mg dose) and FBG 1.94 mmol/L (15 mg dose) and 2.72 mmol/L (30 mg dose). The therapeutic effect of pioglitazone in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin (< 60.5 units per day or ≥ 60.5 units per day).

Triple therapy.

A 7 month, randomized, double blind, placebo controlled study was conducted to evaluate the efficacy and safety of pioglitazone versus placebo in combination with metformin and a sulfonylurea in patients with type 2 diabetes. To qualify for study selection, patients must have been diagnosed with type 2 diabetes mellitus for more than 2 years, have been treated for more than 3 months with metformin and sulfonylurea, be aged 30 years or older and have HbA_1c between 7.0% and 9.5% within 3 months prior to the trial. Patients treated with insulin or a single oral antihyperglycaemic agent or more than 2 antihyperglycaemic agents were excluded from participation.
Following a run in period, 299 patients were randomized to receive either pioglitazone 30 mg or placebo for 3 months while continuing on current doses of sulfonylurea and metformin. At the end of 3 months, depending on HbA_1c results, patients received either pioglitazone 30 mg or 45 mg or placebo 30 mg or 45 mg for 4 months. More than 92% of patients had their dose increased to 45 mg. The dose of sulfonylurea could be reduced during the trial in case of symptomatic hypoglycaemia. Changes in the metformin dosage were strictly prohibited.
The adjusted (for baseline HbA_1c) mean change was -0.90 ± 0.08% in the pioglitazone group and 0.28 ± 0.08% in the placebo group. The difference between the two groups (-1.2 ± 0.11%) was statistically significant (p < 0.001) and in favour of the pioglitazone group (Table 9). A decrease of HbA_1c level of ≥ 0.6% or a level of HbA_1c less than 7% was obtained in 65% of pioglitazone patients compared to only 10% in the placebo group.
A significant effect of pioglitazone compared to placebo (p < 0.01) was also observed on fasting plasma glucose with an adjusted mean change of -2.17 ± 0.18 mmol/L in the pioglitazone group and 0.39 ± 0.18 mmol/L in the placebo group.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Steady-state is achieved after 4-7 days of dosing. Food slightly delays the time to peak serum concentration to 3-4 hours, but does not alter the extent of absorption. The absolute bioavailability following oral administration is approximately 83%.

Distribution.

The mean apparent volume of distribution (Vd/F) of pioglitazone following intravenous administration is 0.25 L/kg of bodyweight.

Protein binding.

Pioglitazone is extensively bound to plasma protein (> 99%), principally to serum albumin. The free fraction is less than 2% and independent of concentration in the range of 34-2000 nanogram/mL (which includes the therapeutic concentration range).

Metabolism.

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 and 3A4. Three of the six metabolites formed are active. The major circulating metabolite is M-IV (1-hydroxyethyl pioglitazone), which accounts for most of the drug related material in human plasma and probably accounts for much of the therapeutic efficacy.
Pioglitazone did not inhibit P450 activity when incubated with human P450 liver microsomes.

Excretion.

Following oral administration of radiolabelled pioglitazone to humans, recovered label was mainly in faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged pioglitazone can be detected in either urine or faeces. The mean plasma elimination half life of unchanged pioglitazone in man is 5-6 hours and for its total active metabolites 16-23 hours.

Special populations.

Renal insufficiency.

In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lower than those seen in subjects with normal renal function, but with similar oral clearance of parent drug. Thus free (unbound) pioglitazone concentration remains unchanged. Dose adjustment in patients with renal dysfunction is not recommended (see Section 4.2 Dose and Method of Administration). No information is available for patients on dialysis, therefore pioglitazone should not be used in such patients.

Hepatic insufficiency.

In subjects with impaired hepatic function, total plasma concentration of pioglitazone is unchanged, but with an increased volume of distribution. Intrinsic clearance is therefore reduced, coupled with a higher unbound fraction of pioglitazone.
Pioglitazone therapy should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 x the upper limit of normal).

Elderly.

No clinically significant differences between elderly and young subjects were observed.

Paediatric.

Pharmacokinetic data in the paediatric population is not available.

Gender.

The mean C_max and AUC values were increased 20-60% in females. As monotherapy and in combination with sulfonylurea, metformin or insulin, pioglitazone improved glycaemic control in both males and females. In controlled clinical trials, HbA_1c decreases from baseline were generally greater for females than for males (average mean difference in HbA_1c 0.5%). See Section 4.2 Dose and Method of Administration, Female patients for recommended dosages in women. Since therapy should be individualized for each patient to achieve glycaemic control, dose adjustment is not recommended based on gender alone.

5.3 Preclinical Safety Data

Genotoxicity.

Pioglitazone was not mutagenic in a battery of tests for gene mutation in bacteria and mammalian cells in vitro, in assays for chromosomal damage in vitro and in vivo and in an assay for DNA damage (unscheduled DNA synthesis in rat hepatocytes in vitro).

Carcinogenicity.

A two year carcinogenicity study in mice showed no drug related increases in tumour incidences at oral doses up to 91 mg/kg/day. Rats dosed orally with pioglitazone at 0.9-57 mg/kg/day for two years showed increased incidences of subcutaneous benign adipose tissue tumours (lipomas) and urinary bladder transitional cell tumours. Systemic exposure (plasma AUC_0-24h) to total active compounds at the highest dose in both studies was 8 x greater than that in humans at the maximum recommended dose. The no-effect doses were not established for either tumour site. Subcutaneous benign adipose tissue tumours (lipomas) have been observed in rats treated with other thiazolidinedione drugs and are probably related to the pharmacodynamic activity of this drug class.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, carmellose calcium, hyprolose, magnesium stearate.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Store in original container.