Consumer medicine information

Vexazone

Pioglitazone

BRAND INFORMATION

Brand name

Vexazone

Active ingredient

Pioglitazone

Schedule

SUMMARY CMI

VEXAZONE^®

Consumer Medicine Information (CMI) summary

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

1. Why am I taking VEXAZONE?

VEXAZONE contains the active ingredient pioglitazone hydrochloride. VEXAZONE is used in the management of type 2 diabetes not controlled by diet.

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

2. What should I know before I take VEXAZONE?

Do not use if you have ever had an allergic reaction to VEXAZONE 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 VEXAZONE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VEXAZONE 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 VEXAZONE?

VEXAZONE should be taken at the same time every day to ensure it works effectively.
Follow all instructions given to you by your doctor.

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

5. What should I know while taking VEXAZONE?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are taking VEXAZONE. Monitor your health and contact your doctor if you notice any changes. Keep all of your doctor's appointments and go for regular check-ups.
Things you should not do	Do not stop using this medicine suddenly.
Driving or using machines	VEXAZONE may cause dizziness in some people. Do not drive or operate machines until you know how this medicine affects you.
Drinking alcohol	Tell your doctor if you drink alcohol.
Looking after your medicine	Store VEXAZONE in a cool dry place, out of direct light, where the temperature is below 25°C. Keep VEXAZONE in the original packaging, in a safe place, away from children.

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

6. Are there any side effects?

Less serious side effects include weight gain, signs of low blood sugar (hypoglycaemia), eye problems, bone fracture and impaired liver function. Serious side effects may include dark urine, pale stools, yellowing skin or eyes, severe stomach cramps, nausea or vomiting, weight loss, tiredness, shortness of breath with swelling of legs, feet and hands, with rapid increase in weight, signs of bladder cancer, and oedema (signs of heart failure).

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

VEXAZONE^®

Active ingredient(s): pioglitazone hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about taking VEXAZONE. 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 VEXAZONE.

Where to find information in this leaflet:

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

1. Why am I taking VEXAZONE?

VEXAZONE contains the active ingredient pioglitazone hydrochloride. VEXAZONE belongs to a group of medicines called glitazones. Glitazones decrease insulin resistance.

VEXAZONE is used in the management of type 2 diabetes not controlled by diet.

VEXAZONE is a tablet that is used to improve the action of the body's naturally produced insulin. VEXAZONE 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. VEXAZONE can be used alone (when diet and exercise is not enough to treat your diabetes) or together with other anti-diabetic medicines.

Your doctor may have prescribed it for another purpose.

2. What should I know before I take VEXAZONE?

Warnings

Do not take VEXAZONE 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 take this medicine.
- 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.
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).

Check with your doctor if you:

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
problems with your liver
problems with your kidneys that require dialysis. VEXAZONE 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 VEXAZONE. 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 VEXAZONE. Talk to your doctor about the risk of fracture and for advice on how to keep your bones healthy.
allergies to any other medicines, foods, preservatives or dyes.

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.

VEXAZONE is not recommended for use during pregnancy. If there is a need to consider VEXAZONE during your pregnancy, your doctor will discuss with you the benefits and risks of taking VEXAZONE.

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

It is recommended you do not breastfeed while taking VEXAZONE and it is not known whether VEXAZONE passes into breast milk.

Use in children

The use of VEXAZONE has not been studies in children.

3. What if I am taking other medicines?

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

Some medicines may interfere with VEXAZONE and affect how it works. These include:

chlorpropamide
glibenclamide
gliclazide
insulin
metformin
oral contraceptives
gemfibrozil
rifampicin
tolbutamide

If you are taking any of these medicines you may need to adjust your dose or take different medicines. Your doctor will be able to provide information.

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

4. How do I take VEXAZONE?

How much to take

Your doctor will tell you how many VEXAZONE 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.
Your doctor may increase or decrease your dose in order to find the appropriate dose for your condition.
Follow the instructions provided by your doctor as they might be different to the information in this leaflet.

When to take VEXAZONE

Take VEXAZONE once a day the same time each day as advised by your doctor.
Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How to take VEXAZONE

VEXAZONE tablets should be swallowed whole with a glass of water.
VEXAZONE tablets can be taken before or after food.

How long to take VEXAZONE for

Continue taking your medicine until your doctor tells you to stop.
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 VEXAZONE

VEXAZONE should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember.

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

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

If you are not sure what to do, ask your pharmacist for help. Your pharmacist can also provide some hints If you have trouble remembering.

If you take too much VEXAZONE

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

You should immediately:

phone the Poisons Information Centre
(Australia telephone 13 11 26) for advice, 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 VEXAZONE?

Things you should do

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 any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

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

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

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.

Call your doctor straight away if you:

become pregnant while taking this medicine

Things you should not do

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.
Do not take VEXAZONE 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.

Hypoglycaemia (low blood sugar)

If you are taking VEXAZONE with other medications used to treat diabetes such as a sulfonylurea or insulin you may at risk for hypoglycaemia.
Signs of hypoglycaemia (low blood sugar), which may include sweating, weakness, hunger, dizziness, trembling or shaking, light-headedness, headache, lack of concentration, tearfulness or crying, irritability, numbness around the lips and fingers.

You should tell your doctor as soon as possible if you notice the above side effects.

Heart failure

If you are taking VEXAZONE in combination with insulin you may be at risk of heart failure which may show as localised swelling of the ankles, feet and hands (oedema) and/or fluid in the lungs (pulmonary oedema).
Tell your doctor if you have gained weight since taking VEXAZONE. Weight gain can be associated with improved blood sugar control; however, it may also be a symptom of heart failure.

You should tell your doctor as soon as possible if you notice the above side effects.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how VEXAZONE affects you.

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

If you experience any side effects which impact your ability to drive or operate machinery when taking this medicine, do not drive or do anything else that could be dangerous and contact your doctor.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

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

Store it in a cool dry place below 25°C, 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.

Getting rid of any unwanted medicine

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

Do not take this medicine after the expiry date.

6. Are there any side effects?

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

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

Some side effects may be related to the dose of VEXAZONE. 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 VEXAZONE you are taking.

Less serious side effects

Less serious side effects

What to do

weight gain
signs of hypoglycaemia (low blood sugar), which may include sweating, weakness, hunger, dizziness, trembling or shaking, light-headedness, headache, lack of concentration, tearfulness or crying, irritability, numbness around the lips and fingers
eye problems including blurred or double vision.
increased risk of fracture in women
macular oedema (an eye disorder that can affect vision)
altered or impaired liver function.

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

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
blood in the urine often accompanied by pain and burning, these can be symptoms of bladder cancer.
shortness of breath when at rest or after minimal physical activity with selling of the legs, feet and hands, rapid increase in weight
heart failure which may show as localised swelling of the ankles, feet and hands (oedema) and/or fluid in the lungs (pulmonary oedema).

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.

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 VEXAZONE contains

Active ingredient (main ingredient)	pioglitazone (as hydrochloride)
Other ingredients (inactive ingredients)	lactose monohydrate hypromellose colloidal anhydrous silica croscarmellose sodium polysorbate 80 magnesium stearate
Potential allergens	Contains sugars as lactose.

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

What VEXAZONE looks like

VEXAZONE tablets come in 3 strengths:

VEXAZONE 15 mg - white to off-white, round, bi-convex, uncoated tablet debossed with "PG" over 15 on one side and "G" on the other side (AUST R 164345)
VEXAZONE 30 mg - white to off-white, round, bi-convex, uncoated tablet debossed with "PG" over 30 on one side and "G" on the other side (AUST R 164344)
VEXAZONE 45 mg - white to off-white, round, bi-convex, uncoated tablet debossed with "PG" over 45 on one side and "G" on the other side. (AUST R 164343).

Who distributes VEXAZONE

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in May 2025.

VEXAZONE^® is a Viatris company trade mark

VEXAZONE_cmi\May25/00

Published by MIMS July 2025

BRAND INFORMATION

Brand name

Vexazone

Active ingredient

Pioglitazone

Schedule

1 Name of Medicine

Pioglitazone hydrochloride.

2 Qualitative and Quantitative Composition

Each Vexazone tablet contains either 15 mg, 30 mg or 45 mg of pioglitazone (as hydrochloride) as the active ingredient.

Excipient with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Vexazone 15 mg white to off-white, round, bi-convex, uncoated tablet debossed with "PG" over 15 on one side and "G" on the other side.
Vexazone 30 mg white to off-white, round, bi-convex, uncoated tablet debossed with "PG" over 30 on one side and "G" on the other side.
Vexazone 45 mg white to off-white, round, bi-convex, uncoated tablet debossed with "PG" over 45 on one side and "G" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Vexazone is indicated for the 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

Vexazone should be taken once daily with or without food.
After initiation of Vexazone 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 Vexazone is 15 mg or 30 mg once daily, increasing after 4 weeks, if greater therapeutic effect is needed, to 45 mg once daily.

Dual therapy.

The recommended dose of Vexazone 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 Vexazone is 30 mg once daily in combination with sulfonylureas 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 Vexazone should not exceed 45 mg/day since doses higher than 45 mg/day have not been studied in clinical trials.

Patients with renal insufficiency.

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

4.3 Contraindications

Vexazone is contraindicated in patients with known hypersensitivity or allergy to pioglitazone or any of the excipients.
Vexazone 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, Vexazone is only active in the presence of insulin. Therefore, Vexazone 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 of 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 post-marketing 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 New York Heart Association (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 US 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 was 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 ischemic attack (4.1%), and congestive heart failure (2.3%).
In this study, two of the 191 patients receiving pioglitazone 15 mg plus insulin (1.1%) and two of the 188 patients receiving pioglitazone 30 mg 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 coronary artery bypass graft (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 post-marketing 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 (EF) less than 40% (mean EF 30% at baseline). Overnight hospitalisation 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 macrovascular disease (PROactive). Pioglitazone 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 1,000 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 (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 8,100 pioglitazone and 7,400 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 fracture per 100 patient years) of pioglitazone treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures/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 times 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 12 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 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.

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, ciclosporin, calcium channel blockers and HMG-CoA reductase inhibitors, are not to be expected. Inhibitors of CYP2C8 (e.g. gemfibrozil) may increase the AUC of pioglitazone, a decrease in the AUC of pioglitazone may occur when administered in combination with CYP2C8 inducers (e.g. rifampicin).

Gemfibrozil.

Co-administration 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.

Co-administration of pioglitazone and rifampicin is reported to result in a 54% decrease in 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 ethinylestradiol 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.

Co-administration of pioglitazone and glipizide does not alter the steady-state pharmacokinetics of glipizide.

Digoxin.

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

Warfarin.

Co-administration 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.

Co-administration 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 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. 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. 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 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 3 and 4. 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.

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 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 an 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 creatinine 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 8,100 patients in the pioglitazone treated groups and 7,400 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 to 4% in patients treated with pioglitazone. 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 pioglitazone therapy and have not been associated with any significant haematological clinical effects.

Serum transaminase levels.

During placebo controlled clinical trials in the US, 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 times the upper limit of normal. During all clinical studies in the US, 11 of 2,561 (0.43%) patients treated with pioglitazone 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 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 US 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 creatinine phosphokinase levels (CPK) were observed. A single, isolated elevation to greater than 10 times the upper limit of normal (values of 2,150 to 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 post-marketing surveillance.

Cardiovascular system.

Cardiac failure. In post-marketing 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 4.4 Special Warnings and Precautions for Use, Cardiac).

Hepatic system.

Hepatocellular dysfunction. In post-marketing experience with pioglitazone, reports of hepatitis and hepatic enzyme elevations to three 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, post-marketing 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 4 days, then 180 mg/day for 7 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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.