Consumer medicine information

Pioglitazone Sandoz

Pioglitazone

BRAND INFORMATION

Brand name

Pioglitazone Sandoz

Active ingredient

Pioglitazone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pioglitazone Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Pioglitazone Sandoz.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

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

WHAT PIOGLITAZONE SANDOZ IS USED FOR

Pioglitazone Sandoz helps to control the level of glucose in your blood when you have type 2 diabetes. This is the 'adult onset' type of diabetes and is controlled by diet, certain oral medications and occasionally insulin.

This medicine is used:

  • to improve the action of the body's naturally produced insulin.
  • in the management of type 2 diabetes not controlled by diet.
  • alone (when diet and exercise is not enough to treat your diabetes) or together with other anti-diabetic medicines.

It contains the active ingredients Pioglitazone hydrochloride.

Pioglitazone hydrochloride belongs to a group of medicines called glitazones.

It works by decreasing insulin resistance.

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

This medicine is not addictive.

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

The use of Pioglitazone Sandoz has not been studied in children.

BEFORE YOU TAKE PIOGLITAZONE SANDOZ

When you must not take it

Do not take this medicine if you have an allergy to:

  • Pioglitazone hydrochloride, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.
  • any other similar medicines (Rosiglitazone maleate).

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you have or have had any of the following medical conditions:

  • heart failure requiring treatment.
    Talk to your doctor if you have heart failure
  • type 1 diabetes or diabetic ketoacidosis
  • bladder cancer
  • hepatic impairment.

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

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

Before you start to take it

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

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

  • red coloured urine
  • heart disease with shortness of breath after minimal physical activity
  • heart disease with severe symptoms at rest
  • swelling of hands, ankles or feet
  • bladder cancer or symptoms associated with bladder cancer such as blood in the urine (hematuria) often accompanied by pain and burning or, sudden urges to urinate
  • problems with your liver
  • problems with your kidneys that requires dialysis. Pioglitazone Sandoz 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 Pioglitazone Sandoz. These women may be at increased risk of pregnancy
  • bone fractures, usually in the hand, upper arm or foot, have been seen in some patients when taking Pioglitazone Sandoz. Talk to your doctor for advice on how to keep your bones healthy.

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

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

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

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

Taking other medicines

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

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

  • gemfibrozil, a medicine used to lower high cholesterol
  • other antidiabetic drugs such as glibenclamide, gliclazide, insulin, metformin, tolbutamide and chlorpropamide
  • oral contraceptives
  • rifampicin, an antibiotic drug.

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

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

HOW TO TAKE PIOGLITAZONE SANDOZ

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

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

How much to take

Your doctor will tell you how many Pioglitazone Sandoz tablets you should take.

The standard dose for this medicine is usually in the range of 15 mg to 45 mg per day.

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Pioglitazone Sandoz may not work as well and your problem may not improve.

The usual starting dose is one tablet each day as advised by your doctor. Depending on your response, your doctor may increase or decrease your dose in order to find the appropriate dose for your condition.

How to take it

Swallow the tablet whole with a full glass of water.

When to take Pioglitazone Sandoz

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 whether you take Pioglitazone Sandoz with food or on an empty stomach.

How long to take Pioglitazone Sandoz

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

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

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

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

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

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Pioglitazone Sandoz. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE USING PIOGLITAZONE SANDOZ

Things you must do

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

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

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

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

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

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

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

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

Things you must not do

Do not take Pioglitazone Sandoz 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

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

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Pioglitazone Sandoz.

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

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

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

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

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

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

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

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

These are more common side effects of the medicine.

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

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

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

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

AFTER TAKING PIOGLITAZONE SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 30°C.

Do not store Pioglitazone Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

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

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Pioglitazone Sandoz comes in three types of tablets:

Pioglitazone Sandoz 15 mg - white, round tablet, with imprint "PGT 15" on one side.

Pioglitazone Sandoz 30 mg - white, round tablet, with imprint "PGT 30" on one side and with score line on both sides.

Pioglitazone Sandoz 45 mg - white, round tablet, with imprint "PGT 45" on one side.

Available in blister packs and bottles of 28 tablets.

Not all strengths or presentations may be marketed.

Ingredients

Active ingredients:

  • Pioglitazone Sandoz 15 mg - 15 mg Pioglitazone (as hydrochloride)
  • Pioglitazone Sandoz 30 mg - 30 mg Pioglitazone (as hydrochloride)
  • Pioglitazone Sandoz 45 mg - 45 mg Pioglitazone (as hydrochloride)

Inactive ingredients:

  • Lactose monohydrate
  • hyprolose
  • carmellose calcium
  • magnesium stearate

This medicine does not contain gluten, tartrazine or any other azo dyes.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Novartis New Zealand Ltd
PO Box 99102
Newmarket
Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was prepared in January 2019.

Australian Register Number:

15 mg tablets: AUST R 162223 (blisters)

30 mg tablets: AUST R 162222 (blisters)

45 mg tablets: AUST R 162225 (blisters)

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Pioglitazone Sandoz

Active ingredient

Pioglitazone

Schedule

S4

 

1 Name of Medicine

Pioglitazone hydrochloride.

6.7 Physicochemical Properties

Pioglitazone hydrochloride is an odourless, white crystalline powder that is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water and insoluble in ether.
The chemical name of Pioglitazone HCl is (5RS)-5-[[4-[2-(5-Ethylpyridin-2-yl) ethoxy]phenyl]methyl] thiazolidine-2,4-dione hydrochloride. Its empirical formula is C19H21N2O3S.HCl (MW: 392.90).

Chemical structure.

Its chemical structure is:

CAS number.

Pioglitazone HCl: 112529-15-4.
Pioglitazone free base: 111025-46-8.

2 Qualitative and Quantitative Composition

Each Pioglitazone Sandoz 15 mg tablets contains 16.535 mg pioglitazone hydrochloride equivalent to 15 mg pioglitazone.
Each Pioglitazone Sandoz 30 mg tablets contains 33.07 mg pioglitazone hydrochloride equivalent to 30 mg pioglitazone.
Each Pioglitazone Sandoz 45 mg tablets contains 49.605 mg pioglitazone hydrochloride equivalent to 45 mg pioglitazone.

Excipient(s) with known effect.

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

3 Pharmaceutical Form

Tablets.
Pioglitazone Sandoz 15 mg tablets are white, round tablet, with imprint "PGT 15" on one side.
Pioglitazone Sandoz 30 mg tablets are white, round tablet, with imprint "PGT 30" on one side and with score line on both sides.
Pioglitazone Sandoz 45 mg tablets are white, round tablet, with imprint "PGT 45" on one side.
Not all strengths may be marketed.

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 HbA1c 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 randomised, double blind, placebo-controlled trials of 16 to 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 to 45 mg/day in 865 patients.
In a 26 week dose ranging study, 408 patients with type 2 diabetes were randomised to receive pioglitazone 7.5, 15, 30 or 45 mg, or placebo. Compared with placebo, treatment with pioglitazone 15 to 45 mg resulted in significant improvements in HbA1c and fasting blood glucose (FBG) (see 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 HbA1c 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 increases in HbA1c and FBG. With pioglitazone, while most patients in the previously treated group had a decrease from baseline in HbA1c 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. Please see Table 5.
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 pioglitazone 15, 30 and 45 mg 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 (see Table 6).
In a separate 24 week study, 260 patients with type 2 diabetes were randomised 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 HbA1c and FBG at endpoint compared with placebo (see Table 7).
For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 10.1% for HbA1c and 13.22 mmol/L for FBG. At baseline, mean HbA1c was 10.2% and mean FBG was 13.5 mmol/L. Compared with placebo, treatment with pioglitazone titrated to a final dose of 30 and 45 mg resulted in reductions from baseline in mean HbA1c of 2.3 and 2.6% and mean FBG of 3.5 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 HbA1c and 12 mmol/L for FBG. At baseline, mean HbA1c was 10.7% and mean FBG was 16.11 mmol/L. Compared with placebo, treatment with pioglitazone titrated to a final dose of 30 and 45 mg resulted in reductions from baseline in mean HbA1c of 1.3 and 1.4% and mean FBG of 3.06 and 3.33 mmol/L, respectively. For many previously treated patients, HbA1c 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 randomised to treatment with pioglitazone 30 mg or placebo once daily. Compared with placebo, treatment with pioglitazone resulted in significant reductions in HbA1c and FBG (see Table 8). Please see Table 8.
For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1c and 13.33 mmol/L for FBG. At baseline, mean HbA1c 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 HbA1c 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 HbA1c and 12 mmol/L for FBG. At baseline, mean HbA1c 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 HbA1c of 1.3% and mean FBG of 2.56 mmol/L. For many previously treated patients, HbA1c and FBG had not returned to screening levels by the end of the study.

Dual therapy.

Three 16 week, randomised, 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 (HbA1c ≥ 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 randomised 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 HbA1c 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 randomised 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 HbA1c 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 (< 2,000 mg/day or ≥ 2,000 mg/day).
In a third combination study, 566 patients with type 2 diabetes receiving a median of insulin 60.5 units/day, either alone or combined with another antidiabetic agent, were randomised to receive either pioglitazone 15 mg, pioglitazone 30 mg or placebo in addition to their insulin. Any other antidiabetic agent was discontinued. Compared to treatment with placebo, treatment with pioglitazone in addition to insulin significantly reduced both HbA1c 0.7% (15 mg dose) and 1.00% (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/day or ≥ 60.5 units/day).

Triple therapy.

A seven month, randomised, 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 two years, have been treated for more than three months with metformin and sulfonylurea, be aged 30 years or older and have HbA1c between 7.0 and 9.5% within three months prior to the trial. Patients treated with insulin or a single oral antihyperglycaemic agent or more than two antihyperglycaemic agents were excluded from participation.
Following a run-in period, 299 patients were randomised to receive either pioglitazone 30 mg or placebo for three months while continuing on current doses of sulfonylurea and metformin. At the end of three months, depending on HbA1c results, patients received either pioglitazone 30 or 45 mg or placebo 30 or 45 mg for four 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 HbA1c) 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 (see Table 9). A decrease of HbA1c level of ≥ 0.6% or a level of HbA1c 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. Please see Table 9.

5.2 Pharmacokinetic Properties

A bioequivalence study compared 45 mg Pioglitazone Sandoz tablets (A) with the innovator's tablets (B). It was of open label, randomised (AB vs BA), single dose, two treatment, two period, two sequence, two-way crossover design. Forty adult male volunteers completed the study.
Following an oral administration of a single-dose of Pioglitazone Sandoz to healthy male subjects under fasting conditions, a mean peak plasma concentration (Cmax) of pioglitazone of approximately 1298.49 nanogram/mL was achieved within approximately 2.71 hours (Tmax).
For key PK parameters, results were as follows (A/B). See Table 10.
The criteria for assessing bioequivalence for pioglitazone were standard, i.e. 90% confidence intervals around the exponential of the difference between least-squares means of test and reference products for ln-transformed AUCt, AUCi and Cmax were to be between 80% and 125%.
These criteria were satisfied and bioequivalence was demonstrated. Formulation A had a Tmax of 2.71 hours and formulation B had a Tmax of 2.19 hours for pioglitazone.

Absorption.

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within two hours. Steady state is achieved after four to seven days of dosing. Food slightly delays the time to peak serum concentration to three to four 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 to 2,000 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 humans is five to six hours and for its total active metabolites 16 to 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 Sandoz 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 times the upper limit of normal).

Elderly.

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

Paediatric.

Pharmacokinetic data in the paediatric population are not available.

Gender.

The mean Cmax and area under the curve (AUC) values were increased 20% to 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, haemoglobin A1c (HbA1c) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). See Section 4.2 Dose and Method of Administration, Female patients for recommended dosages in women.

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 to 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 to 24 hours)) to total active compounds at the highest dose in both studies was eight times 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Pioglitazone Sandoz 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.

4.3 Contraindications

Pioglitazone Sandoz is contraindicated in patients with known hypersensitivity or allergy to pioglitazone or any of the excipients.
Pioglitazone is contraindicated in patients with cardiac failure or history of cardiac failure (New York Heart Association [NYHA] Class I, II, III or IV).
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.
Pioglitazone is contraindicated in patients with current bladder cancer or a history of bladder cancer.
Pioglitazone is contraindicated in patients with uninvestigated macroscopic haematuria.
Pioglitazone is contraindicated in patients with hepatic impairment.

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 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 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. 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 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 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 HbA1C 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 glyburide with a treatment difference observed from six 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.
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.
Post-marketing cases of peripheral oedema and cardiac failure have also been reported in patients with concomitant use of pioglitazone and nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors.

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. Please see Table 1.
In some cases weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.

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). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.
Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.
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.
Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded.

Monitoring of liver function.

In clinical trials worldwide, over 4,500 patients have been treated with pioglitazone. There was no evidence of drug induced hepatotoxicity.
There have been rare reports of hepatocellular dysfunction during post-marketing experience (see Section 4.8 Adverse Effects (Undesirable Effects)). It is recommended, therefore, that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. 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 3x 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.

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/100 patient years in women treated with pioglitazone and 1.1 fractures/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/100 patient years of use.
In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fracture/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%).
A similar increased risk of fracture has been suggested in both men and women.
The risk of fractures should be considered in the long-term care of patients 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 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.
Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure.
In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.

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, cyclosporin, 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).
Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Pioglitazone dose adjustment within the recommended dosage or changes in diabetic treatment should be considered.

Gemfibrozil.

Coadministration of pioglitazone and gemfibrozil is reported to result in a three-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 to 24 hours)) to total active compounds at the highest dose was about seven times 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 to 24 hours)) to total active compounds at the highest dose was about 12 times (rats) and seven times (rabbits) greater than that in humans at the maximum recommended dose. Embryotoxicity (increased post-implantation loss) was observed in both animal species, and fetotoxic effects (reduced fetal 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.

4.8 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. Please see Table 2. Also see Tables 3 and 4.
In the PROactive study, which involved a high risk population of patients with pre-existing macrovascular disease, treatment emergent adverse events that occurred more often in the 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 non-serious 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 HbA1c 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%). Additional adverse events reported in combination with other hypoglycaemic agents:
Increased appetite, dizziness, vertigo, flatulence, sweating, glycosuria, proteinuria and increased lactic dehydrogenase have been reported in combination with sulfonylurea.
There have been reports of dyspnoea in combination with insulin.
Haematuria and erectile dysfunction have been reported in combination with metformin.

Laboratory test abnormalities.

Haematological.

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 ≥ three 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 ≥ three 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 pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see Section 4.4 Special Warnings and Precautions for Use, Monitoring of liver function).

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 ten times the upper limit of normal (values of 2,150 to 8,610 IU/L) was noted in seven 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 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 4.3 Contraindications and 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. Doctors should consider the possibility of macular oedema if a patient reports decreased visual acuity; an appropriate ophthalmological referral should be considered.

Others.

Post-marketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria.

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.

4.2 Dose and Method of Administration

Dosage.

Pioglitazone Sandoz should be taken once daily with or without food.
After initiation of Pioglitazone Sandoz 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 Sandoz is 15 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 Sandoz 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 Sandoz 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 Sandoz should not exceed 45 mg/day since doses higher than 45 mg/day have not been studied in clinical trials.

Dosage adjustment.

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 Sandoz should not be used in such patients.

Hepatic impairment.

Pioglitazone Sandoz should not be used in patients with hepatic impairment (see Section 4.3 Contraindications).

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.

4.9 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, hyprolose, carmellose calcium and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, 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 the original package.

6.5 Nature and Contents of Container

Pioglitazone Sandoz tablets are available in Al/Al blister packs of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes