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PIOGLITAZONE ZENTIVA 15MG TABLETS

Active substance(s): PIOGLITAZONE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Pioglitazone Zentiva 15mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 16.54mg of pioglitazone hydrochloride, equivalent to
15mg of pioglitazone.
Excipients with known effect:
Pioglitazone 15mg Tablets contains 37.76mg lactose monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
Pioglitazone 15mg tablets: round, biconvex, white tablet, diameter 5.13mm.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus
as described below:
as monotherapy
in adult patients (particularly overweight patients) inadequately controlled by
diet and exercise for whom metformin is inappropriate because of contraindications
or intolerance
as dual oral therapy in combination with
metformin, in adult patients (particularly overweight patients) with
insufficient glycaemic control despite maximal tolerated dose of monotherapy with
metformin
a sulphonylurea, only in adult patients who show intolerance to metformin or
for whom metformin is contraindicated, with insufficient glycaemic control despite
maximal tolerated dose of monotherapy with a sulphonylurea.
as triple oral therapy in combination with

metformin and a sulphonylurea, in adult patients (particularly overweight
patients) with insufficient glycaemic control despite dual oral therapy.
pioglitazone is also indicated for combination with insulin in type 2 diabetes
mellitus adult patients with insufficient glycaemic control on insulin for whom
metformin is inappropriate because of contraindications or intolerance (see section
4.4).
After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6
months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In
patients who fail to show an adequate response, pioglitazone should be discontinued.
In light of potential risks with prolonged therapy, prescribers should confirm at
subsequent routine reviews that the benefit of pioglitazone is maintained (see section
4.4).

4.2

Posology and method of administration
Posology
Pioglitazone treatment may be initiated at 15mg or 30mg once daily. The dose may
be increased in increments up to 45mg once daily.
In combination with insulin, the current insulin dose can be continued upon initiation
of pioglitazone therapy. If patients report hypoglycaemia, the dose of insulin should
be decreased.
Special population
Elderly
No dose adjustment is necessary for elderly patients (see section 5.2). Physicians
should start treatment with the lowest available dose and increase the dose gradually,
particularly when pioglitazone is used in combination with insulin (see section 4.4
‘Fluid retention and cardiac failure’).
Renal impairment
No dose adjustment is necessary in patients with impaired renal function (creatinine
clearance > 4ml/min) (see section 5.2). No information is available from dialysed
patients therefore pioglitazone should not be used in such patients.
Hepatic impairment
Pioglitazone should not be used in patients with hepatic impairment (see section 4.3
and 4.4).
Paediatric population
The safety and efficacy of pioglitazone in children and adolescents under 18 years of
age have not been established. No data are available.

Method of administration

Pioglitazone tablets are taken orally once daily with or without food. Tablets should
be swallowed with a glass of water.

4.3

Contraindications
-

4.4

Pioglitazone is contraindicated in patients with:
hypersensitivity to the active substance or to any of the excipients listed in section 6.1
cardiac failure or history of cardiac failure (NYHA stages I to IV)
hepatic impairment
diabetic ketoacidosis
current bladder cancer or a history of bladder cancer,
uninvestigated macroscopic haematuria.

Special warnings and precautions for use
Fluid retention and cardiac failure
Pioglitazone can cause fluid retention, which may exacerbate or precipitate
heart failure. When treating patients who have at least one risk factor for
development of congestive heart failure (e.g. prior myocardial infarction or
symptomatic coronary artery disease or the elderly), physicians should start
with the lowest available dose and increase the dose gradually. Patients should
be observed for signs and symptoms of heart failure, weight gain or oedema,
particularly those with reduced cardiac reserve. There have been postmarketing cases of cardiac failure reported when pioglitazone was used in
combination with insulin or in patients with a history of cardiac failure.
Patients should be observed for signs and symptoms of heart failure, weight
gain and oedema when pioglitazone is used in combination with insulin. Since
insulin and pioglitazone are both associated with fluid retention, concomitant
administration may increase the risk of oedema. 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. Pioglitazone should be discontinued if
any deterioration in cardiac status occurs.
A cardiovascular outcome study of pioglitazone has been performed in
patients under 75 years with type 2 diabetes mellitus and pre-existing major
macrovascular disease. Pioglitazone or placebo was added to existing
antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed
an increase in reports of heart failure, however this did not lead to an increase
in mortality in this study.
Elderly
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.

Bladder Cancer
Cases of bladder cancer were reported more frequently in a meta-analysis of
controlled clinical trials with pioglitazone (19 cases from 12506 patients,
0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR = 2.64
(95% CI 1.11 – 6.31, P = 0.029). After excluding patients in whom exposure to
study drug was less than one year at the time of diagnosis of bladder cancer,
there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control
groups. 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.
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.

Monitoring of liver function
There have been rare reports of hepatocellular dysfunction during postmarketing experience (see section 4.8). 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 with pioglitazone should not be
initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 X
upper limit of normal) or with any other evidence of liver disease.
Following initiation of therapy with pioglitazone, it is recommended that liver
enzymes be monitored periodically based on clinical judgement. If ALT levels
are increased to 3 X upper limit of normal during pioglitazone therapy, liver
enzyme levels should be reassessed as soon as possible. If ALT levels remain
> 3 X the upper limit of normal, therapy should be discontinued. If any patient
develops symptoms suggesting hepatic dysfunction, which may include
unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark
urine, liver enzymes should be checked. The decision whether to continue the
patient on therapy with pioglitazone should be guided by clinical judgement
pending laboratory evaluations. If jaundice is observed, the medicinal product
should be discontinued.
Weight gain
In clinical trials with pioglitazone there was evidence of dose related weight
gain, which may be due to fat accumulation and in some cases associated with
fluid retention. 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.
Haematology
There was a small reduction in mean haemoglobin (4% relative reduction) and
haematocrit (4.1% relative reduction) during therapy with pioglitazone,
consistent with haemodilution. Similar changes were seen in metformin
(haemoglobin 3 - 4% and haematocrit 3.6 – 4.1% relative reductions) and to a
lesser extent sulphonylurea and insulin (haemoglobin 1 – 2% and haematocrit
1 – 3.2% relative reductions) treated patients in comparative controlled trials
with pioglitazone.
Hypoglycaemia
As a consequence of increased insulin sensitivity, patients receiving
pioglitazone in dual oral therapy with a sulphonylurea or in dual therapy with
insulin may be at risk for dose-related hypoglycaemia, and a reduction in the
dose of the sulphonylurea or insulin may be necessary.
Eye disorders
Post-marketing reports of new-onset or worsening diabetic macular oedema
with decreased visual acuity have been reported with thiazolidinediones,
including pioglitazone. Many of these patients reported concurrent peripheral
oedema. It is unclear whether or not there is a direct association between
pioglitazone and macular oedema but prescribers should be alert to the
possibility of macular oedema if patients report disturbances in visual acuity;
an appropriate ophthalmological referral should be considered.
Others
An increased incidence in bone fractures in women was seen in a pooled
analysis of adverse reactions of bone fracture from randomised, controlled,
double blind clinical trials in over 8100 pioglitazone and 7400 comparator
treated patients, on treatment for up to 3.5 years.
Fractures were observed in 2.6% of women taking pioglitazone compared to
1.7% of women treated with a comparator. No increase in fracture rates was
observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
The fracture incidence calculated was 1.9 fractures per 100 patient years in
women treated with pioglitazone and 1.1 fractures per 100 patient years in
women treated with a comparator. The observed excess risk of fractures for
women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient
years of use.
In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0
fractures per 100 patient years) of pioglitazone-treated female patients
experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient
years) of female patients treated with comparator. No increase in fracture rates

was observed in men treated with pioglitazone (1.7%) versus comparator
(2.1%).
Some epidemiological studies have suggested a similarly increased risk of
fracture in both men and women.
The risk of fractures should be considered in the long term care of patients
treated with pioglitazone.
As a consequence of enhancing insulin action, pioglitazone treatment in
patients with polycystic ovarian syndrome may result in resumption of
ovulation. These patients may be at risk of pregnancy. Patients should be
aware of the risk of pregnancy and if a patient wishes to become pregnant or if
pregnancy occurs, the treatment should be discontinued (see section 4.6).
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 posology or changes in diabetic treatment
should be considered (see section 4.5).
Pioglitazone contains

lactose monohydrate. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
Interaction studies have shown that pioglitazone has no relevant effect on
either the pharmacokinetics or pharmacodynamics of digoxin, warfarin,
phenprocoumon and metformin. Co-administration of pioglitazone with
sulphonylureas does not appear to affect the pharmacokinetics of the
sulphonylurea. Studies in man suggest no induction of the main inducible
cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no
inhibition of any subtype of cytochrome P450. Interactions with substances
metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium
channel blockers, and HMGCoA reductase inhibitors are not to be expected.
Co-administration of pioglitazone with gemfibrozil (an inhibitor of
cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of
pioglitazone. Since there is a potential for an increase in dose-related adverse
events, a decrease in the dose of pioglitazone may be needed when gemfibrozil
is concomitantly administered. Close monitoring of glycaemic control should
be considered (see section 4.4). Co-administration of pioglitazone with
rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54%
decrease in AUC of pioglitazone. The pioglitazone dose may need to be
increased when rifampicin is concomitantly administered. Close monitoring of
glycaemic control should be considered (see section 4.4).

4.6

Fertility, Pregnancy and Lactation'
Pregnancy
There are no adequate human data to determine the safety of pioglitazone
during pregnancy. Foetal growth restriction was apparent in animal studies
with pioglitazone. This was attributable to the action of pioglitazone in
diminishing the maternal hyperinsulinaemia and increased insulin resistance
that occurs during pregnancy thereby reducing the availability of metabolic
substrates for foetal growth. The relevance of such a mechanism in humans is
unclear and pioglitazone should not be used in pregnancy.
Breastfeeding
Pioglitazone has been shown to be present in the milk of lactating rats. It is not
known whether pioglitazone is secreted in human milk. Therefore,
pioglitazone should not be administered to breast-feeding women.
Fertility
In animal fertility studies there was no effect on copulation, impregnation or
fertility index.

4.7

Effects on ability to drive and use machines
Pioglitazone has no or negligible effect on the ability to drive and use
machines. However patients who experience visual disturbance should be
cautious when driving or using machines.

4.8

Undesirable effects
Tabulated list of adverse reactions
Adverse reactions reported in excess (> 0.5%) of placebo and as more than an
isolated case in patients receiving pioglitazone in double-blind studies are
listed below as MedDRA preferred term by system organ class and absolute
frequency. Frequencies are defined as: very common (≥1/10); common (≥
1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to <
1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the
available data). Within each system organ class, adverse reactions are
presented in order of decreasing incidence followed by decreasing seriousness.

Adverse
reaction

Frequency of adverse reactions of pioglitazone by treatment
regimen
Combination

Monotherapy

with
metformin

with
insulin

with
sulphonylurea

with
metformin
and sulphonylurea

common

common

common

uncommon

uncommon

common
uncommon

not known

not known

not known

uncommon

very
common

common

Infections and infestations
upper respiratory
common
common
tract infection
bronchitis
sinusitis
uncommon uncommon
Blood and lymphatic system disorders
anaemia
common
Immune system
disorders
Hypersensitivity
and allergic
not known not known
reaction1
Metabolism and nutrition disorders
hypo-glycaemia

appetite
uncommon
increased
Nervous system disorders
hypo-aesthesia
common
common
common
common
common
headache
common
uncommon
dizziness
common
insomnia
uncommon uncommon uncommon uncommon uncommon
Eye disorders
visual
common
common
uncommon
disturbance2
macular oedema3 not known not known not known
not known
not known
Ear and labyrinth disorders
vertigo
uncommon
Cardiac disorders
heart failure4
common
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Bladder cancer uncommon uncommon uncommon uncommon uncommon
Respiratory, thoracic and mediastinal disorders
dyspnoea
common
Gastrointestinal
disorders
flatulence
uncommon
common
Skin and subcutaneous tissue disorders
sweating
uncommon
Musculoskeletal and connective tissue disorders
fracture bone5
common
common
common
common
common
arthralgia
common
common
common

Adverse
reaction

Frequency of adverse reactions of pioglitazone by treatment
regimen
Combination
Monowith
with
with
therapy
insulin
with
metformin
sulphometformin
and sulphonylurea
nylurea
back pain
common
Renal and urinary disorders
haematuria
common
glycosuria
uncommon
proteinuria
uncommon
Reproductive system and breast disorders
erectile
common
dysfunction
General disorders and administration site conditions
very
oedema
common
fatigue
uncommon
Investigations
weight
common
common
common
common
common
increased6
blood creatine
common
phospho-kinase
increased
increased lactic
uncommon
dehydro-genase
Alanine
not known
not known not known
not known
not known
aminotransferase
increased 7
Description of selected adverse reactions
1

Postmarketing reports of hypersensitivity reactions in patients treated with
pioglitazone have been reported. These reactions include anaphylaxis,
angioedema, and urticarial.

2

Visual disturbance has been reported mainly early in treatment and is related
to changes in blood glucose due to temporary alteration in the turgidity and
refractive index of the lens as seen with other hypoglycaemic treatments.
3

Oedema was reported in 6–9% of patients treated with pioglitazone over one
year in controlled clinical trials. The oedema rates for comparator groups
(sulphonylurea, metformin) were 2–5%. The reports of oedema were generally
mild to moderate and usually did not require discontinuation of treatment.

4

In controlled clinical trials the incidence of reports of heart failure with
pioglitazone treatment was the same as in placebo, metformin and
sulphonylurea treatment groups, but was increased when used in combination
therapy with insulin. In an outcome study of patients with pre-existing major

macrovascular disease, the incidence of serious heart failure was 1.6% higher
with pioglitazone than with placebo, when added to therapy that included
insulin. However, this did not lead to an increase in mortality in this study. In
this study in patients receiving pioglitazone and insulin, a higher percentage of
patients with heart failure was observed in patients aged ≥65 years compared
with those less than 65 years (9.7% compared to 4.0%). In patients on insulin
with no pioglitazone the incidence of heart failure was 8.2% in those ≥65
years compared to 4.0% in patients less than 65 years. Heart failure has been
reported with marketing use of pioglitazone, and more frequently when
pioglitazone was used in combination with insulin or in patients with a history
of cardiac failure.
5

A pooled analysis was conducted of adverse reactions of bone fractures from
randomised, comparator controlled, double blind clinical trials in over 8100
patients in the pioglitazone-treated groups and 7400 in the comparator-treated
groups of up to 3.5 years duration. A higher rate of fractures was observed in
women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in
fracture rates was observed in men treated with pioglitazone (1.3%) versus
comparator (1.5%). 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%).
6

In active comparator controlled trials mean weight increase with pioglitazone
given as monotherapy was 2–3kg over one year. This is similar to that seen in
a sulphonylurea active comparator group. In combination trials pioglitazone
added to metformin resulted in mean weight increase over one year of 1.5kg
and added to a sulphonylurea of 2.8kg. In comparator groups addition of
sulphonylurea to metformin resulted in a mean weight gain of 1.3kg and
addition of metformin to a sulphonylurea a mean weight loss of 1.0kg.

7

In clinical trials with pioglitazone the incidence of elevations of ALT greater
than three times the upper limit of normal was equal to placebo but less than
that seen in metformin or sulphonylurea comparator groups. Mean levels of
liver enzymes decreased with treatment with pioglitazone. Rare cases of
elevated liver enzymes and hepatocellular dysfunction have occurred in postmarketing experience. Although in very rare cases fatal outcome has been
reported, causal relationship has not been established.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 reaction via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.

4.9

Overdose
In clinical studies, patients have taken pioglitazone at higher than the

recommended highest dose of 45mg daily. The maximum reported dose of
120mg/day for four days, then 180mg/day for seven days was not associated
with any symptoms.
Hypoglycaemia may occur in combination with sulphonylureas or insulin.
Symptomatic and general supportive measures should be taken in case of
overdose.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering
drugs, excl. insulins;
ATC code: A10 BG 03.
Pioglitazone effects may be mediated by a reduction of insulin resistance.
Pioglitazone appears to act via activation of specific nuclear receptors
(peroxisome proliferator activated receptor gamma) leading to increased
insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment
with pioglitazone has been shown to reduce hepatic glucose output and to
increase peripheral glucose disposal in the case of insulin resistance.
Fasting and postprandial glycaemic control is improved in patients with type 2
diabetes mellitus. The improved glycaemic control is associated with a
reduction in both fasting and postprandial plasma insulin concentrations. A
clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to
two years in order to assess time to treatment failure (defined as appearance of
HbA1c ≥ 8.0% after the first six months of therapy). Kaplan-Meier analysis
showed shorter time to treatment failure in patients treated with gliclazide,
compared with pioglitazone. At two years, glycaemic control (defined as
HbA1c < 8.0%) was sustained in 69 % of patients treated with pioglitazone,
compared with 50% of patients on gliclazide. In a two-year study of
combination therapy comparing pioglitazone with gliclazide when added to
metformin, glycaemic control measured as mean change from baseline in
HbA1c was similar between treatment groups after one year. The rate of
deterioration of HbA1c during the second year was less with pioglitazone than
with gliclazide.
In a placebo controlled trial, patients with inadequate glycaemic control
despite a three month insulin optimisation period were randomised to
pioglitazone or placebo for 12 months. Patients receiving pioglitazone had a
mean reduction in HbA1c of 0.45 % compared with those continuing on
insulin alone, and a reduction of insulin dose in the pioglitazone treated group.
HOMA analysis shows that pioglitazone improves beta cell function as well as
increasing insulin sensitivity. Two-year clinical studies have shown

maintenance of this effect.
In one year clinical trials, pioglitazone consistently gave a statistically
significant reduction in the albumin/creatinine ratio compared to baseline.
The effect of pioglitazone (45mg monotherapy vs. placebo) was studied in a
small 18-week trial in type 2 diabetics. Pioglitazone was associated with
significant weight gain. Visceral fat was significantly decreased, while there
was an increase in extra-abdominal fat mass. Similar changes in body fat
distribution on pioglitazone have been accompanied by an improvement in
insulin sensitivity. In most clinical trials, reduced total plasma triglycerides
and free fatty acids, and increased HDL-cholesterol levels were observed as
compared to placebo, with small, but not clinically significant increases in
LDL-cholesterol levels.
In clinical trials of up to two years duration, pioglitazone reduced total plasma
triglycerides and free fatty acids, and increased HDL cholesterol levels,
compared with placebo, metformin or gliclazide. Pioglitazone did not cause
statistically significant increases in LDL cholesterol levels compared with
placebo, whilst reductions were observed with metformin and gliclazide. In a
20-week study, as well as reducing fasting triglycerides, pioglitazone reduced
post prandial hypertriglyceridaemia through an effect on both absorbed and
hepatically synthesised triglycerides. These effects were independent of
pioglitazone’s effects on glycaemia and were statistically significant different
to glibenclamide.
In PROactive, a cardiovascular outcome study, 5238 patients with type 2
diabetes mellitus and preexisting major macrovascular disease were
randomised to pioglitazone or placebo in addition to existing antidiabetic and
cardiovascular therapy, for up to 3.5 years. The study population had an
average age of 62 years; the average duration of diabetes was 9.5 years.
Approximately one third of patients were receiving insulin in combination
with metformin and/or a sulphonylurea. To be eligible patients had to have had
one or more of the following: myocardial infarction, stroke, percutaneous
cardiac intervention or coronary artery bypass graft, acute coronary syndrome,
coronary artery disease, or peripheral arterial obstructive disease. Almost half
of the patients had a previous myocardial infarction and approximately 20%
had had a stroke. Approximately half of the study population had at least two
of the cardiovascular history entry criteria. Almost all subjects (95%) were
receiving cardiovascular medicinal products (beta blockers, ACE inhibitors,
angiotensin II antagonists, calcium channel blockers, nitrates, diuretics,
aspirin, statins, fibrates).
Although the study failed regarding its primary endpoint, which was a
composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute
coronary syndrome, major leg amputation, coronary revascularisation and leg
revascularisation, the results suggest that there are no long-term cardiovascular
concerns regarding use of pioglitazone. However, the incidences of oedema,
weight gain and heart failure were increased. No increase in mortality from
heart failure was observed.

Paediatric population
The European Medicines Agency has waived the obligation to submit the
results of studies with pioglitazone in all subsets of the paediatric population
in Type 2 Diabetes Mellitus. See section 4.2 for information on paediatric use.

5.2

Pharmacokinetic properties
Absorption
Following oral administration, pioglitazone is rapidly absorbed, and peak
plasma concentrations of unchanged pioglitazone are usually achieved 2 hours
after administration. Proportional increases of the plasma concentration were
observed for doses from 2 – 60mg. Steady state is achieved after 4 – 7 days of
dosing. Repeated dosing does not result in accumulation of the compound or
metabolites. Absorption is not influenced by food intake. Absolute
bioavailability is greater than 80 %.
Distribution
The estimated volume of distribution in humans is 0.25l/kg.
Pioglitazone and all active metabolites are extensively bound to plasma
protein (> 99%).
Biotransformation
Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of
aliphatic methylene groups. This is predominantly via cytochrome P450 2C8
although other isoforms may be involved to a lesser degree. Three of the six
identified metabolites are active (M-II, M-III, and M-IV). When activity,
concentrations and protein binding are taken into account, pioglitazone and
metabolite M-III contribute equally to efficacy. On this basis M-IV
contribution to efficacy is approximately three-fold that of pioglitazone, whilst
the relative efficacy of M-II is minimal.
In vitro studies have shown no evidence that pioglitazone inhibits any subtype
of cytochrome P450. There is no induction of the main inducible P450
isoenzymes 1A, 2C8/9, and 3A4 in man.
Interaction studies have shown that pioglitazone has no relevant effect on
either the pharmacokinetics or pharmacodynamics of digoxin, warfarin,
phenprocoumon and metformin. Concomitant administration of pioglitazone
with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with rifampicin (an
inducer of cytochrome P450 2C8) is reported to increase or decrease,
respectively, the plasma concentration of pioglitazone (see section 4.5).
Elimination

Following oral administration of radiolabelled pioglitazone to man, recovered
label was mainly in faeces (55%) and a lesser amount in urine (45%). In
animals, only a small amount of unchanged pioglitazone can be detected in
either urine or faeces. The mean plasma elimination half-life of unchanged
pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23
hours.
Elderly
Steady state pharmacokinetics are similar in patients age 65 and over and
young subjects.
Patients with renal impairment
In patients with renal impairment, plasma concentrations of pioglitazone and
its metabolites are lower than those seen in subjects with normal renal
function, but oral clearance of parent substance is similar. Thus free (unbound)
pioglitazone concentration is unchanged.
Patients with hepatic impairment
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.

5.3

Preclinical safety data
In toxicology studies, plasma volume expansion with haemodilution, anaemia,
and reversible eccentric cardiac hypertrophy was consistently apparent after
repeated dosing of mice, rats, dogs, and monkeys. In addition, increased fatty
deposition and infiltration were observed. These findings were observed
across species at plasma concentrations ≤ 4 times the clinical exposure. Foetal
growth restriction was apparent in animal studies with pioglitazone. This was
attributable to the action of pioglitazone in diminishing the maternal
hyperinsulinaemia and increased insulin resistance that occurs during
pregnancy thereby reducing the availability of metabolic substrates for foetal
growth.
Pioglitazone was devoid of genotoxic potential in a comprehensive battery of
in vivo and in vitro genotoxicity assays. An increased incidence of hyperplasia
(males and females) and tumours (males) of the urinary bladder epithelium
was apparent in rats treated with pioglitazone for up to 2 years.
The formation and presence of urinary calculi with subsequent irritation and
hyperplasia was postulated as the mechanistic basis for the observed
tumourigenic response in the male rat. A 24-month mechanistic study in male
rats demonstrated that administration of pioglitazone resulted in an increased
incidence of hyperplastic changes in the bladder. Dietary acidification
significantly decreased but did not abolish the incidence of tumours. The

presence of microcrystals exacerbated the hyperplastic response but was not
considered to be the primary cause of hyperplastic changes. The relevance to
humans of the tumourigenic findings in the male rat cannot be excluded.
There was no tumorigenic response in mice of either sex. Hyperplasia of the
urinary bladder was not seen in dogs or monkeys treated with pioglitazone for
up to 12 months.
In an animal model of familial adenomatous polyposis (FAP), treatment with
two other thiazolidinediones increased tumour multiplicity in the colon. The
relevance of this finding is unknown.
Environmental Risk Assessment: no environmental impact is anticipated from
the clinical use of pioglitazone.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate
Croscarmellose sodium
Hydroxypropylcellulose
Low substituted hydroxypropyl cellulose (LH-11)
Magnesium stearate

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years

6.4

Special precautions for storage
Store below 25°C in its original package in order to protect from moisture.

6.5

Nature and contents of container
OPA/Al/PVC//Al blisters, packs of 14, 28, 30, 50, 56, 60, 84, 90, 98, 100, 112,
120 and 196 tablets. Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Winthrop Pharmaceuticals UK Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
United Kingdom
Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS

8

MARKETING AUTHORISATION NUMBER(S)
PL 17780/0549

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/01/2012

10

DATE OF REVISION OF THE TEXT
10/11/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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