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PIOGLITAZONE SPECIFAR 15 MG TABLETS

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Pioglitazone Specifar 15 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15 mg of pioglitazone (as hydrochloride).
Excipients: Each tablet contains 36,866 mg of lactose monohydrate (see section 4.4).
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
Pioglitazone Specifar 15 mg tablets are white, round, flat tablets, with “15” embossed
on one side and a diameter of approximately 5.5 mm.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Pioglitazone is indicated in the treatment of type 2 diabetes mellitus:


in adult patients (particularly overweight patients) inadequately controlled by diet and
exercise for whom metformin is inappropriate because of contraindications or
intolerance
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 15 mg or 30 mg once daily. The dose may
be increased in increments up to 45 mg 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 > 4 ml/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
Pioglitazone is contraindicated in patients with:


hypersensitivity to the active substance or to any of the excipients



cardiac failure or history of cardiac failure (NYHA stages I to IV)



hepatic impairment




current bladder cancer or a history of bladder cancer



4.4

diabetic ketoacidosis

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 post-marketing 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. 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 post-marketing
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 or triple 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%).
The risk of fractures should be considered in the long term care of women 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 Specifar tablets contain lactose monohydrate and therefore should not be
administered to patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose- galactose malabsorption.

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). Coadministration 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 data from the use of pioglitazone in pregnant women. Studies
in animals have shown reproductive toxicity (see section 5.3). The potential risk for
humans is unknown thus 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 breastfeeding 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 Specifar 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

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
frequency grouping, adverse reactions are presented in order of decreasing incidence
and seriousness.









Adverse reaction

Frequency of adverse reactions of pioglitazone by treatment regimen
Combination
Monotherapy

Infections and
infestations
upper respiratory
tract infection
bronchitis
sinusitis
Blood and
lymphatic system
disorders
anaemia
Metabolism and
nutrition
disorders
hypo-glycaemia
appetite increased
Nervous system
disorders
hypo-aesthesia
headache
dizziness
insomnia
Eye disorders
visual disturbance1
macular oedema2
Ear and labyrinth
disorders
vertigo
Cardiac disorders
heart failure3
Neoplasms
benign, malignant
and unspecified
(including cysts
and polyps)
bladder cancer

with
metformin

with sulphonylurea

with
metformin
and sulphonylurea

with insulin

common

common

common

common

common

uncommon

uncommon

uncommon

uncommon

common
uncommon

uncommon
uncommon

very common

common

common

common

uncommon

uncommon

not known

not known

common

common

common
common

uncommon

uncommon

common
uncommon
common
uncommon

common
not known

common
not known

uncommon
not known

uncommon
common

uncommon

uncommon

uncommon

uncommon

uncommon

Adverse reaction

Frequency of adverse reactions of pioglitazone by treatment regimen
Combination
Monotherapy

Respiratory,
thoracic and
mediastinal
disorders
dyspnoea
Gastrointestinal
disorders
flatulence
Skin and
subcutaneous
tissue disorders
sweating
Musculoskeletal
and connective
tissue disorders
fracture bone4
arthralgia
back pain
Renal and urinary
disorders
haematuria
glycosuria
proteinuria
Reproductive
system and breast
disorders
erectile dysfunction
General disorders
and
administration
site conditions
oedema
fatigue
Investigations
weight increased5
blood creatine
phospho-kinase
increased
increased lactic
dehydro-genase
Alanine
aminotransferase
increased 6

with
metformin

with sulphonylurea

with
metformin
and sulphonylurea

with insulin

common

uncommon

common

uncommon

common

common
common

common

common
common

common
common
common

common
uncommon
uncommon

common

very common
uncommon
common

common

common

common
common

common

not known

not known

uncommon
not known

not known

not known

1

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.

2

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.
3

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. Heart failure has been reported rarely with marketing use of
pioglitazone, but more frequently when pioglitazone was used in combination with
insulin or in patients with a history of cardiac failure.
4

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%).

5

In active comparator controlled trials mean weight increase with pioglitazone given
as monotherapy was 2–3 kg 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 1.5 kg and added to a
sulphonylurea of 2.8 kg. In comparator groups addition of sulphonylurea to
metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a
sulphonylurea a mean weight loss of 1.0 kg.
6

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 post-marketing experience. Although in
very rare cases fatal outcome has been reported, causal relationship has not been
established.

4.9

Overdose
In clinical studies, patients have taken pioglitazone at higher than the recommended
highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four
days, then 180 mg/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; Thiazolidinediones; 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 HbA 1c 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 (45 mg 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 extraabdominal 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 pre-existing 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 – 60 mg. 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 0.25 l/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.

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. The relevance of such mechanism in humans is unclear
(see section 4.6).



5.3

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
Carmellose calcium
Hydroxypropylcellulose
Magnesium stearate

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions

6.5

Nature and contents of container
PA/Aluminium/PVC/Aluminium blisters, packs of 14, 28, 30, 50, 56, 90 and 98
tablets.
Not all pack sizes may be marketed

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Specifar S.A.
1,28 Octovriou str.
123 51 Ag. Varvara
Athens- Greece

8

MARKETING AUTHORISATION NUMBER(S)
PL 20354/0154

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/10/2011

10

DATE OF REVISION OF THE TEXT
26/10/2011

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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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