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Paglitaz (pioglitazone hydrochloride) – Summary of product characteristics - A10BG03

Updated on site: 09-Oct-2017

Medication namePaglitaz
ATC CodeA10BG03
Substancepioglitazone hydrochloride
ManufacturerKrka, d.d., Novo mesto

1. NAME OF THE MEDICINAL PRODUCT

Paglitaz 15 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 15 mg of pioglitazone (as hydrochloride).
Excipient with known effect:
Each tablet contains 88.83 mg of lactose (see section 4.4). For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

4.

CLINICAL PARTICULARS

 

authorised

 

 

4.1

Therapeutic indications

 

 

Pioglitazone is indicated as second or third line in the treatment of type 2 diabetes mellitus as

described below:

no

longer

 

as monotherapy

 

-

in adult patients (particularly overweight patients) inadequately controlled by diet and exercise

as dual oral therapy in combinationproductwith

 

 

White to almost white round tablets with bevelled edges and with engraved "15" n one side of tablet (diameter 7.0 mm).

for whom metformin is inappropriate because of contraindications or intolerance;

-metformin, in adult patients ( articularly overweight patients) with insufficient glycaemic

control despite maxim tolerated dose of monotherapy with metformin;

-a sulphonylurea, o ly in adult patients who show intolerance to metformin or for whom

metforminMedicinalis ontra ndicated, 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 in 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).

4.2Posology 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

Older people

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).

Patients with renal impairment

authorised

 

No dose adjustment is necessary in patients with impaired renal function (creat n ne clearance

> 4 ml/min) (see section 5.2). No information is available from dialysed patients therefore pioglitazone should not be used in such patients.

Patients with hepatic impairment

Pioglitazone should not be used in patients with hepatic impairm nt (see section 4.3 and 4.4).

Paediatric population

 

 

longer

 

 

 

The safety and efficacy of pioglitazone in children and adolescents under 18 years of age have not

been established. No data are available.

no

 

Method of administration

product

 

 

 

 

 

 

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

-hypersensitivityMedicinalto 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.

4.4 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.

Bladder Cancer

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. 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.

Older people authorised

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 rea ment in the elderly.

Cases of bladder cancer were reported more frequentlylongerin a m ta-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 f 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 ca cer in diabetic patients treated with pioglitazone in

product

particular in patients treated for the longest dura noions and with the highest cumulative doses. A

possible risk after short term treatment cannot be excluded.

Risk factors for bladder cancer sh

uld be assessed before initiating pioglitazone treatment (risks

include age, smoking history, ex

osu e to some occupational or chemotherapy agents

e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigatedMedicinalbefore starting pioglitazone therapy.

Patients should be adv sed 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 times the 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 times the upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 times 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

As a consequence of increased insulin sensitivity, patients receiving pioglitazoneauthorisedin dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be t risk for dose-related

lesser extent sulphonylurea and insulin (haemoglobin 1 – 2% and haematocrit 1 – 3.2% relative reductions) treated patients in comparative controlled trials with pioglitazone.

Hypoglycaemia

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

longer

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 prescribersno

should be alert to the possibility of macular

product

 

oedema if patients report disturbances in vis al acuity; an appropriate ophthalmological referral should be considered.

Others

7400 comparator treated patients, on treatment for up to 3.5 years.

An increasedMedicinalincidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from ra domised, controlled, double blind clinical trials in over 8100 pioglitazone and

Fractures were obs rved 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).

Paglitaz 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

or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of

Interaction studies have shown that pioglitazone has no relevant effectauthorisedon either the pharmacokinetics blockers, and HMGCoA reductase inhibitors are not to be expected.

pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics f 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

Co-administration of pioglitazone with gemfibrozil (anlongerinhibitor 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 pi glitazone 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

 

 

product

Close monitoring of glycaemic control

increased when rifampicin is concomitantly administered.no

should be considered (see section 4.4).

 

4.6 Fertility, pregnancy and lactati n

 

Pregnancy

Medicinal

 

 

 

 

 

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 m nishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pr gnancy 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.

Breast-feeding

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.

4.7Effects on ability to drive and use machines

Pioglitazone has no or negligible influence 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)

 

 

 

 

 

 

 

 

 

authorised

Within each frequency grouping, adverse reactions are presented in order of decreasing incidence and

seriousness.

 

 

 

 

 

 

 

 

 

 

Tabulated list of adverse reactions

 

 

 

 

 

 

 

 

 

Adverse

Frequency of adverse reactions of pioglitazone by reatment regimen

 

 

reaction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Combin tion

 

 

 

 

Mono-

with

 

 

longer

 

with

with insulin

 

 

 

 

 

with

 

 

 

 

therapy

metformin

 

sulpho-

 

metformin

 

 

 

 

 

 

 

 

 

nylurea

 

and sulpho-

 

 

 

 

 

 

 

 

 

 

 

nylurea

 

 

 

Infections and

 

 

 

no

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

infestations

 

 

 

 

 

 

 

 

 

 

 

lymphatic

 

product

 

 

common

 

common

common

 

 

upper respiratory

common

common

 

 

 

 

 

tract infection

 

 

 

 

 

 

 

 

 

 

 

bronchitis

 

 

 

 

 

 

 

 

common

 

 

sinusitis

uncommon

uncommon

 

uncommon

 

uncommon

uncommon

 

 

Blood and

 

 

 

 

 

 

 

 

 

 

 

reactions1 Medicinal

 

 

 

 

 

 

 

 

 

 

system disorders

 

 

 

 

 

 

 

 

 

 

 

anaemia

 

 

common

 

 

 

 

 

 

 

 

Immune System

 

 

 

 

 

 

 

 

 

 

 

Disorders

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity

not known

not known

 

not known

 

not known

not known

 

 

and allergic

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Metabolism and

 

 

 

 

 

 

 

 

 

 

 

nutrition

 

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

hypo-glycaemia

 

 

 

 

 

uncommon

 

very

common

 

 

 

 

 

 

 

 

 

 

common

 

 

 

appetite increased

 

 

 

 

 

uncommon

 

 

 

 

 

Nervous system

 

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

hypo-aesthesia

common

common

 

 

common

 

common

common

 

 

headache

 

 

common

 

 

uncommon

 

 

 

 

 

dizziness

 

 

 

 

 

common

 

 

 

 

 

insomnia

uncommon

uncommon

 

uncommon

 

uncommon

uncommon

 

 

Eye disorders

 

 

 

 

 

 

 

 

 

 

Adverse

Frequency of adverse reactions of pioglitazone by treatment regimen

reaction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Combination

 

 

 

Mono-

with

 

 

with

 

with

with insulin

 

 

therapy

metformin

 

sulpho-

 

metformin

 

 

 

 

 

 

 

 

nylurea

 

and sulpho-

 

 

 

 

 

 

 

 

 

 

nylurea

 

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

 

 

 

 

 

 

 

authorised

benign,

 

 

 

 

 

 

 

 

malignant and

 

 

 

 

 

 

 

unspecified

 

 

 

 

 

 

 

(including cysts

 

 

 

 

 

 

 

and polyps)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

bladder cancer

uncommon

uncommon

 

uncommon

 

uncommon

uncommon

Respiratory,

 

 

 

 

 

longer

 

 

thoracic and

 

 

 

 

 

 

 

mediastinal

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

dyspnoea

 

 

 

 

no

 

 

 

common

Gastrointestinal

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

flatulence

 

 

 

uncommon

 

common

 

 

 

Skin and

 

 

product

 

 

 

 

 

 

subcutaneous

 

 

 

 

 

 

 

tissue disorders

 

 

 

 

 

 

 

sweating

 

 

 

 

 

 

uncommon

 

 

 

Musculoskeletal

 

 

 

 

 

 

 

 

 

and connective

 

 

 

 

 

 

 

 

 

tissue disord rs

 

 

 

 

 

 

 

 

 

fracture bone5

common

common

 

 

common

 

common

common

arthralgia

Medicinal

 

common

 

 

 

 

common

common

back pain

 

 

 

 

 

 

 

 

 

common

Renal and

 

 

 

 

 

 

 

 

 

urinary

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

haematuria

 

 

common

 

 

 

 

 

 

glycosuria

 

 

 

 

 

uncommon

 

 

 

proteinuria

 

 

 

 

 

uncommon

 

 

 

Reproductive

 

 

 

 

 

 

 

 

 

system and

 

 

 

 

 

 

 

 

 

breast disorders

 

 

 

 

 

 

 

 

 

erectile

 

 

 

common

 

 

 

 

 

 

dysfunction

 

 

 

 

 

 

 

 

 

General

 

 

 

 

 

 

 

 

 

 

disorders and

 

 

 

 

 

 

 

 

 

Adverse reaction

Frequency of adverse reactions of pioglitazone by treatment regimen

 

 

 

 

Combination

 

 

 

Mono-

with

with

with

with insulin

 

 

therapy

metformin

sulpho-

metformin

 

 

 

 

 

nylurea

and sulpho-

 

 

 

 

 

 

nylurea

 

 

administration

 

 

 

 

 

 

site conditions

 

 

 

 

 

 

oedema

 

 

 

 

very

 

 

 

 

 

 

common

 

fatigue

 

 

uncommon

 

 

 

Investigations

 

 

 

 

 

 

weight increased6

common

common

common

common

common

 

blood creatine

 

 

 

common

 

 

phospho-kinase

 

 

 

 

 

 

increased

 

 

 

 

 

 

increased lactic

 

 

uncommon

 

 

 

dehydro-genase

 

 

 

 

 

 

Alanine

not known

not known

not known

not known

not known

 

aminotransferase

 

 

 

authorised

 

increased 7

 

 

 

Description of selected adverse reactions

 

 

 

1 Postmarketing reports of hypersensitivity reactions inlongerpatients treated with pioglitazone have been reported. These reactions include anaphylaxis, anginoedema, and urticaria.

2Visual disturbance has been reported mainly early in treatment and is related to changes in blood glucose due to temporary alterationproductin the turgidity and refractive index of the lens as seen with other hypoglycaemic treatments.

3Oedema was reported in 6 – 9% of patients treated with pioglitazone over one year in controlled

reports of oedema were genera y mild to moderate and usually did not require discontinuation of

clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2 – 5%. The

treatment.

Medicinal

 

4In 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 th rapy 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.

5A 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%).

6In 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.

7In 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.

authorised

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal pr duct 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 via the national reporting system listed in Appendix V.

4.9 Overdose

Symptoms

longer

 

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.

 

product

or insulin.

Hypoglycaemia may occur in combination wi h sulphonylureasno

Management

Symptomatic and general supportive measures should be taken in case of overdose.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynam c properties

 

Medicinal

Pharmacotherapeut c group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; ATC code: A10BG03.

Mechanism of action

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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 statisticallyauthorisedsignificant r duction 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 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.

 

 

longer

In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free

fatty acids, and increased HDL cholesterol levels, c

mpared with placebo, metformin or gliclazide.

Pioglitazone did not cause statistically significa t i

creases in LDL cholesterol levels compared with

no

 

placebo, whilst reductions were observed wi h metformin and gliclazide. In a 20-week study, as well

In PROactive, a cardiovascular productoutcome 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 c rdiovascular therapy, for up to 3.5 years. The study population had an

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.

average ageMedicinalof 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiv ng nsulin 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 interv ntion 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%).

contribute equally to efficacy. On this basis M-IV contribution to efficauthorisedcy is approximately three-fold that of pioglitazone, whilst the relative efficacy of M-II is minimal.

Biotransformation

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphat c 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

rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of pioglitazone (see section 4.5).

In vitro studies have shown no evidence that pioglitazone i hibits any subtype of cytochrome P450.

There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man.

 

 

longer

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics

or pharmacodynamics of digoxin, warfarin, phe procoumon and metformin. Concomitant

 

no

 

administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with

product

 

 

Elimination

pioglitazone can be dete ted 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.

Following oralMedicinaladministration 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

Older people

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects.

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.

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 microcry tals xacerbated the hyperplastic response but was not considered to be the primary cause of hype plast c 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.

 

 

 

 

 

authorised

In an animal model of familial adenomatous polyposis (FAP), tr atment with two other

thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is

unknown.

 

 

longer

 

 

 

 

 

 

Environmental Risk Assessment (ERA) : no envir nmental impact is anticipated from the clinical use

of pioglitazone.

 

no

 

 

 

 

 

 

 

6.

PHARMACEUTICAL PARTICULARS

 

 

6.1

List of excipients

product

 

 

 

Lactose monohydrate

 

 

 

 

 

 

 

Hydroxypropylcellulose (E463)

 

 

 

 

Croscarmellose sod um

 

 

 

 

Magnesium stearate (E572)

 

 

 

 

6.2

Incompatibilities

 

 

 

 

 

Medicinal

 

 

 

 

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister packs (OPA/Al/PVC-Al foil): 14, 28, 30, 56, 60, 90 and 98 tablets in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

14 tablets: EU/1/11/721/001

28 tablets: EU/1/11/721/002

30 tablets: EU/1/11/721/003

56 tablets: EU/1/11/721/004

60 tablets: EU/1/11/721/005

90 tablets: EU/1/11/721/006

98 tablets: EU/1/11/721/007

 

 

 

longer

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THEauthorisedAUTHORISATION

Date of first authorisation: 21 March 2012

 

 

Date of latest renewal:

 

no

 

10. DATE OF REVISION OF THE TEXT

 

 

product

 

 

Detailed information on this medicinal pro ct is available on the website of the European Medicines

Agency http://www.ema.europa.eu

 

 

Medicinal

 

 

 

1. NAME OF THE MEDICINAL PRODUCT
Paglitaz 30 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 30 mg of pioglitazone (as hydrochloride).
Excipient with known effect:
Each tablet contains 176.46 mg of lactose (see section 4.4). For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

 

 

White to almost white round tablets with bevelled edges (diameter 8.0 mm).

4.

CLINICAL PARTICULARS

 

authorised

 

 

4.1

Therapeutic indications

 

 

Pioglitazone is indicated as second or third line in the treatme t of type 2 diabetes mellitus as

described below:

longer

as monotherapy

-

in adult patients (particularly overweight patients)no

inadequately controlled by diet and exercise

as dual oral therapy in combinatiproductn with

 

 

for whom metformin is inappropriate be ause of contraindications or intolerance;

-metformin, in adult patients ( a ticularly overweight patients) with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin;

as triple oralMedicinalth rapy in combination with

-

a sulphonylurea, only in dult patients who show intolerance to metformin or for whom

metformin is contra dicated, with insufficient glycaemic control despite maximal tolerated dose of monotherapy with a sulphonylurea;

-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 in 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).

4.2Posology 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

Older people

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).

Patients with renal impairment

No dose adjustment is necessary in patients with impaired renal functionauthorised(creatin ne cl arance

> 4 ml/min) (see section 5.2). No information is available from dialysed patients therefore pioglitazone should not be used in such patients.

Patients with hepatic impairment

Pioglitazone should not be used in patients with hepatic impairment (see section 4.3 and 4.4).

Paediatric population

 

 

 

longer

 

 

 

 

The safety and efficacy of pioglitazone in children and ad lescents under 18 years of age have not

been established. No data are available.

 

no

 

Method of administration

 

 

 

Pioglitazone tablets are taken orally once

aily with or without food. Tablets should be swallowed

with a glass of water.

product

 

 

 

 

 

-hypersensitivMedicinalty 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.

4.3 Contraindications

4.4 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.

Bladder Cancer

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. 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.

Older people authorised

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 rea ment in the elderly.

Cases of bladder cancer were reported more frequentlylongerin a m ta-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 f 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 ca cer in diabetic patients treated with pioglitazone in

product

particular in patients treated for the longest dura noions and with the highest cumulative doses. A

possible risk after short term treatment cannot be excluded.

Risk factors for bladder cancer sh

uld be assessed before initiating pioglitazone treatment (risks

include age, smoking history, ex

osu e to some occupational or chemotherapy agents

e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigatedMedicinalbefore starting pioglitazone therapy.

Patients should be adv sed 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 times the 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 times the upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 times 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

As a consequence of increased insulin sensitivity, patients receiving pioglitazoneauthorisedin dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be t risk for dose-related

lesser extent sulphonylurea and insulin (haemoglobin 1 – 2% and haematocrit 1 – 3.2% relative reductions) treated patients in comparative controlled trials with pioglitazone.

Hypoglycaemia

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

longer

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 prescribersno

should be alert to the possibility of macular

product

 

oedema if patients report disturbances in vis al acuity; an appropriate ophthalmological referral should be considered.

Others

7400 comparator treated patients, on treatment for up to 3.5 years.

An increasedMedicinalincidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from ra domised, controlled, double blind clinical trials in over 8100 pioglitazone and

Fractures were obs rved 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).

Paglitaz 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

or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of

Interaction studies have shown that pioglitazone has no relevant effectauthorisedon either the pharmacokinetics blockers, and HMGCoA reductase inhibitors are not to be expected.

pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics f 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

Co-administration of pioglitazone with gemfibrozil (anlongerinhibitor 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 pi glitazone 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

 

 

product

Close monitoring of glycaemic control

increased when rifampicin is concomitantly administered.no

should be considered (see section 4.4).

 

4.6 Fertility, pregnancy and lactati n

 

Pregnancy

Medicinal

 

 

 

 

 

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 m nishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pr gnancy 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.

Breast-feeding

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.

4.7Effects on ability to drive and use machines

Pioglitazone has no or negligible influence 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)

 

 

 

 

 

 

 

 

 

authorised

Within each frequency grouping, adverse reactions are presented in order of decreasing incidence and

seriousness.

 

 

 

 

 

 

 

 

 

 

Tabulated list of adverse reactions

 

 

 

 

 

 

 

 

 

Adverse

Frequency of adverse reactions of pioglitazone by treatment regimen

 

 

reaction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Combin tion

 

 

 

 

Mono-

with

 

 

longer

 

with

with insulin

 

 

 

 

 

with

 

 

 

 

therapy

metformin

 

sulpho-

 

metformin

 

 

 

 

 

 

 

 

 

nylurea

 

and sulpho-

 

 

 

 

 

 

 

 

 

 

 

nylurea

 

 

 

Infections and

 

 

 

no

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

infestations

 

 

 

 

 

 

 

 

 

 

 

lymphatic

 

product

 

 

common

 

common

common

 

 

upper respiratory

common

common

 

 

 

 

 

tract infection

 

 

 

 

 

 

 

 

 

 

 

bronchitis

 

 

 

 

 

 

 

 

common

 

 

sinusitis

uncommon

uncommon

 

uncommon

 

uncommon

uncommon

 

 

Blood and

 

 

 

 

 

 

 

 

 

 

 

reactions1 Medicinal

 

 

 

 

 

 

 

 

 

 

system disorders

 

 

 

 

 

 

 

 

 

 

 

anaemia

 

 

common

 

 

 

 

 

 

 

 

Immune System

 

 

 

 

 

 

 

 

 

 

 

Disorders

 

 

 

 

 

 

 

 

 

 

 

Hypersensitivity

not known

not known

 

not known

 

not known

not known

 

 

and allergic

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Metabolism and

 

 

 

 

 

 

 

 

 

 

 

nutrition

 

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

hypo-glycaemia

 

 

 

 

 

uncommon

 

very

common

 

 

 

 

 

 

 

 

 

 

common

 

 

 

appetite increased

 

 

 

 

 

uncommon

 

 

 

 

 

Nervous system

 

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

hypo-aesthesia

common

common

 

 

common

 

common

common

 

 

headache

 

 

common

 

 

uncommon

 

 

 

 

 

dizziness

 

 

 

 

 

common

 

 

 

 

 

insomnia

uncommon

uncommon

 

uncommon

 

uncommon

uncommon

 

 

Eye disorders

 

 

 

 

 

 

 

 

 

 

Adverse

Frequency of adverse reactions of pioglitazone by treatment regimen

reaction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Combination

 

 

 

Mono-

with

 

 

with

 

with

with insulin

 

 

therapy

metformin

 

sulpho-

 

metformin

 

 

 

 

 

 

 

 

nylurea

 

and sulpho-

 

 

 

 

 

 

 

 

 

 

nylurea

 

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

 

 

 

 

 

 

 

authorised

benign,

 

 

 

 

 

 

 

 

malignant and

 

 

 

 

 

 

 

unspecified

 

 

 

 

 

 

 

(including cysts

 

 

 

 

 

 

 

and polyps)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

bladder cancer

uncommon

uncommon

 

uncommon

 

uncommon

uncommon

Respiratory,

 

 

 

 

 

longer

 

 

thoracic and

 

 

 

 

 

 

 

mediastinal

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

dyspnoea

 

 

 

 

no

 

 

 

common

Gastrointestinal

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

flatulence

 

 

 

uncommon

 

common

 

 

 

Skin and

 

 

product

 

 

 

 

 

 

subcutaneous

 

 

 

 

 

 

 

tissue disorders

 

 

 

 

 

 

 

sweating

 

 

 

 

 

 

uncommon

 

 

 

Musculoskeletal

 

 

 

 

 

 

 

 

 

and connective

 

 

 

 

 

 

 

 

 

tissue disord rs

 

 

 

 

 

 

 

 

 

fracture bone5

common

common

 

 

common

 

common

common

arthralgia

Medicinal

 

common

 

 

 

 

common

common

back pain

 

 

 

 

 

 

 

 

 

common

Renal and

 

 

 

 

 

 

 

 

 

urinary

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

haematuria

 

 

common

 

 

 

 

 

 

glycosuria

 

 

 

 

 

uncommon

 

 

 

proteinuria

 

 

 

 

 

uncommon

 

 

 

Reproductive

 

 

 

 

 

 

 

 

 

system and

 

 

 

 

 

 

 

 

 

breast disorders

 

 

 

 

 

 

 

 

 

erectile

 

 

 

common

 

 

 

 

 

 

dysfunction

 

 

 

 

 

 

 

 

 

General

 

 

 

 

 

 

 

 

 

 

disorders and

 

 

 

 

 

 

 

 

 

Adverse reaction

Frequency of adverse reactions of pioglitazone by treatment regimen

 

 

 

 

Combination

 

 

 

Mono-

with

with

with

with insulin

 

 

therapy

metformin

sulpho-

metformin

 

 

 

 

 

nylurea

and sulpho-

 

 

 

 

 

 

nylurea

 

 

administration

 

 

 

 

 

 

site conditions

 

 

 

 

 

 

oedema

 

 

 

 

very

 

 

 

 

 

 

common

 

fatigue

 

 

uncommon

 

 

 

Investigations

 

 

 

 

 

 

weight increased6

common

common

common

common

common

 

blood creatine

 

 

 

common

 

 

phospho-kinase

 

 

 

 

 

 

increased

 

 

 

 

 

 

increased lactic

 

 

uncommon

 

 

 

dehydro-genase

 

 

 

 

 

 

Alanine

not known

not known

not known

not known

not known

 

aminotransferase

 

 

 

authorised

 

increased 7

 

 

 

Description of selected adverse reactions

 

 

 

1 Postmarketing reports of hypersensitivity reactions inlongerpatients treated with pioglitazone have been reported. These reactions include anaphylaxis, anginoedema, and urticaria.

2Visual disturbance has been reported mainly early in treatment and is related to changes in blood glucose due to temporary alterationproductin the turgidity and refractive index of the lens as seen with other hypoglycaemic treatments.

3Oedema was reported in 6 – 9% of patients treated with pioglitazone over one year in controlled

reports of oedema were gener y mild to moderate and usually did not require discontinuation of

clinical trials. The oedema rates for comparator groups (sulphonylurea, metformin) were 2 – 5%. The

treatment.

Medicinal

 

4In 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 th rapy 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.

5A 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%).

6In 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.

7In 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.

authorised

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal pr duct 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 via the national reporting system listed in Appendix V.

4.9 Overdose

Symptoms

longer

 

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.

 

product

or insulin.

Hypoglycaemia may occur in combination wi h sulphonylureasno

Management

Symptomatic and general supportive measures should be taken in case of overdose.

5.

Medicinal

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynam properties

Pharmacotherap utic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins; ATC code: A10BG03.

Mechanism of action

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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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 thisauthorisedeffect.

In one year clinical trials, pioglitazone consistently gave a statistically significant eduction 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 g in. Visceral fat was

body fat distribution on pioglitazone have been accompaniedlongerby an improvement in insulin sensitivity. In most clinical trials, reduced total plasma triglycerides a d free fatty acids, and increased HDL-

significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in

cholesterol levels were observed as compared to placeb , with small, but not clinically significant increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, pioglitazoneno reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterolproductlevels, compared with placebo, metformin or gliclazide.

Pioglitazone did not cause statistically signifi ant 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, pi glitazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and he atically synthesised triglycerides. These effects were independent of

pioglitazone’s effects on glycaemia and were statistically significant different to glibenclamide.

In PROactive,Medicinala cardiovascu r 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 ardiovascular 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 r c iving 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.

degree. Three of the six identified metabolites are active (M-II, M-III,authorisednd M-IV). When activity, concentrations and protein binding are taken into account, pioglitazone and metabolite M-III

Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99%). Biotransformation

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of alip atic methylene groups.

This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser

contribute equally to efficacy. On this basis M-IV contribution to fficacy is approximately three-fold that of pioglitazone, whilst the relative efficacy of M-II is mi imal.

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).

In vitro studies have shown no evidence that pioglitaz ne inhibits any subtype of cytochrome P450.

 

 

longer

There is no induction of the main inducible P450 is enzymes 1A, 2C8/9, and 3A4 in man.

 

no

 

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics

or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant

product

 

 

Elimination

Medicinal

 

Following oral adm n strat on 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 etected 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.

Older people

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects. 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.

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 responseauthorisedin the male rat. A 24- month mechanistic study in male rats demonstrated that administration of piogl tazone resulted in an

increased incidence of hyperplastic changes in the bladder. Dietary acidification s gnificantly decreased but did not abolish the incidence of tumours. The presence of micr crystals exacerbated the hyperplastic response but was not considered to be the primary cause of yperplastic 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 c l

n. The relevance of this finding is

unknown.

 

longer

Environmental Risk Assessment (ERA): no environmentalno

impact is anticipated from the clinical use

of pioglitazone.

 

 

 

6.

PHARMACEUTICAL PARTICULARS

 

 

6.1

List of excipients

product

 

 

 

 

 

Lactose monohydrate

 

 

 

Hydroxypropylcellulose (E463)

 

 

 

Croscarmellose so ium

 

 

 

Magnesium stearate (E572)

 

 

 

6.2

Medicinal

 

 

 

Incompatibilities

 

 

 

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister packs (OPA/Al/PVC-Al foil): 14, 28, 30, 56, 60, 90 and 98 tablets in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

14 tablets: EU/1/11/721/008

 

 

authorised

 

 

 

28 tablets: EU/1/11/721/009

 

 

 

30 tablets: EU/1/11/721/010

 

 

 

56 tablets: EU/1/11/721/011

 

 

 

60 tablets: EU/1/11/721/012

 

 

 

90 tablets: EU/1/11/721/013

 

 

 

98 tablets: EU/1/11/721/014

 

longer

 

9.

 

 

 

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2012

no

 

 

Date of latest renewal:

 

 

 

 

 

10.

product

 

 

 

DATE OF REVISION OF THE TEXT

 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu Medicinal

1. NAME OF THE MEDICINAL PRODUCT
Paglitaz 45 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 45 mg of pioglitazone (as hydrochloride).
Excipient with known effect:
Each tablet contains 264.68 mg of lactose (see section 4.4). For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

4.

CLINICAL PARTICULARS

 

authorised

 

 

4.1

Therapeutic indications

 

 

Pioglitazone is indicated as second or third line in the treatment of type 2 diabetes mellitus as

described below:

no

longer

 

as monotherapy

 

-

in adult patients (particularly overweight patients) inadequately controlled by diet and exercise

as dual oral therapy in combinationproductwith

 

 

White to almost white round tablets with bevelled edges and with engraved "45" n one side of tablet (diameter 10.0 mm).

for whom metformin is inappropriate because of contraindications or intolerance;

-metformin, in adult patients ( articularly overweight patients) with insufficient glycaemic

control despite maxim tolerated dose of monotherapy with metformin;

-a sulphonylurea, o ly in adult patients who show intolerance to metformin or for whom

metforminMedicinalis ontra ndicated, 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 in 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).

4.2Posology 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

Older people

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).

Patients with renal impairment

No dose adjustment is necessary in patients with impaired renal functionauthorised(creatin ne cl arance

> 4 ml/min) (see section 5.2). No information is available from dialysed patients therefore pioglitazone should not be used in such patients.

Patients with hepatic impairment

Pioglitazone should not be used in patients with hepatic impairment (see section 4.3 and 4.4).

Paediatric population

 

 

 

longer

 

 

 

 

The safety and efficacy of pioglitazone in children and ad lescents under 18 years of age have not

been established. No data are available.

 

no

 

Method of administration

 

 

 

Pioglitazone tablets are taken orally once

aily with or without food. Tablets should be swallowed

with a glass of water.

product

 

 

 

 

 

-hypersensitivMedicinalty 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.4.3 Contraindications

4.4 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.

Bladder Cancer

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. 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.

Older people authorised

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 rea ment in the elderly.

Cases of bladder cancer were reported more frequentlylongerin a m ta-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 f 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 ca cer in diabetic patients treated with pioglitazone in

product

particular in patients treated for the longest dura noions and with the highest cumulative doses. A

possible risk after short term treatment cannot be excluded.

Risk factors for bladder cancer sh

uld be assessed before initiating pioglitazone treatment (risks

include age, smoking history, ex

osu e to some occupational or chemotherapy agents

e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigatedMedicinalbefore starting pioglitazone therapy.

Patients should be adv sed 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 liv r 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 times the 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 times the upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 times 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.

Eye disorders

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

authorised

 

As a consequence of increased insulin sensitivity, patients receiving pioglitaz ne 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 ins lin may be necessary.

acuity have been reported with thiazolidinediones, includi g pioglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association

Post-marketing reports of new-onset or worsening diabeticlongermacular oedema with decreased visual

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.

product

no

 

Others

An increased incidence in bone f actu es in women was seen in a pooled analysis of adverse reactions

Fractures were observed n 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No ncrease in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparatorMedicinaltreated p tients, on treatment for up to 3.5 years.

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).

Paglitaz 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

Studies in man suggest no induction of the main inducible cytochromeauthorisedP450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with

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.

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 th re 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 pi

longer

glitazone. The pioglitazone dose may need to be

increased when rifampicin is concomitantly admi

istered. Close monitoring of glycaemic control

should be considered (see section 4.4).

no

 

 

4.6 Fertility, pregnancy and lactation

 

 

Pregnancy

 

product

 

 

 

 

 

 

There are no adequate hum n d ta to determine the safety of pioglitazone during pregnancy. Foetal

 

Medicinal

 

 

 

growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in d m n shing 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.

Breast-feeding

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 influence 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.

Tabulated list of adverse reactions

 

 

 

 

 

authorised

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Adverse

Frequency of adverse reactions of pioglitazone by t eatment regimen

 

reaction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Combination

 

 

 

Mono-

with

 

 

with

 

with

with insulin

 

 

therapy

metformin

 

longer

 

metformin

 

 

 

 

sulpho-

 

 

 

 

 

 

 

 

 

nylur a

 

and sulpho-

 

 

 

 

 

 

 

 

 

 

nylurea

 

 

Infections and

 

 

 

 

 

 

 

 

 

 

infestations

 

 

 

 

 

 

 

 

 

 

upper respiratory

common

common

no

common

 

common

common

 

 

 

 

 

tract infection

 

 

 

 

 

 

 

 

 

 

anaemia

 

productcommon

 

 

 

 

 

common

 

bronchitis

 

 

 

 

 

 

 

 

 

sinusitis

uncommon

uncommon

uncommon

 

uncommon

uncommon

 

Blood and

 

 

 

 

 

 

 

 

 

 

lymphatic

 

 

 

 

 

 

 

 

 

 

system disorders

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

nutrition Medicinal

 

 

 

 

 

 

 

 

 

Immune System

 

 

 

 

 

 

 

 

 

 

Disorders

 

 

 

 

 

 

 

 

 

 

Hypersensitivity

not known

not known

 

not known

 

not known

not known

 

and allergic

 

 

 

 

 

 

 

 

 

 

reactions1

 

 

 

 

 

 

 

 

 

 

Metabolism and

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

 

hypo-glycaemia

 

 

 

 

 

uncommon

 

very

common

 

 

 

 

 

 

 

 

 

common

 

 

appetite increased

 

 

 

 

 

uncommon

 

 

 

 

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

 

 

 

 

 

 

 

 

 

Adverse

Frequency of adverse reactions of pioglitazone by treatment regimen

reaction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Combination

 

 

 

Mono-

with

 

 

with

with

with insulin

 

 

therapy

metformin

 

sulpho-

metformin

 

 

 

 

 

 

 

 

nylurea

and sulpho-

 

 

 

 

 

 

 

 

 

nylurea

 

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

 

 

 

 

 

 

 

 

authorised

Respiratory,

 

 

 

 

 

 

 

 

thoracic and

 

 

 

 

 

 

 

 

mediastinal

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

dyspnoea

 

 

 

 

 

 

longer

 

common

Gastrointestinal

 

 

 

no

 

 

 

disorders

 

 

 

 

 

 

 

flatulence

 

 

 

uncommon

 

common

 

 

Skin and

 

 

 

 

 

 

 

 

 

subcutaneous

 

 

 

 

 

 

 

 

tissue disorders

 

 

 

 

 

 

 

 

sweating

 

 

product

 

 

uncommon

 

 

Musculoskeletal

 

 

 

 

 

 

 

 

and connective

 

 

 

 

 

 

 

 

tissue disorders

 

 

 

 

 

 

 

 

fracture bone5

ommon

common

 

 

common

common

common

arthralgia

 

 

 

common

 

 

 

common

common

back pain

 

 

 

 

 

 

 

 

common

Renal and

 

 

 

 

 

 

 

 

urinary

Medicinal

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

disorders

 

 

 

 

 

 

 

 

 

haematuria

 

 

common

 

 

 

 

 

glycosuria

 

 

 

 

 

uncommon

 

 

proteinuria

 

 

 

 

 

uncommon

 

 

Reproductive

 

 

 

 

 

 

 

 

system and

 

 

 

 

 

 

 

 

breast disorders

 

 

 

 

 

 

 

 

erectile

 

 

 

common

 

 

 

 

 

dysfunction

 

 

 

 

 

 

 

 

General

 

 

 

 

 

 

 

 

 

disorders and

 

 

 

 

 

 

 

 

administration

 

 

 

 

 

 

 

 

site conditions

 

 

 

 

 

 

 

 

 

Adverse

Frequency of adverse reactions of pioglitazone by treatment regimen

 

reaction

 

 

 

 

 

 

 

 

 

Combination

 

 

 

Mono-

with

with

with

with insulin

 

 

therapy

metformin

sulpho-

metformin

 

 

 

 

 

nylurea

and sulpho-

 

 

 

 

 

 

nylurea

 

 

oedema

 

 

 

 

very

 

 

 

 

 

 

common

 

fatigue

 

 

uncommon

 

 

 

Investigations

 

 

 

 

 

 

weight increased6

common

common

common

common

common

 

blood creatine

 

 

 

common

 

 

phospho-kinase

 

 

 

 

 

 

increased

 

 

 

 

 

 

increased lactic

 

 

uncommon

 

 

 

dehydro-genase

 

 

 

 

 

 

Alanine

not known

not known

not known

not kn wn

not known

 

aminotransferase

 

 

 

 

 

 

increased 7

 

 

 

 

 

Description of selected adverse reactions

 

authorised

1 Postmarketing reports of hypersensitivity reactions inlongerpatients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, a d urticaria.

2Visual 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.

no

product 4In controlledMedicinalclinical 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

3Oedema 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.

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, wh n 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.

5A 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%).

6In 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.

7In 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.

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 medicinalauthorisedproduct. H althcare professionals are asked to report any suspected adverse reactions via the national r porting system

listed in Appendix V.

4.9 Overdose

Symptoms

In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of

Mechanism of action

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 sulph nylureas or insulin.

Management

 

 

longer

 

 

 

Symptomatic and general supportive measures should be taken in case of overdose.

 

 

 

no

 

5.

PHARMACOLOGICAL PROPERTIES

 

5.1

Pharmacodynamic pro e ties

 

 

 

 

product

 

 

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins;

ATC code: A10BG03.

 

 

 

 

Medicinal

 

 

 

Pioglitazone eff cts 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.

Pharmacodynamic effects

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.

Clinical efficacy and safety

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 (45 mg monotherapy vs. placebo) was studiedauthorisedin 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. S milar 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, b t not clinically significant

increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, pioglitazonelongerreduc d 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 reducedno post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone’s effects on glycaemiaproductand were s a istically significant different to glibenclamide.

In PROactive, a cardiovascular outcome st dy, 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 wereMedicinalreceiving insu in 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 coro ary 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 approx mately 20% had had a stroke. Approximately half of the study population had at least two of the car iovascular 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

concentrations and protein binding are taken into account, pioglitazone and metabol te 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.

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoformsauthorisedmay be involv to a lesser degree. Three of the six identified metabolites are active (M-II, M-III, and M-IV). Wh n activity,

In vitro studies have shown no evidence that pioglitazone inhibits ny 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 releva t effect on either the pharmacokinetics

Following oral administration of radi labelled pioglitazone to man, recovered label was mainly in faeces (55%) and a lesser amount in u ine (45%). In animals, only a small amount of unchanged

or pharmacodynamics of digoxin, warfarin, phenproc um

a d metformin. Concomitant

administration of pioglitazone with gemfibrozil (an inhibit

r of cytochrome P450 2C8) or with

 

 

 

longer

rifampicin (an inducer of cytochrome P450 2C8) is rep rted to increase or decrease, respectively, the

plasma concentration of pioglitazone (see section 4.5).

 

 

Elimination

product

no

 

 

 

 

 

 

 

 

 

Steady state pharmacokinetics are similar in patients age 65 and over and young subjects. Renal impairment

pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged pioglitazoneMedicinalin m n is 5 to 6 hours and for its total active metabolites 16 to 23 hours. Older people

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.

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.

5.3Preclinical 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

unknown.

authorised

relevance to humans of the tumourigenic findings in the male rat cannot be exclud d.

There was no tumorigenic response in mice of either sex. Hyperplasia of the u na y 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 relev nce of this finding is

 

 

 

longer

Environmental Risk Assessment (ERA): no environmental impact is anticipated from the clinical use

of pioglitazone.

 

 

6.

PHARMACEUTICAL PARTICULARSno

 

6.1

List of excipients

product

 

Lactose monohydrate

 

 

 

Hydroxypropylcellulose (E463)

 

 

 

Medicinal

 

 

Croscarmellose sodium

 

 

Magnesium stearate (E572)

 

 

6.2 Incompatib l t es

 

 

Not applicable.

 

 

6.3

Shelf life

 

 

3 years

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Blister packs (OPA/Al/PVC-Al foil): 14, 28, 30, 56, 60, 90 and 98 tablets in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

14 tablets: EU/1/11/721/015

 

28 tablets: EU/1/11/721/016

 

30 tablets: EU/1/11/721/017

 

56 tablets: EU/1/11/721/018

authorised

60 tablets: EU/1/11/721/019

 

90 tablets: EU/1/11/721/020

 

98 tablets: EU/1/11/721/021

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2012

Date of latest renewal:

10. DATE OF REVISION OF THE TEXT

longer

 

 

Detailed information on this medicinal produ isnoavailable on the website of the European Medicines

Agency http://www.ema.europa.eu

 

Medicinal

product

 

 

 

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