GLIDIPION 45mg tablets medication leaflet

Glidipion 15 mg tablets

Glidipion 30 mg tablets

Glidipion 45 mg tablets

Glidipion 15 mg tablets

Each tablet contains 15 mg of pioglitazone (as hydrochloride).

Each tablet contains 37.77 mg of lactose monohydrate (see section 4.4).

Glidipion 30 mg tablets

Each tablet contains 30 mg of pioglitazone (as hydrochloride).

Each tablet contains 75.54 mg of lactose monohydrate (see section 4.4).

Glidipion 45 mg tablets

Each tablet contains 45 mg of pioglitazone (as hydrochloride).

Each tablet contains 113.31 mg of lactose monohydrate (see section 4.4).

For the full list of excipients, see section 6.1.

Tablet.

Glidipion 15 mg tablets

The tablets are white, round, flat, bevelled, 5.5 mm in diameter and engraved with ‘TZ15’ on one side.

Glidipion 30 mg tablets

The tablets are white, round, flat, bevelled, 7 mm in diameter and engraved with ‘TZ30’ on one side.

Glidipion 45 mg tablets

The tablets are white, round, flat, bevelled, 8 mm in diameter and engraved with ‘TZ45’ on one side.

Pioglitazone is indicated as second or third line treatment of type 2 diabetes mellitus as describedbelow:

as monotherapy

- in adult patients (particularly overweight patients) inadequately controlled by diet and exercisefor whom metformin is inappropriate because of contraindications or intolerance.

as dual oral therapy in combination with

- metformin, in adult patients (particularly overweight patients) with insufficient glycaemiccontrol despite maximal tolerated dose of monotherapy with metformin.

- a sulphonylurea, only in adult patients who show intolerance to metformin or for whommetformin is contraindicated, with insufficient glycaemic control despite maximal tolerateddose of monotherapy with a sulphonylurea.

as triple oral therapy in combination with

- metformin and a sulphonylurea, in adult patients (particularly overweight patients) withinsufficient glycaemic control despite dual oral therapy.

- Pioglitazone is also indicated for combination with insulin in type 2 diabetes mellitus adultpatients with insufficient glycaemic control on insulin for whom metformin is inappropriatebecause of contraindications or intolerance (see section 4.4).

After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assessadequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show anadequate response, pioglitazone should be discontinued. In light of potential risks with prolongedtherapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone ismaintained (see section 4.4).

Pioglitazone treatment may be initiated at 15 mg or 30 mg once daily. The dose may be increased inincrements up to 45 mg once daily.

In combination with insulin, the current insulin dose can be continued upon initiation of pioglitazonetherapy. If patients report hypoglycaemia, the dose of insulin should be decreased.

Special population

No dose adjustment is necessary for elderly patients (see section 5.2). Physicians should starttreatment with the lowest available dose and increase the dose gradually, particularly whenpioglitazone is used in combination with insulin (see section 4.4 Fluid retention and cardiac failure).

No dose adjustment is necessary in patients with impaired renal function (creatinineclearance > 4 ml/min) (see section 5.2). No information is available from dialysed patients, thereforepioglitazone should not be used in such patients.

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

The safety and efficacy of pioglitazone in children and adolescents under 18 years of age have notbeen established. No data are available.

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

Pioglitazone is contraindicated in patients with:

- hypersensitivity to the active substance or to any of the excipients

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

- hepatic impairment

- diabetic ketoacidosis

- current bladder cancer or a history of bladder cancer

- uninvestigated macroscopic haematuria.

Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. Whentreating 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 shouldstart with the lowest available dose and increase the dose gradually. Patients should be observed forsigns and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiacreserve. There have been post-marketing cases of cardiac failure reported when pioglitazone was usedin combination with insulin or in patients with a history of cardiac failure. Patients should be observedfor signs and symptoms of heart failure, weight gain and oedema when pioglitazone is used incombination with insulin. Since insulin and pioglitazone are both associated with fluid retention,concomitant administration may increase the risk of oedema. Post marketing cases of peripheraloedema and cardiac failure have also been reported in patients with concomitant use of pioglitazoneand nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Pioglitazone shouldbe discontinued if any deterioration in cardiac status occurs.

A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years withtype 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo wasadded to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed anincrease in reports of heart failure, however this did not lead to an increase in mortality in this study.

Combination use with insulin should be considered with caution in the elderly because of increasedrisk of serious heart failure.

In light of age-related risks (especially bladder cancer, fractures and heart failure), the balance ofbenefits and risks should be considered carefully both before and during treatment in the elderly.

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trialswith pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whomexposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Epidemiological studies havealso suggested a small increased risk of bladder cancer in diabetic patients treated with pioglitazone,although not all studies identified a statistically significant increased risk.

Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risksinclude age, smoking history, exposure to some occupational or chemotherapy agentse.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuriashould be investigated before starting pioglitazone therapy.

Patients should be advised to promptly seek the attention of their physician if macroscopichaematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

There have been rare reports of hepatocellular dysfunction during post-marketing experience (seesection 4.8). It is recommended, therefore, that patients treated with pioglitazone undergo periodicmonitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy withpioglitazone in all patients. Therapy with pioglitazone should not be initiated in patients withincreased baseline liver enzyme levels (ALT > 2.5 X upper limit of normal) or with any other evidenceof liver disease.

Following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitoredperiodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normalduring pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALTlevels remain > 3 X the upper limit of normal, therapy should be discontinued. If any patient developssymptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting,abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decisionwhether to continue the patient on therapy with pioglitazone should be guided by clinical judgementpending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.

In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be dueto fat accumulation and in some cases associated with fluid retention. In some cases weight increasemay be a symptom of cardiac failure, therefore weight should be closely monitored. Part of thetreatment of diabetes is dietary control. Patients should be advised to adhere strictly to acalorie-controlled diet.

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 changeswere seen in metformin (haemoglobin 3-4% and haematocrit 3.6-4.1% relative reductions) and to alesser extent sulphonylurea and insulin (haemoglobin 1-2% and haematocrit 1-3.2% relativereductions) treated patients in comparative controlled trials with pioglitazone.

As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oraltherapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-relatedhypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visualacuity have been reported with thiazolidinediones, including pioglitazone. Many of these patientsreported concurrent peripheral oedema. It is unclear whether or not there is a direct associationbetween pioglitazone and macular oedema but prescribers should be alert to the possibility of macularoedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral shouldbe considered.

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactionsof bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and7400 comparator treated patients, on treatment for up to 3.5 years.

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treatedwith 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 withpioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observedexcess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per100 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 fracturesper 100 patient years) of female patients treated with comparator. No increase in fracture rates wasobserved 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 andwomen.

The risk of fractures should be considered in the long term care of patients treated with pioglitazone(see section 4.8).

As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycysticovarian 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 ifpregnancy occurs, the treatment should be discontinued (see section 4.6).

Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitoredclosely. Pioglitazone dose adjustment within the recommended posology or changes in diabetictreatment should be considered (see section 4.5).

Glidipion tablets contain lactose monohydrate and therefore should not be administered to patientswith rare hereditary problems of galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption.

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokineticsor pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration ofpioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea.

Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4.

In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions withsubstances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channelblockers, and HMGCoA reductase inhibitors are not to be expected.

Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reportedto result in a 3-fold increase in AUC of pioglitazone. Since there is a potential for an increase indose-related adverse events, a decrease in the dose of pioglitazone may be needed when gemfibrozil isconcomitantly administered. Close monitoring of glycaemic control should be considered (seesection 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 beincreased when rifampicin is concomitantly administered. Close monitoring of glycaemic controlshould be considered (see section 4.4).

There are no adequate human data to determine the safety of pioglitazone during pregnancy. Foetalgrowth restriction was apparent in animal studies with pioglitazone. This was attributable to the actionof pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance thatoccurs 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 inpregnancy.

Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whetherpioglitazone is secreted in human milk. Therefore, pioglitazone should not be administered tobreast-feeding women.

In animal fertility studies there was no effect on copulation, impregnation or fertility index.

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

Adverse reactions reported in excess (> 0.5%) of placebo and as more than an isolated case in patientsreceiving pioglitazone in double-blind studies are listed below as MedDRA preferred term by systemorgan 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 frequencygrouping, adverse reactions are presented in order of decreasing incidence and seriousness.

Frequency of adverse reactions of pioglitazone by treatment regimen

Combination

Adverse reaction Mono- withtherapy with withsulpho- metforminmetformin nylurea and sulpho- with insulinnylurea

Infections andinfestationsupper respiratory common common common common commontract infectionbronchitis commonsinusitis uncommon uncommon uncommon uncommon uncommon

Blood andlymphatic systemdisordersanaemia common

Immune System

Frequency of adverse reactions of pioglitazone by treatment regimen

Combination

Adverse reaction Mono- with with withtherapy metformin sulpho- metforminand sulpho- with insulinnylurea nylurea

Disorders

Hypersensitivity not known not known not known not known not knownand allergicreactions1

Metabolism andnutritiondisordershypo-glycaemia uncommon very commoncommonappetite increased uncommon

Nervous systemdisordershypo-aesthesia common common common common commonheadache common uncommondizziness commoninsomnia uncommon uncommon uncommon uncommon uncommon

Eye disordersvisual common common uncommondisturbance2macular oedema not known not known not known not known not known

Ear andlabyrinthdisordersvertigo uncommon

Cardiacdisordersheart failure3 common

Neoplasmsbenign,malignant andunspecified(including cystsand polyps)bladder cancer uncommon uncommon uncommon uncommon uncommon

Respiratory,thoracic andmediastinaldisordersdyspnoea common

Gastrointestinaldisordersflatulence uncommon common

Skin andsubcutaneoustissue disorderssweating uncommon

Frequency of adverse reactions of pioglitazone by treatment regimen

Combination

Adverse reaction Mono- withtherapy with with metforminmetformin sulpho- with insulinnylurea and sulpho-nylurea

Musculoskeletaland connectivetissue disordersfracture bone4 common common common common commonarthralgia common common commonback pain common

Renal andurinarydisordershaematuria commonglycosuria uncommonproteinuria uncommon

Reproductivesystem andbreast disorderserectile commondysfunction

Generaldisorders andadministrationsite conditionsoedema5 verycommonfatigue uncommon

Investigationsweight increased6 common common common common commonblood creatine commonphospho-kinaseincreasedincreased lactic uncommondehydro-genase

Alanine not known not known not known not known not knownaminotransferaseincreased7

Description of selected adverse reactions1 Postmarketing reports of hypersensitivity reactions in patients treated with pioglitazone have beenreported. These reactions include anaphylaxis, angioedema, and urticaria.

2 Visual disturbance has been reported mainly early in treatment and is related to changes in bloodglucose due to temporary alteration in the turgidity and refractive index of the lens as seen with otherhypoglycaemic treatments.

3 In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment wasthe same as in placebo, metformin and sulphonylurea treatment groups, but was increased when usedin combination therapy with insulin. In an outcome study of patients with pre-existing majormacrovascular disease, the incidence of serious heart failure was 1.6% higher with pioglitazone thanwith placebo, when added to therapy that included insulin. However, this did not lead to an increase inmortality in this study. In this study in patients receiving pioglitazone and insulin, a higher percentageof patients with heart failure was observed in patients aged ≥65 years compared with those less than65 years (9.7% compared to 4.0%). In patients on insulin with no pioglitazone the incidence of heartfailure was 8.2% in those ≥65 years compared to 4.0% in patients less than 65 years. Heart failure hasbeen reported with marketing use of pioglitazone, and more frequently when pioglitazone was used incombination with insulin or in patients with a history of cardiac failure.

4 A pooled analysis was conducted of adverse reactions of bone fractures from randomised,comparator controlled, double blind clinical trials in over 8100 patients in the pioglitazone-treatedgroups and 7400 in the comparator-treated groups of up to 3.5 years duration. A higher rate offractures was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase infracture 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 experiencedfractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase infracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%). Post-marketing, bone fractures have been reported in both male and female patients (see section 4.4).

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

6 In active comparator controlled trials mean weight increase with pioglitazone given as monotherapywas 2-3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. Incombination trials pioglitazone added to metformin resulted in mean weight increase over one year of1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups, addition of sulphonylurea tometformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea amean weight loss of 1.0 kg.

7 In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times theupper limit of normal was equal to placebo but less than that seen in metformin or sulphonylureacomparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. Rarecases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketingexperience. Although in very rare cases fatal outcome has been reported, causal relationship has notbeen established.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for sevendays was not associated with any symptoms.

Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and generalsupportive measures should be taken in case of overdose.

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

ATC code: A10BG03.

Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to actvia activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leadingto increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment withpioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucosedisposal in the case of insulin resistance.

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. Theimproved glycaemic control is associated with a reduction in both fasting and postprandial plasmainsulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended totwo years in order to assess time to treatment failure (defined as appearance of HbA1c ≥ 8.0% after thefirst six months of therapy). Kaplan-Meier analysis showed shorter time to treatment failure in patientstreated 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% ofpatients on gliclazide. In a two-year study of combination therapy comparing pioglitazone withgliclazide 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 duringthe second year was less with pioglitazone than with gliclazide.

In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulinoptimisation period were randomised to pioglitazone or placebo for 12 months. Patients receivingpioglitazone had a mean reduction in HbA1c of 0.45% compared with those continuing on insulinalone, and a reduction of insulin dose in the pioglitazone treated group.

HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulinsensitivity. Two-year clinical studies have shown maintenance of this effect.

In one year clinical trials, pioglitazone consistently gave a statistically significant reduction in thealbumin/creatinine ratio compared to baseline.

The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial intype 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat wassignificantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes inbody 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 clinicallysignificant increases in LDL-cholesterol levels.

In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and freefatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide.

Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared withplacebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as wellas reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through aneffect on both absorbed and hepatically synthesised triglycerides. These effects were independent ofpioglitazone’s effects on glycaemia and were statistically significant different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus andpre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition toexisting antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had anaverage age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third ofpatients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligiblepatients had to have had one or more of the following: myocardial infarction, stroke, percutaneouscardiac 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 myocardialinfarction and approximately 20% had had a stroke. Approximately half of the study population had atleast two of the cardiovascular history entry criteria. Almost all subjects (95%) were receivingcardiovascular medicinal products (beta blockers, ACE inhibitors, angiotensin II antagonists, calciumchannel blockers, nitrates, diuretics, aspirin, statins, fibrates).

Although the study failed regarding its primary endpoint, which was a composite of all-causemortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation,coronary revascularisation and leg revascularisation, the results suggest that there are no long-termcardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weightgain and heart failure were increased. No increase in mortality from heart failure was observed.

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

Following oral administration, pioglitazone is rapidly absorbed, and peak plasma concentrations ofunchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases ofthe plasma concentration were observed for doses from 2-60 mg. Steady state is achieved after4-7 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%.

The estimated volume of distribution in humans is 0.25 l/kg.

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

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups.

This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesserdegree. 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-IIIcontribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-foldthat of pioglitazone, whilst the relative efficacy of M-II is minimal.

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

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

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokineticsor pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitantadministration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or withrifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, theplasma concentration of pioglitazone (see section 4.5).

Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly infaeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchangedpioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life ofunchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.

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

In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lowerthan those seen in subjects with normal renal function, but oral clearance of parent substance issimilar. Thus free (unbound) pioglitazone concentration is unchanged.

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.

In toxicology studies, plasma volume expansion with haemodilution, anaemia, and reversible eccentriccardiac 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 observedacross species at plasma concentrations ≤ 4 times the clinical exposure. Foetal growth restriction wasapparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone indiminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs duringpregnancy 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 vitrogenotoxicity 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 waspostulated as the mechanistic basis for the observed tumourigenic response in the male rat. A24-month mechanistic study in male rats demonstrated that administration of pioglitazone resulted inan increased incidence of hyperplastic changes in the bladder. Dietary acidification significantlydecreased but did not abolish the incidence of tumours. The presence of microcrystals exacerbated thehyperplastic response but was not considered to be the primary cause of hyperplastic changes. Therelevance 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 notseen in dogs or monkeys treated with pioglitazone for up to 12 months.

In an animal model of familial adenomatous polyposis (FAP), treatment with two otherthiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding isunknown.

Environmental Risk Assessment: no environmental impact is anticipated from the clinical use ofpioglitazone.

Carmellose calcium

Hydroxypropylcellulose

Lactose monohydrate

Magnesium stearate

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium/aluminium blisters, packs of 14, 28, 30, 50, 56, 84, 90, 98 and 100 tablets.

The packs with 14, 28, 56, 84 and 98 tablets contain blisters with abbreviations for days of the weekprinted on the blister (Mon., Tue., Wed., Thu., Fri., Sat., Sun.).

Not all pack sizes may be marketed.

No special requirements.

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78220 Hafnarfjörður

Iceland

EU/1/12/756/001

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Date of first authorisation: 15 March 2012

Date of latest renewal: 11 November 2016

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

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