Competact 15 mg/850 mg film-coated tablets.

Each tablet contains 15 mg of pioglitazone (as hydrochloride) and 850 mg of metformin hydrochloride.

For a full list of excipients, see section 6.1.

Film-coated tablet

The tablets are white to off-white, oblong, film-coated, embossed '15 / 850' on one face and '4833M' on the other.

Competact is indicated in the treatment of type 2 diabetes mellitus patients, particularly overweight patients, who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone.

Dosage in adults:

The usual dose of Competact is 30 mg/day pioglitazone plus 1700 mg/day of metformin hydrochloride (this dosage is achievable with one tablet of Competact 15 mg/850 mg, taken twice a day).

Dose titration with pioglitazone (added to the optimal dose of metformin) should be considered before the patient is switched to Competact.

When clinically appropriate, direct change from metformin monotherapy to Competact may be considered.

Taking Competact with, or just after food, may reduce gastrointestinal symptoms associated with metformin.

Elderly:

As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking Competact should have their renal function monitored regularly (see sections 4.3 and 4.4).

Patients with renal impairment:

Competact should not be used in patients with renal failure or renal dysfunction (creatinine clearance < 60 ml/min)(see sections 4.3 and 4.4).

Patients with hepatic impairment:

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

Children and adolescents:

There are no data available on the use of pioglitazone in patients under 18 years of age and therefore the use of Competact in this age group is not recommended.

Competact is contraindicated in patients with:

- Hypersensitivity to the active substances or to any of the excipients

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

- Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock

- Hepatic impairment

- Acute alcohol intoxication, alcoholism

- Diabetic ketoacidosis or diabetic pre-coma

- Renal failure or renal dysfunction (creatinine clearance <60 ml/min) (see section 4.4).

- Acute conditions with the potential to alter renal function such as:

- Dehydration

- Severe infection

- Shock

- Intravascular administration of iodinated contrast agents (see section 4.4)

- Lactation

There is no clinical experience of pioglitazone in triple combination with other oral antidiabetic agents.

Lactic acidosis:,

Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Diagnosis:

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see section 4.9).

Renal Function:

As metformin is excreted by the kidney, serum creatinine concentrations should be determined regularly:

- at least once a year in patients with normal renal function

- at least two to four times a year in patients with serum creatinine levels at the upper limits of normal and in elderly subjects

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting treatment with a NSAID.

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), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema particularly those with reduced cardiac reserve. There have been cases of cardiac failure reported from the market when pioglitazone was used in combination with insulin or patients with a history of cardiac failure. Since insulin and pioglitazone are associated with fluid retention, concomitant administration of insulin and Competact may increase the risk of oedema. Competact 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. Caution should be exercised in patients over 75 years because of the limited experience in this patient group.

Monitoring of Liver Function:

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

Following initiation of therapy with Competact, it is recommended that liver enzymes be monitored periodically according to clinical judgement. If ALT levels are increased to 3 X upper limit of normal during Competact therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain>3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Competact should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, drug therapy 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.

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) treated patients in comparative controlled trials with pioglitazone.

Hypoglycaemia

Patients receiving pioglitazone in dual oral therapy with a sulphonylurea may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea may be necessary.

Eye disorders:

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

Surgery:

As Competact contains metformin hydrochloride, the treatment should be discontinued 48 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards.

Administration of iodinated contrast agent:

The intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure. Therefore, due to the metformin active substance, Competact should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Polycystic ovarian syndrome:

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).

Others:

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse event reports of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.

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

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%). The observed excess risk of fractures for women on pioglitazone in this study is therefore 0.5 fractures per 100 patient years of use.

The risk of fractures should be considered in the long term care of women treated with pioglitazone.

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).

There have been no formal interaction studies for Competact. The following statements reflect the information available on the individual active substances (pioglitazone and metformin).

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to be expected.

Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of pioglitazone. Since there is a potential for an increase in dose-related adverse events, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4). Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of pioglitazone. The pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4).

There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Competact (see section 4.4). Avoid consumption of alcohol and medicinal products containing alcohol.

Intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Cationic drugs that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50% and C_max by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic drugs that are eliminated by renal tubular secretion are co-administered.

Combinations requiring precautions for use

Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

For Competact no preclinical or clinical data on exposed pregnancies or lactation are available.

Risk related to pioglitazone:

There are no adequate human data from the use of pioglitazone in pregnant women. Animal studies have not shown teratogenic effects but have shown foetotoxicity related to the pharmacologic action (see section 5.3).

Risk related to metformin:

Animal studies have not revealed teratogenic effects. Small clinical trials have not revealed metformin to have malformative effects.

However, Competact should not be used during pregnancy and in women of child-bearing age not using contraceptive measures. If a patient wishes to become pregnant or if a pregnancy occurs, treatment with Competact should be discontinued.

Both pioglitazone and metformin have been shown to be present in the milk of lactating rats. It is not known whether breast-feeding will lead to exposure of the infant to the medicinal product. Competact must therefore not be used in women who are breast-feeding (see section 4.3).

No effects on ability to drive and use machines have been observed.

Clinical trials have been conducted with Competact tablets and co-administered pioglitazone and metformin (see section 5.1). Bioequivalence of Competact with co-administered pioglitazone and metformin has also been demonstrated (see section 5.2).

Adverse reactions reported in excess (>0.5%) of placebo and as more than an isolated case in patients receiving pioglitazone in combination with metformin in double-blind studies are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (>1/10000, < 1/1000); very rare (< 1/10000); isolated reports; not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

PIOGLITAZONE IN COMBINATION THERAPY WITH METFORMIN

Blood and lymphatic system disorders

Eye disorders

Gastrointestinal disorders

Metabolism and nutrition disorders

Musculoskeletal system and connective tissue disorders

Nervous system disorders

Renal and urinary disorders

Reproductive system and breast disorders

In active comparator controlled trials oedema was reported in 6.3% of patients treated with metformin and pioglitazone, whereas the addition of sulphonylurea to metformin treatment resulted in oedema in 2.2% of patients. The reports of oedema were generally mild to moderate and usually did not require discontinuation of treatment.

In active comparator controlled trials mean weight increase with pioglitazone given as monotherapy was 2 – 3 kg over one year. In combination trials pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg.

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

In clinical trials with pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. Heart failure has been reported rarely with marketing use of pioglitazone, but more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

Additional information on the individual active substances of the fixed dose combination

Pioglitazone

In double blind placebo controlled clinical trials with pioglitazone upper respiratory tract infection and hypoaesthesia were common; sinusitis and insomnia were uncommon.

POST-MARKETING DATA

Eye disorders

Metformin

Metabolism and nutrition disorders:

Nervous system disorders:

Gastrointestinal disorders:

Hepatobiliary disorders:

Skin and subcutaneous tissue disorders:

A pooled analysis was conducted of adverse event reports 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%).

No data are available with regard to overdose of Competact.

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.

A large overdose of metformin (or coexisting risks of lactic acidosis) may lead to lactic acidosis which is a medical emergency and must be treated in hospital.

The most effective method to remove lactate and metformin is haemodialysis.

Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs, ATC code: A10BD05.

Competact combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: pioglitazone, a member of the thiazolidinedione class and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone and metformin combination

The fixed dose combination tablet of pioglitazone 15 mg/metformin 850 mg BID (N=201), pioglitazone 15 mg BID (N=189), and metformin 850 mg BID (N=210) were evaluated in type 2 diabetes mellitus patients with mean baseline HbA1C of 9.5% in a randomised double-blind, parallel-group study. Previous anti-diabetic medication was discontinued for 12 weeks prior to baseline measurements. After 24 weeks of treatment, the primary endpoint of mean change from baseline in HbA1c was -1.83% in the combination group versus -0.96% in the pioglitazone group (p<0.0001) and -0.99% in the metformin group (p<0.0001).

The safety profile seen in this study reflected the known adverse reactions seen with the individual products and did not suggest any new safety issues.

Pioglitazone

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

Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to two years in order to assess time to treatment failure (defined as appearance of HbA_1c 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 HbA_1c <8.0%) was sustained in 69% of patients treated with pioglitazone, compared with 50% of patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with gliclazide when added to metformin, glycaemic control measured as mean change from baseline in HbA_1c was similar between treatment groups after one year. The rate of deterioration of HbA_1c 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 HbA_1c of 0.45% compared with those continuing on insulin alone, and a reduction of insulin dose in the pioglitazone treated group.

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

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

The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in body fat distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity. In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were observed as compared to placebo, with small, but not clinically significant increases in LDL-cholesterol levels. In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically significant increases in LDL-cholesterol levels compared with placebo, whilst reductions where observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced postprandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone's effects on glycaemia and were statistically significantly different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medications (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 incidence of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.

Metformin

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via three mechanisms:

- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis

- in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation

- by delaying intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.

The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034

- a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017

- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021)

- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).

Competact

Bioequivalence studies in healthy volunteers have shown Competact to be bioequivalent to the administration of pioglitazone and metformin given as separate tablets.

Food had no effect on the AUC and C_max of pioglitazone when Competact was administered to healthy volunteers. However, in the case of metformin, in the fed state the mean AUC and C_max were lower (13% and 28% respectively). Tmax was delayed by food by approximately 1.9h for pioglitazone and 0.8 h for metformin.

The following statements reflect the pharmacokinetic properties of the individual active substances of Competact.

Pioglitazone

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 %).

Metabolism:

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified metabolites are active (MII, M-III, and M-IV). When activity, concentrations and protein binding are taken into account, pioglitazone and metabolite M-III contribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold that of pioglitazone, whilst the relative efficacy of M-II is minimal.

In vitro studies have shown no evidence that pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in man.

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

Elimination:

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

Elderly:

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

Patients with renal impairment:

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

Patients with hepatic impairment:

Total plasma concentration of pioglitazone is unchanged, but with an increased volume of distribution. Intrinsic clearance is therefore reduced, coupled with a higher unbound fraction of pioglitazone.

Metformin

Absorption:

After an oral dose of metformin, t_max is reached in 2.5 h. Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 μg/ml. In controlled clinical trials, maximum metformin plasma levels (C_max) did not exceed 4 μg/ml, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed. The clinical relevance of this decrease is unknown.

Distribution:

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean V_d ranged between 63 – 276 l.

Metabolism:

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination:

Renal clearance of metformin is >400ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

No animal studies have been conducted with the combined products in Competact. The following data are findings in studies performed with pioglitazone or metformin individually.

Pioglitazone:

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 relevance of this finding is unknown. There was no tumorigenic response in mice of either sex. Hyperplasia of the urinary bladder was not seen in dogs or monkeys treated for up to 12 months.

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

Metformin:

Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Tablet Core:

Microcrystalline cellulose

Povidone (K30)

Croscarmellose sodium

Magnesium stearate

Film Coat:

Hypromellose

Macrogol 8000

Talc

Titanium dioxide.

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium/aluminium blisters, packs of 14, 28, 30, 50, 56, 60, 90, 98 and 180 tablets.

Not all pack sizes may be marketed.

No special requirements.

Takeda Global Research and Development Centre (Europe) Ltd

61 Aldwych

London WC2B 4AE

United Kingdom

EU/1/06/354/001-9

28 July 2006

August 2009

CM090913 Date of preparation: 02 September 09