COMPETACT 15mg / 850mg tablets medication leaflet

Competact 15 mg/850 mg film-coated tablets

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

For the full list of excipients, see section 6.1.

Film-coated tablet (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 as second line treatment of type 2 diabetes mellitus adult patients, particularlyoverweight patients, who are unable to achieve sufficient glycaemic control at their maximallytolerated dose of oral metformin alone.

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 an adequateresponse, 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).

Adults with normal renal function (GFR ≥ 90 mL/min)

The recommended dose of Competact is 30 mg/day pioglitazone plus 1,700 mg/day of metforminhydrochloride (this dose 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 beforethe patient is switched to Competact.

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

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

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 andcardiac failure).

A GFR should be assessed before initiation of treatment with metformin containing products and atleast annually thereafter. In patients at increased risk of further progression of renal impairment and inthe elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors thatmay increase the risk of lactic acidosis (see section 4.4) should be reviewed before consideringinitiation of metformin in patients with GFR < 60 mL/min.

If no adequate strength of Competact is available, individual monocomponents should be used insteadof the fixed dose combination.

GFR mL/min Metformin Pioglitazone60-89 Maximum daily dose is 3,000 mg.

Dose reduction may be considered inrelation to declining renal function.

45-59 Maximum daily dose is 2,000 mg. No dose adjustment.

The starting dose is at most half of the Maximum daily dose is 45 mgmaximum dose.

30-44 Maximum daily dose is 1,000 mg.

The starting dose is at most half of themaximum dose.

< 30 Metformin is contra-indicated

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

The safety and efficacy of Competact in children and adolescents under 18 years of age have not beenestablished. No data are available.

Tablets should be swallowed with a glass of water. Taking Competact with, or just after food, mayreduce gastrointestinal symptoms associated with metformin.

Competact is contraindicated in patients with:

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1

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

- Current bladder cancer or a history of bladder cancer

- Uninvestigated macroscopic haematuria

- 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

- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

- Diabetic pre-coma

- Severe renal failure (GFR < 30 mL/min)

- 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)

- Breast-feeding (see section 4.6)

There is no clinical experience of pioglitazone in triple combination with other oral antidiabeticmedicinal products.

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worseningof renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acuteworsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever, heat, reduced fluid intake), Competactshould be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics andnonsteroidal anti-inflammatory drugs (NSAIDs)) should be initiated with caution in metformin treatedpatients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency,inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated withhypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (seesections 4.3 and 4.5).

Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis ischaracterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermiafollowed by coma. In case of suspected symptoms, the patient should stop taking Competact and seekimmediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35),increased plasma lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2. Metforminis contraindicated in patients with GFR < 30 mL/min and should be temporarily discontinued in thepresence of conditions that alter renal function, see section 4.3.

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

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), physiciansshould start with the lowest available dose and increase the dose gradually. Patients should beobserved for signs and symptoms of heart failure, weight gain or oedema; particularly those withreduced cardiac reserve. There have been post-marketing cases of cardiac failure reported whenpioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Sinceinsulin and pioglitazone are both associated with fluid retention, concomitant administration of insulinand Competact may increase the risk of oedema. Post-marketing cases of peripheral oedema andcardiac failure have also been reported in patients with concomitant use of pioglitazone andnonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Competact should bediscontinued 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 12,506 patients, 0.15%) than in control groups (7 cases from10,212 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 macroscopic haematuriaor other symptoms such as dysuria or urinary urgency develop during treatment.

There have been rare reports of elevated liver enzymes and hepatocellular dysfunction duringpost-marketing experience with pioglitazone (see section 4.8). Although in very rare cases fataloutcome has been reported, causal relationship has not been established.

It is recommended, therefore, that patients treated with Competact undergo periodic monitoring ofliver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Competact inall patients. Therapy with Competact should not be initiated in patients with increased baseline liverenzyme 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 monitoredperiodically according to clinical judgement. If ALT levels are increased to 3 x upper limit of normalduring Competact therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levelsremain > 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 Competact 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.

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) treatedpatients in comparative controlled trials with pioglitazone.

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

As Competact contains metformin hydrochloride,it must be discontinued at the time of surgery undergeneral, spinal or epidural anesthesia. Therapy may be restarted no earlier than 48 hours followingsurgery or resumption of oral nutrition and provided that renal function has been re-evaluated andfound to be stable.

Administration of iodinated contrast agent

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy,resulting in metformin accumulation and an increased risk of lactic acidosis. Competact should bediscontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable, see sections 4.2and 4.5.

Polycystic ovarian syndrome

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).

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 (see section 4.8)

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.

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 withpioglitazone (see section 4.8).

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).

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

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

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case offasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Competact must be discontinued prior to or at the time of the imaging procedure and not restarted untilat least 48 hours after, provided that renal function has been re-evaluated and found to be stable, seesections 4.2 and 4.4.

Combinations requiring precautions for use

Some medicinal products that can adversely affect renal function which may increase the risk of lacticacidosis, e.g. NSAIDS, including selective cyclo-oxygenase (COX) II inhibitors,angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics,especially loop diuretics. When starting or using such products in combination with Competact, closemonitoring of renal function is necessary.

Cationic medicinal products that are eliminated by renal tubular secretion (e.g. cimetidine) mayinteract with metformin by competing for common renal tubular transport systems. A study conductedin seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily,increased metformin systemic exposure (AUC) by 50% and Cmax by 81%. Therefore, close monitoringof glycaemic control, dose adjustment within the recommended posology and changes in diabetictreatment should be considered when cationic medicinal products that are eliminated by renal tubularsecretion are co-administered.

Pioglitazone

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).

Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsichyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoringperformed, especially at the beginning of treatment. If necessary, the dose of the antihyperglycaemicmedicinal product should be adjusted during therapy with the other medicinal product and on itsdiscontinuation.

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

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

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

Competact is not recommended in women of childbearing potential not using contraception. If apatient wishes to become pregnant, treatment with Competact should be discontinued.

Risk related to pioglitazone

There are no adequate human data from the use of pioglitazone in pregnant women. Animal studieshave 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 metforminto have malformative effects.

Competact should not be used during pregnancy. If a pregnancy occurs, treatment with Competactshould be discontinued.

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

In animal fertility studies with pioglitazone, there was no effect on copulation, impregnation orfertility index.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as600 mg/kg/day, which is approximately three times the maximum recommended human daily dosebased on body surface area comparisons.

Competact has no or negligible influence on the ability to drive and use machines. However patientswho experience visual disturbance should be cautious when driving or using machines.

Clinical trials have been conducted with Competact tablets and co-administered pioglitazone andmetformin (see section 5.1). At the initiation of the treatment abdominal pain, diarrhoea, loss ofappetite, nausea and vomiting may occur, these reactions are very common but usually disappearspontaneously in most cases. Lactic acidosis is a serious reaction which may occur very rarely(< 1/10,000) (see section 4.4) and other reactions such as bone fracture, weight increase and oedemamay occur commonly (≥ 1/100 to < 1/10) (see section 4.4).

Adverse reactions reported in double-blind studies and post-marketing experience 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 availabledata). Within each system organ class, adverse reactions are presented in order of decreasing incidencefollowed by decreasing seriousness.

Adverse reaction Frequency of adverse reactions

Pioglitazone Metformin Competact

Infections and infestationsupper respiratory tract infection common commonsinusitis uncommon uncommon

Neoplasms benign, malignant and unspecified(including cysts and polyps)bladder cancer uncommon uncommon

Blood and lymphatic system disordersanaemia common

Immune System Disordershypersensitivity and allergic reactions1 not known not known

Vitamin B12 absorption decreased2 very rare very rarelactic acidosis very rare very rare

Nervous system disordershypo-aesthesia common commoninsomnia uncommon uncommonheadache commontaste disturbance common common

Eye disordersvisual disturbance3 common commonmacular oedema not known not known

Gastrointestinal disorders4abdominal pain very verycommon commondiarrhoea very verycommon commonflatulence uncommonloss of appetite very very

Adverse reaction Frequency of adverse reactions

Pioglitazone Metformin Competactcommon commonnausea very verycommon commonvomiting very verycommon common

Hepatobiliary disordershepatitis5 not known not known

Skin and subcutaneous tissue disorderserythema very rare very rarepruritis very rare very rareurticaria very rare very rare

Musculoskeletal and connective tissue disordersbone fracture6 common commonarthralgia common

Renal and urinary disordershaematuria common

Reproductive system and breast disorderserectile dysfunction common

General disorders and administration siteconditionsoedema7 common

Investigationsweight increased8 common commonalanine aminotransferase increased9 not known not knownliver function tests abnormal5 not known not known

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

2 Long term treatment of metformin has been associated with a decrease of vitamin B12 absorptionwith decrease of serum levels. Consideration of such aetiology is recommended if a patient presentswith megaloplastic anaemia.

3 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.

4 Gastrointestinal disorders occur most frequently during initiation of therapy and resolvespontaneously in most cases.

5 Isolated reports: liver function tests abnormalities or hepatitis resolving upon metformindiscontinuation.

6 A pooled analysis was conducted of adverse reactions of bone fractures from randomised,comparator controlled, double blind clinical trials in over 8,100 patients in the pioglitazone-treatedgroups and 7,400 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%; 1.0 fractures per 100 patient years) ofpioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per100 patient years) of female patients treated with comparator. The observed excess risk of fractures forwomen on pioglitazone in this study is therefore 0.5 fractures per 100 patient years of use. No increasein fracture 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).

7 In active comparator controlled trials oedema was reported in 6.3% of patients treated withmetformin and pioglitazone, whereas the addition of sulphonylurea to metformin treatment resulted inoedema in 2.2% of patients. The reports of oedema were generally mild to moderate and usually didnot require discontinuation of treatment.

8 In active comparator controlled trials mean weight increase with pioglitazone given as monotherapywas 2-3 kg over one year. In combination trials pioglitazone added to metformin resulted in meanweight increase over one year of 1.5 kg.

9 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.

In controlled clinical trials the incidence of reports of heart failure with pioglitazone treatment was thesame as in placebo, metformin and sulphonylurea treatment groups, but was increased when used incombination 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 (see section 4.4).

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.

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

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

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose loweringdrugs, ATC code: A10BD05.

Competact combines two antihyperglycaemic active substances with complementary mechanisms ofaction to improve glycaemic control in patients with type 2 diabetes mellitus: pioglitazone, a memberof the thiazolidinedione class and metformin hydrochloride, a member of the biguanide class.

Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily bydecreasing 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 2diabetes mellitus patients with mean baseline HbA1c of 9.5% in a randomised double-blind,parallel-group study. Previous anti-diabetic medicinal products were discontinued for 12 weeks priorto baseline measurements. After 24 weeks of treatment, the primary endpoint of mean change frombaseline 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 individualproducts and did not suggest any new safety issues.

Pioglitazone

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 free fatty acids, and increased HDL-cholesterollevels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statisticallysignificant increases in LDL-cholesterol levels compared with placebo, whilst reductions whereobserved 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 andhepatically synthesised triglycerides. These effects were independent of pioglitazone’s effects onglycaemia and were statistically significantly different to glibenclamide.

In PROactive, a cardiovascular outcome study, 5,238 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, acetylsalicylic acid, 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 incidence of oedema, weight gainand heart failure were increased. No increase in mortality from heart failure was observed.

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandialplasma 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 andutilisation

- by delaying intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metforminincreases 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 lipidmetabolism. This has been shown at therapeutic doses in controlled, medium-term or long-termclinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.

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

- a significant reduction of the absolute risk of any diabetes-related complication in the metformingroup (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: metformin7.5 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: metformin13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), andversus the combined sulphonylurea and insulin monotherapy groups18.9 events/1,000 patient-years (p=0.021)

- a significant reduction in the absolute risk of myocardial infarction: metformin11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).

The European Medicines Agency has waived the obligation to submit the results of studies with

Competact in all subsets of the paediatric population in type 2 diabetes mellitus. See section 4.2 forinformation on paediatric use.

Competact

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

Food had no effect on the AUC and Cmax of pioglitazone when Competact was administered to healthyvolunteers. However, in the case of metformin, in the fed state the mean AUC and Cmax were lower(13% and 28% respectively). Tmax was delayed by food by approximately 1.9 h for pioglitazone and0.8 h for metformin.

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

Competact.

Pioglitazone

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.

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

After oral administration, metformin absorption is saturable and incomplete. It is assumed that thepharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosingschedules, steady state plasma concentrations are reached within 24-48 h and are generally less than1 µg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed4 µg/mL, even at maximum doses.

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

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lowerthan the plasma peak and appears at approximately the same time. The red blood cells most likelyrepresent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.

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

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

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

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 tumourigenic 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.

Preclinical data for metformin reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity toreproduction.

Microcrystalline cellulose

Povidone (K30)

Croscarmellose sodium

Magnesium stearate

Hypromellose

Macrogol 8000

Talc

Titanium dioxide (E171).

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium/aluminium blisters.

Packs of 56, 112.

Not all pack sizes may be marketed.

No special requirements.

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 2417489 Greifswald

Germany

EU/1/06/354/005

EU/1/06/354/010

Date of first authorisation: 28/07/2006

Date of latest renewal: 25/04/2016

08/2023

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

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