4.1. Therapeutic indications

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

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

4.2. Posology and method of administration

Posology

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 metformin hydrochloride (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 before the patient is switched to Competact.

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

Special populations

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).

Physicians should start treatment with the lowest available dose and increase the dose gradually, particularly when pioglitazone is used in combination with insulin (see section 4.4 Fluid retention and cardiac failure).

Renal impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the 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 that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin in patients with GFR < 60 mL/min.

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

GFR mL/min

Metformin

Pioglitazone

60-89

Maximum daily dose is 3,000 mg. Dose reduction may be considered in relation to declining renal function.

No dose adjustment. Maximum daily dose is 45 mg

45-59

Maximum daily dose is 2,000 mg. The starting dose is at most half of the maximum dose.

30-44

Maximum daily dose is 1,000 mg.

The starting dose is at most half of the maximum dose.

< 30

Metformin is contra-indicated

Hepatic impairment

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

Paediatric population

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

Method of administration

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

4.3. Contraindications

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)

4.4. Special warnings and precautions for use

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

Lactic acidosis

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

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

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

Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking Competact and seek immediate 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.

Patients with known or suspected mitochondrial diseases:

In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.

Renal function

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

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 or the elderly), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Since insulin and pioglitazone are both associated with fluid retention, concomitant administration of insulin and Competact may increase the risk of oedema. Post-marketing cases of peripheral oedema and cardiac failure have also been reported in patients with concomitant use of pioglitazone and nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. 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.

Elderly

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

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

Bladder cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12,506 patients, 0.15%) than in control groups (7 cases from 10,212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, p=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Epidemiological studies have also 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 (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.

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

Monitoring of liver function

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

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, the medicinal product should be discontinued.

Weight gain

In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may be a symptom of cardiac failure; therefore weight should be closely monitored.

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,it must be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found 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 be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 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 reactions of 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 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.

Some epidemiological studies have suggested a similarly increased risk of fracture in both men and women. The risk of fractures should be considered in the long term care of patients treated with pioglitazone (see section 4.8).

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).

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.

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

4.5. Interaction with other medicinal products and other forms of interaction

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

Metformin

Concomitant use not recommended

Alcohol

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

Iodinated contrast agents

Competact must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 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 lactic acidosis, 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, close monitoring of renal function is necessary.

Cationic medicinal products 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 Cmax by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered.

Pioglitazone

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).

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 dose 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 dose of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

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.

4.6. Fertility, pregnancy and lactation

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

Women of childbearing potential / Contraception in males and females

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

Pregnancy

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.

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

Breast-feeding

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).

Fertility

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

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Clinical trials have been conducted with Competact tablets and co-administered pioglitazone and metformin (see section 5.1). At the initiation of the treatment abdominal pain, diarrhoea, loss of appetite, nausea and vomiting may occur, these reactions are very common but usually disappear spontaneously 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 oedema may occur commonly (≥ 1/100 to < 1/10) (see section 4.4).

Tabulated list of adverse reactions

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 available data). Within each system organ class, adverse reactions are presented in order of decreasing incidence followed by decreasing seriousness.

Adverse reaction

Frequency of adverse reactions

Pioglitazone

Metformin

Competact

Infections and infestations

upper respiratory tract infection

common

common

sinusitis

uncommon

uncommon

Neoplasms benign, malignant and unspecified (including cysts and polyps)

bladder cancer

uncommon

uncommon

Blood and lymphatic system disorders

anaemia

common

Immune System Disorders

hypersensitivity and allergic reactions1

not known

not known

Metabolism and nutrition disorders

Vitamin B12 decrease/deficiency (see section 4.4)

common

common

lactic acidosis

very rare

very rare

Nervous system disorders

hypo-aesthesia

common

common

insomnia

uncommon

uncommon

headache

common

taste disturbance

common

common

Eye disorders

visual disturbance2

common

common

macular oedema

not known

not known

Gastrointestinal disorders3

abdominal pain

very common

very common

diarrhoea

very common

very common

flatulence

uncommon

loss of appetite

very common

very common

nausea

very common

very common

vomiting

very common

very common

Hepatobiliary disorders

Hepatitis4

not known

not known

Skin and subcutaneous tissue disorders

erythema

very rare

very rare

pruritis

very rare

very rare

urticaria

very rare

very rare

Musculoskeletal and connective tissue disorders

bone fracture5

common

common

arthralgia

common

Renal and urinary disorders

haematuria

common

Reproductive system and breast disorders

erectile dysfunction

common

General disorders and administration site conditions

Oedema6

common

Investigations

weight increased7

common

common

alanine aminotransferase increased8

not known

not known

liver function tests abnormal4

not known

not known

Description of selected adverse reactions

1 Post-marketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria.

2 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.

3 Gastrointestinal disorders occur most frequently during initiation of therapy and resolve spontaneously in most cases.

4 Isolated reports: liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

5 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-treated groups and 7,400 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%; 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. The observed excess risk of fractures for women on pioglitazone in this study is therefore 0.5 fractures per 100 patient years of use. No increase in 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).

6 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.

7 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.

8 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.

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. In this study in patients receiving pioglitazone and insulin, a higher percentage of patients with heart failure was observed in patients aged ≥ 65 years compared with those less than 65 years (9.7% compared to 4.0%). In patients on insulin with no pioglitazone the incidence of heart failure was 8.2% in those ≥ 65 years compared to 4.0% in patients less than 65 years. Heart failure has been reported with marketing use of pioglitazone, and more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.

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.