Competact · 4.4 Special warnings and precautions for use · 1

HOS-094252 · has-adverse-reaction-information · PDF-Seite 9

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 absorption decreased2 very rare very rare lactic acidosis very rare very rare Nervous system disorders hypo-aesthesia common common insomnia uncommon unco

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HOS-094248 · has-contraindication-information · PDF-Seite 3

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) 3 - 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)

HOS-094247 · has-indication-information · PDF-Seite 2

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).

HOS-094250 · has-interaction-information · PDF-Seite 7

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 7 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

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HOS-094251 · has-pregnancy-information · PDF-Seite 8

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). 8 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.

HOS-094249 · has-warning-information · PDF-Seite 4

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 secti

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