PIOGLITAZONE AND METFORMIN HYDROCHLORIDE

Posology Adults with normal renal function (GFR ≥ 90mL/min) The recommended dose of Pioglitazone and Metformin hydrochloride 15 mg/850 mg film-coated tablets is 30 mg/day pioglitazone plus 1700 mg/day of metformin hydrochloride (this dose is achievable with one tablet of Pioglitazone and Metformin hydrochloride 15 mg/850 mg film-coated tablets 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 Pioglitazone and Metformin hydrochloride 15 mg/850 mg film-coated tablets. When clinically appropriate, direct change from metformin monotherapy to Pioglitazone and Metformin hydrochloride 15 mg/850 mg film-coated tablets may be considered.

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

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. 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.

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 diarrhea 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 Postmarketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported.

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. g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses.

4) should be reviewed before considering initiation of metformin in patients with GFR < 60 mL/min. If no adequate strength of Pioglitazone and Metformin hydrochloride 15 mg/850 mg film-coated tablets is available, individual monocomponents should be used instead of the fixed dose combination.

GFR mL/min Metformin Pioglitazone 60-89 Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function. 45-59 Maximum daily dose is 2000 mg. The starting dose is at most half of the maximum dose.

30-44 Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose. < 30 Metformin is contra-indicated No dose adjustment. 4). Paediatric population The safety and efficacy of pioglitazone/metformin hydrochloride 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 Pioglitazone and Metformin hydrochloride 15 mg/850 mg film-coated tablets with, or just after food, may reduce gastrointestinal symptoms associated with metformin.

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), Pioglitazone and Metformin hydrochloride 15 mg/850 mg film-coated tablets should be temporarily discontinued and contact with a health care professional is recommended.

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