Metformin and Pioglitazone interacts in the following cases:
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 should be reviewed before considering initiation of metformin in patients with GFR <60 mL/min. If no adequate strength of pioglitazone/metformin 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. |
For metformin/pioglitazone no preclinical or clinical data on exposed pregnancies are available.
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.
Animal studies have not revealed teratogenic effects. Small clinical trials have not revealed metformin to have malformative effects.
Metformin/pioglitazone should not be used during pregnancy. If a pregnancy occurs, treatment with metformin/pioglitazone should be discontinued.
For metformin/pioglitazone no preclinical or clinical data on exposed lactation are available.
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. Metformin/pioglitazone must therefore not be used in women who are breast-feeding.
Metformin/pioglitazone is not recommended in women of childbearing potential not using contraception. If a patient wishes to become pregnant, treatment with metformin/pioglitazone should be discontinued.
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.
Metformin/pioglitazone combination 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.
Clinical trials have been conducted with pioglitazone/metformin fixed dose combination tablets and co-administered pioglitazone and metformin. 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) and other reactions such as bone fracture, weight increase and oedema may occur commonly (≥1/100 to <1/10).
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 | Pioglitazone/metformin | |
| 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 | uncommon | |
| headache | common | ||
| taste disturbance | common | common | |
| Eye disorders | |||
| visual disturbance3 | common | common | |
| macular oedema | not known | not known | |
| Gastrointestinal disorders4 | |||
| 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 | |||
| hepatitis5 | 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 fracture6 | common | common | |
| arthralgia | common | ||
| Renal and urinary disorders | |||
| haematuria | common | ||
| Reproductive system and breast disorders | |||
| erectile dysfunction | common | ||
| General disorders and administration site conditions | |||
| oedema7 | common | ||
| Investigations | |||
| weight increased8 | common | common | |
| alanine aminotransferase increased9 | not known | not known | |
| liver function tests abnormal5 | not known | not known | |
1 Post-marketing reports of hypersensitivity reactions in patients treated with pioglitazone have been reported. These reactions include anaphylaxis, angioedema, and urticaria.
2 Long term treatment of metformin has been associated with a decrease of vitamin B12 absorption with decrease of serum levels. Consideration of such aetiology is recommended if a patient presents with megaloplastic anaemia.
3 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.
4 Gastrointestinal disorders occur most frequently during initiation of therapy and resolve spontaneously in most cases.
5 Isolated reports: liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.
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-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.
7 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.
8 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.
9 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.
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