Glubrava

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Glubrava 15 mg/850 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 15 mg of pioglitazone (as hydrochloride) and 850 mg of metformin 
hydrochloride. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
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.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications  
 
Glubrava 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 Glubrava is 30 mg/day pioglitazone plus 1,700 mg/day of metformin 
hydrochloride (this dose is achievable with one tablet of Glubrava 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 Glubrava. 
 
When clinically appropriate, direct change from metformin monotherapy to Glubrava 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 Glubrava should have their renal function monitored regularly (see 
sections 4.3 and 4.4).  
 



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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 Glubrava 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 
Glubrava should not be used in patients with hepatic impairment (see sections 4.3 and 4.4). 
 
Paediatric population 
The safety and efficacy of Glubrava 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 Glubrava with, or just after food, may 
reduce gastrointestinal symptoms associated with metformin. 
 
4.3 Contraindications  
 
Glubrava 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) 



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- 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), Glubrava 
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 Glubrava 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. 
 
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 
Glubrava 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 



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anti-inflammatory drugs, including selective COX-2 inhibitors. Glubrava 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 Glubrava undergo periodic monitoring of liver 
enzymes. Liver enzymes should be checked prior to the initiation of therapy with Glubrava in all 
patients. Therapy with Glubrava 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 Glubrava, 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 Glubrava 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 Glubrava should be guided by clinical judgement 
pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued. 
 



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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 Glubrava 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. Glubrava 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 



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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). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
There have been no formal interaction studies for Glubrava. The following statements reflect the 
information available on the individual active substances (pioglitazone and metformin). 
 
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. 
 
Angiotensin-converting enzyme (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. 
 
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 
Glubrava 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. 
 



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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, ACE inhibitors, 
angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such 
products in combination with Glubrava, 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. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception in males and females 
 
Glubrava is not recommended in women of childbearing potential not using contraception. If a patient 
wishes to become pregnant, treatment with Glubrava should be discontinued. 
 
Pregnancy 
 
Pioglitazone 
There are no adequate human data from the use of pioglitazone in pregnant women. Studies of 
pioglitazone in animals have shown reproductive toxicity (see section 5.3). The potential risk for 
humans is unknown. 
 
Metformin 
There are limited amount of data from the use of metformin in pregnant women. Animal studies have 
not revealed teratogenic effects or do not indicate direct or indirect harmful effects with respect to 
reproductive toxicity (see section 5.3).  
 
Glubrava should not be used during pregnancy. If a pregnancy occurs, treatment with Glubrava should 
be discontinued. 
 
Breast-feeding 
 
It is unknown whether pioglitazone and metformin are excreted in human milk. Available 
toxicological data in animals have shown excretion of pioglitazone and metformin in the milk of 
lactating rats (see section 5.3). A risk to the newborns/infants cannot be excluded.  
 
Glubrava is contraindicated during 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 
 
Glubrava 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. 
 



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4.8 Undesirable effects 
 
Summary of the safety profile 
 
Clinical trials have been conducted with Glubrava 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 Glubrava 

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 



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Adverse reaction Frequency of adverse reactions 
 Pioglitazone Metformin Glubrava 

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 

 
Description of selected adverse reactions 
 
1 Postmarketing 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 event reports 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). 
 
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 

javascript:%20OpenTerm%20('PT:10001551')


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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 (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 national reporting system 
listed in Appendix V. 
 
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.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering 
drugs, ATC code: A10BD05. 
 
Glubrava combines two antihyperglycaemic active substances with complementary mechanisms of 
action to improve glycaemic control in patients with type 2 diabetes mellitus: pioglitazone, a member 
of the thiazolidinedione class and metformin hydrochloride, a member of the biguanide class. 
Thiazolidinediones act primarily by reducing insulin resistance and biguanides act primarily by 
decreasing endogenous hepatic glucose production. 
 

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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 2 
diabetes 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 prior 
to baseline measurements. After 24 weeks of treatment, the primary endpoint of mean change from 
baseline 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 individual 
products and did not suggest any new safety issues. 
 
Pioglitazone 
 
Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act 
via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading 
to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with 
pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose 
disposal in the case of insulin resistance. 
 
Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The 
improved glycaemic control is associated with a reduction in both fasting and postprandial plasma 
insulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to 
two years in order to assess time to treatment failure (defined as appearance of HbA1c ≥8.0% after the 
first six months of therapy). Kaplan-Meier analysis showed shorter time to treatment failure in patients 
treated 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% of 
patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with 
gliclazide 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 during 
the second year was less with pioglitazone than with gliclazide. 
 
In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin 
optimisation period were randomised to pioglitazone or placebo for 12 months. Patients receiving 
pioglitazone had a mean reduction in HbA1c of 0.45% compared with those continuing on insulin 
alone, and a reduction of insulin dose in the pioglitazone treated group. 
 
HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulin 
sensitivity. Two-year clinical studies have shown maintenance of this effect. 
 
In one year clinical trials, pioglitazone consistently gave a statistically significant reduction in the 
albumin/creatinine ratio compared to baseline. 
 
The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in 
type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was 
significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in 
body 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 clinically 
significant 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-cholesterol 
levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically 
significant increases in LDL-cholesterol levels compared with placebo, whilst reductions where 
observed 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 and 



13 

hepatically synthesised triglycerides. These effects were independent of pioglitazone’s effects on 
glycaemia and were statistically significantly different to glibenclamide. 
 
In PROactive, a cardiovascular outcome study, 5,238 patients with type 2 diabetes mellitus and 
pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to 
existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an 
average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of 
patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible 
patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous 
cardiac 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 myocardial 
infarction and approximately 20% had had a stroke. Approximately half of the study population had at 
least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving 
cardiovascular medicinal products (beta blockers, ACE inhibitors, angiotensin II antagonists, calcium 
channel blockers, nitrates, diuretics, acetylsalicylic acid, statins, fibrates). 
 
Although the study failed regarding its primary endpoint, which was a composite of all-cause 
mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, 
coronary revascularisation and leg revascularisation, the results suggest that there are no long-term 
cardiovascular concerns regarding use of pioglitazone. However, the incidence of oedema, weight gain 
and heart failure were increased. No increase in mortality from heart failure was observed. 
 
Metformin 
 
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial 
plasma 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 and 

utilisation 
- by delaying intestinal glucose absorption. 
 
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin 
increases 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 lipid 
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term 
clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels. 
 
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood 
glucose control in type 2 diabetes mellitus. Analysis of the results for overweight patients treated with 
metformin after failure of diet alone showed: 
 
- a significant reduction of the absolute risk of any diabetes-related complication in the metformin 

group (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: 
metformin 7.5 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: 
metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, 
(p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 
18.9 events/1,000 patient-years (p=0.021) 



14 

- a significant reduction in the absolute risk of myocardial infarction: 
metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01). 

 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Glubrava in all subsets of the paediatric population in type 2 diabetes mellitus. See section 4.2 for 
information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
Glubrava 
 
Bioequivalence studies in healthy volunteers have shown Glubrava to be bioequivalent to the 
administration of pioglitazone and metformin given as separate tablets. 
 
Food had no effect on the AUC and Cmax of pioglitazone when Glubrava was administered to healthy 
volunteers. 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 and 
0.8 h for metformin. 
 
The following statements reflect the pharmacokinetic properties of the individual active substances of 
Glubrava. 
 
Pioglitazone 
 
Absorption 
Following oral administration, pioglitazone is rapidly absorbed, and peak plasma concentrations of 
unchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases of 
the plasma concentration were observed for doses from 2-60 mg. Steady state is achieved after 
4-7 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%. 
 
Distribution 
The estimated volume of distribution in humans is 0.25 L/kg. 
 
Pioglitazone and all active metabolites are extensively bound to plasma protein (> 99%). 
 
Biotransformation 
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 lesser 
degree. 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-III 
contribute equally to efficacy. On this basis M-IV contribution to efficacy is approximately three-fold 
that 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 pharmacokinetics 
or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant 
administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with 
rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the 
plasma concentration of pioglitazone (see section 4.5).  
 



15 

Elimination 
Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in 
faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged 
pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of 
unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.  
 
Linearity/non-linearity 
Single dose studies demonstrate linearity of pharmacokinetics in the therapeutic dose range. 
 
Elderly 
Steady state pharmacokinetics are similar in patients age 65 and over and young subjects. 
 
Patients with renal impairment 
In patients with renal impairment, plasma concentrations of pioglitazone and its metabolites are lower 
than those seen in subjects with normal renal function, but oral clearance of parent substance is 
similar. Thus free (unbound) pioglitazone concentration is unchanged. 
 
Patients with hepatic impairment 
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. 
 
Metformin 
 
Absorption 
After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg 
metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed 
fraction recovered in faeces was 20-30%. 
 
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the 
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing 
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 
1 µg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 
4 µg/mL, even at maximum doses. 
 
Food decreases the extent and slightly delays the absorption of metformin. Following administration 
of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min 
prolongation of time to peak plasma concentration was observed. The clinical relevance of this 
decrease is unknown. 
 
Distribution 
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower 
than the plasma peak and appears at approximately the same time. The red blood cells most likely 
represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L. 
 
Biotransformation 
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans. 
 
Elimination 
Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular 
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is 
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to 
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of 
metformin in plasma. 
 
Linearity/non-linearity 
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the 
pharmacokinetics of metformin absorption is non-linear. 



16 

 
5.3 Preclinical safety data 
 
No animal studies have been conducted with the combined products of Glubrava. The following data 
are findings in studies performed with pioglitazone or metformin individually. 
 
Pioglitazone 
 
In toxicology studies, plasma volume expansion with haemodilution, anaemia, and reversible eccentric 
cardiac 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 observed 
across species at plasma concentrations ≤4 times the clinical exposure. Foetal growth restriction was 
apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in 
diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during 
pregnancy 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 vitro 
genotoxicity 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 was 
postulated as the mechanistic basis for the observed tumourigenic response in the male rat. A 
24-month mechanistic study in male rats demonstrated that administration of pioglitazone resulted in 
an increased incidence of hyperplastic changes in the bladder. Dietary acidification significantly 
decreased but did not abolish the incidence of tumours. The presence of microcrystals exacerbated the 
hyperplastic response but was not considered to be the primary cause of hyperplastic changes. The 
relevance 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 not 
seen in dogs or monkeys treated with pioglitazone for up to 12 months. 
 
In an animal model of familial adenomatous polyposis (FAP), treatment with two other 
thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is 
unknown. 
 
Metformin 
 
Non-clinical data for metformin reveal no special hazard for humans based on conventional studies of 
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to 
reproduction. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Microcrystalline cellulose 
Povidone (K30) 
Croscarmellose sodium 
Magnesium stearate 
 
Film coat 
Hypromellose 
Macrogol 8000 
Talc 
Titanium dioxide (E171).  



17 

 
6.2 Incompatibilities  
 
Not applicable. 
 
6.3 Shelf life  
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blisters.  
Packs of 14, 28, 30, 50, 56, 60, 90, 98 and 180 tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/07/421/001 
EU/1/07/421/002 
EU/1/07/421/003 
EU/1/07/421/004 
EU/1/07/421/005 
EU/1/07/421/006 
EU/1/07/421/007 
EU/1/07/421/008 
EU/1/07/421/009 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 11 December 2007 
Date of latest renewal: 10 November 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

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


18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURERS RESPONSIBLE FOR BATCH 

RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
 



19 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Delpharm Novara S.r.l.  
Via Crosa, 86 
28065 Cerano (NO) 
Italy 
 
Takeda Ireland Limited 
Bray Business Park 
Kilruddery 
County Wicklow 
Ireland 
 
Lilly S.A. 
Avda. de la Industria 30 
28108 Alcobendas 
Madrid 
Spain 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



22 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Glubrava 15 mg/850 mg film-coated tablets 
 
pioglitazone/metformin hydrochloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 15 mg pioglitazone (as hydrochloride) and 850 mg metformin hydrochloride. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet. 
14 tablets 
28 tablets 
30 tablets 
50 tablets 
56 tablets 
60 tablets 
90 tablets 
98 tablets 
180 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



23 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/07/421/001 14 tablets 
EU/1/07/421/002 28 tablets 
EU/1/07/421/003 30 tablets 
EU/1/07/421/004 50 tablets 
EU/1/07/421/005 56 tablets 
EU/1/07/421/006 60 tablets 
EU/1/07/421/007 90 tablets 
EU/1/07/421/008 98 tablets 
EU/1/07/421/009 180 tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Glubrava 15 mg/850 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



24 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Glubrava 15 mg/850 mg tablets 
 
pioglitazone/metformin hydrochloride 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER  
 
FOR CALENDARISED PACKS: 
Mon. 1  Mon. 2 
Tue. 1   Tue. 2 
Wed. 1  Wed. 2 
Thu. 1  Thu. 2 
Fri. 1   Fri. 2 
Sat. 1   Sat. 2 
Sun. 1   Sun. 2 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



26 

Package leaflet: Information for the patient 
 

Glubrava 15 mg/850 mg film-coated tablets 
pioglitazone/metformin hydrochloride 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What Glubrava is and what it is used for 
2. What you need to know before you take Glubrava  
3. How to take Glubrava  
4. Possible side effects 
5 How to store Glubrava 
6. Contents of the pack and other information 
 
 
1. What Glubrava is and what it is used for 
 
Glubrava contains pioglitazone and metformin which are anti-diabetic medicines, used to control 
blood sugar level.  
 
It is used in adults to treat type 2 (non-insulin dependent) diabetes mellitus when treatment with 
metformin alone is not sufficient. This type 2 diabetes usually develops in adulthood particularly as a 
result of the person being overweight and where the body either does not produce enough insulin (a 
hormone that controls blood sugar levels), or cannot effectively use the insulin it produces.  
 
Glubrava helps control the level of sugar in your blood when you have type 2 diabetes by helping your 
body make better use of the insulin it produces. If 3 to 6 months after starting Glubrava your sugar 
control is not improved, the medicine should be discontinued. 
 
 
2. What you need to know before you take Glubrava  
 
Do not take Glubrava: 
- if you are allergic to pioglitazone, metformin or any of the other ingredients of this medicine 

(listed in section 6). 
- if you have heart failure or have had heart failure in the past. 
- if you recently had a heart attack, have severe circulatory problems including shock, or 

breathing difficulties. 
- if you have liver disease. 
- if you drink alcohol excessively (either every day or only from time to time). 
- if you have uncontrolled diabetes with, for example, severe hyperglycaemia (high blood 

glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic acidosis (see section “Risk of 
lactic acidosis”) or ketoacidosis. Ketoacidosis is a condition in which substances called 'ketone 
bodies' accumulate in the blood and which can lead to diabetic pre-coma. Symptoms include 
stomach pain, fast and deep breathing, sleepiness or your breath developing an unusual fruity 
smell. 

- if you have or have ever had bladder cancer. 
- if you have blood in your urine that your doctor has not checked. 



27 

- if you have severely reduced kidney function. 
- if you have a severe infection or are dehydrated. 
- if you are going to have a certain type of X-ray with an injectable dye, talk to your doctor as you 

must stop taking Glubrava for a certain period of time before and after the examination. 
- if you are breast-feeding. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Glubrava (also see section 4) 
- if you have a problem with your heart. Some patients with long-standing type 2 diabetes 

mellitus and heart disease or previous stroke who were treated with pioglitazone and insulin 
together experienced the development of heart failure. Inform your doctor as soon as possible if 
you experience signs of heart failure such as unusual shortness of breath or rapid increase in 
weight or localised swelling (oedema).  

- if you retain water (fluid retention) or have heart failure problems in particular if you are over 
75 years old. If you take anti-inflammatory medicines which can also cause fluid retention and 
swelling, you must also tell your doctor. 

- if you have a special type of diabetic eye disease called macular oedema (swelling of the back 
of the eye), talk to your doctor if you notice any change to your vision. 

- if you have cysts on your ovaries (polycystic ovary syndrome). There may be an increased 
possibility of becoming pregnant because you may ovulate again when you take Glubrava. If 
this applies to you, use appropriate contraception to avoid the possibility of an unplanned 
pregnancy. 

- if you have a problem with your liver. Before you start taking Glubrava you will have a blood 
sample taken to check your liver function. This check should be repeated at intervals. Inform 
your doctor as soon as possible if you develop symptoms suggesting a problem with your liver 
(like feeling sick without explanations, vomiting, stomach ache, tiredness, loss of appetite 
and/or dark urine) as your liver function should be checked.  

 
You may also experience a reduction in blood count (anaemia).  
Your doctor may take blood tests to monitor your blood cell levels and liver function. 
 
Risk of lactic acidosis 
Glubrava may cause a very rare, but very serious side effect called lactic acidosis, particularly if your 
kidneys are not working properly. The risk of developing lactic acidosis is also increased with 
uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further 
information below), liver problems and any medical conditions in which a part of the body has a 
reduced supply of oxygen (such as acute severe heart disease).  
If any of the above apply to you, talk to your doctor for further instructions. 
 
Stop taking Glubrava for a short time if you have a condition that may be associated with 
dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to 
heat or if you drink less fluid than normal. Talk to your doctor for further instructions. 
 
Stop taking Glubrava and contact a doctor or the nearest hospital immediately if you experience 
some of the symptoms of lactic acidosis, as this condition may lead to coma.  
Symptoms of lactic acidosis include: 
- vomiting 
- stomach ache (abdominal pain) 
- muscle cramps 
- a general feeling of not being well with severe tiredness 
- difficulty in breathing 
- reduced body temperature and heartbeat 
 
Lactic acidosis is a medical emergency and must be treated in a hospital. 
 
During treatment with Glubrava, your doctor will check your kidney function at least once a year or 
more frequently if you are elderly and/or if you have worsening kidney function. 



28 

 
If you need to have major surgery you must stop taking Glubrava during and for some time after the 
procedure. Your doctor will decide when you must stop and when to restart your treatment with 
Glubrava. 
 
Hypoglycaemia 
If you take Glubrava with other medicines for diabetes, it is more likely that your blood sugar could 
fall below the normal level (hypoglycaemia). If you experience symptoms of hypoglycaemia such as 
weakness, dizziness, increased sweating, fast heart-beating, vision disorders or difficulty in 
concentration, you should take some sugar to increase your blood sugar level again. Ask your doctor 
or pharmacist for more information if you are not sure how to recognise this. It is recommended that 
you carry some sugar lumps, sweets, biscuits or sugary fruit juice. 
The level of sugar in your blood or urine should be checked regularly.  
 
Broken bones 
A higher number of bone fractures was seen in patients, particularly women taking pioglitazone. Your 
doctor will take this into account when treating your diabetes. 
 
Children and adolescents 
Use in children and adolescents under 18 years is not recommended. 
 
Other medicines and Glubrava 
If you need to have an injection of a contrast medium that contains iodine into your bloodstream, for 
example in the context of an X-ray or scan, you must stop taking Glubrava before or at the time of the 
injection. Your doctor will decide when you must stop and when to restart your treatment with 
Glubrava. 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. You may need more frequent blood glucose and kidney function tests, or your doctor may 
need to adjust the dose of Glubrava. This is because some medicines can weaken or strenghten the 
effect of Glubrava on the level of sugar in your blood.  
 
The following medicines can increase the blood sugar lowering effect of Glubrava. This can lead to a 
risk of hypoglycaemia (low blood sugar): 
- gemfibrozil (to lower high cholesterol level) 
- angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (to 

treat high blood pressure) 
- cimetidine (to reduce stomach acid) 
 
The following medicines may decrease the blood sugar lowering effect of Glubrava. This can lead to a 
risk of hyperglycaemia (high blood sugar level): 
- rifampicin (to treat tuberculosis and other infections) 
- glucocorticoids (to treat allergies and inflammation) 
- beta-2-agonists (to treat asthma) 
- medicines which increase urine production (diuretics, to treat high blood pressure) 
 
Other:  
Medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors, such as ibuprofen and  
celecoxib). 
 
Glubrava with alcohol 
Avoid excessive alcohol intake while taking Glubrava since this may increase the risk of lactic 
acidosis (see section “Risk of lactic acidosis”). 
 



29 

Pregnancy and breast-feeding 
- you must tell your doctor if you are pregnant, think you may be pregnant or are planning to have 

a baby. You should not use this medicine if you are pregnant. If you wish to become pregnant, 
your doctor will advise you to discontinue this medicine.  

 
- do not use this medicine if you are breastfeeding or are planning to breast-feed (see section “Do 

not take Glubrava”).  
 
Driving and using machines 
This medicine will not affect your ability to drive or use machines but take care if you experience 
abnormal vision. 
 
 
3. How to take Glubrava  
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
The recommended dose is one tablet taken twice daily. If necessary your doctor may tell you to take a 
different dose. If you have reduced kidney function, your doctor may prescribe a lower dose, which 
may need to be given as separate tablets of pioglitazone and metformin.  
You should swallow the tablets with a glass of water. You may take your tablets with or just after food 
to reduce the chance of an upset stomach. 
 
If you are following a special diet for diabetes, you should continue with this while you are taking 
Glubrava. 
 
Your weight should be checked at regular intervals; if your weight increases, inform your doctor. 
 
Your doctor will ask you to have blood tests periodically during treatment with Glubrava. This is to 
check that your liver is working normally. At least once a year (more often if you are elderly or have 
kidney problems) your doctor will check that your kidneys are working normally. 
 
If you take more Glubrava than you should 
If you accidentally take too many tablets, or if someone else or a child takes your medicine, talk to a 
doctor or pharmacist immediately. Your blood sugar could fall below the normal level and can be 
increased by taking sugar. It is recommended that you carry some sugar lumps, sweets, biscuits or 
sugary fruit juice. 
 
If you forget to take Glubrava 
Take Glubrava daily as prescribed. However if you miss a dose, skip the missed dose and just carry on 
with the next dose as normal. Do not take a double dose to make up for a forgotten tablet. 
 
If you stop taking Glubrava 
Glubrava should be used every day to work properly. If you stop using Glubrava, your blood sugar 
may go up. Talk to your doctor before stopping this treatment. 
 
If you have any further questions on the use of this medicine ask your doctor or pharmacist. 
 
 



30 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
In particular, patients have experienced the following serious side effects: 
 
Glubrava may cause a very rare (may affect up to 1 in 10,000), but very serious side effect called 
lactic acidosis (see section “Warnings and precautions”). If this happens you must stop taking 
Glubrava and contact a doctor or the nearest hospital immediately, as lactic acidosis may lead to 
coma. 
 
Bladder cancer has been experienced uncommonly (may affect up to 1 in 100 people) in patients 
taking Glubrava. Signs and symptoms include blood in your urine, pain when urinating or a sudden 
need to urinate. If you experience any of these, talk to your doctor as soon as possible. 
 
Localised swelling (oedema) has also been experienced commonly (may affect up to 1 in 10 people) in 
patients taking Glubrava in combination with insulin. If you experience this side effect, talk to your 
doctor as soon as possible. 
 
Broken bones have been reported commonly (may affect up to 1 in 10 people) in female patients 
taking Glubrava and have also been reported in male patients (frequency cannot be estimated from the 
available data) taking Glubrava. If you experience this side effect, talk to your doctor as soon as 
possible. 
 
Blurred vision due to swelling (or fluid) at the back of the eye (macular oedema) has also been 
reported in patients taking Glubrava (frequency cannot be estimated from the available data). If you 
experience this symptom for the first time, talk to your doctor as soon as possible. Also, if you already 
have blurred vision and the symptom gets worse, talk to your doctor as soon as possible. 
 
Allergic reactions have been reported with frequency not known (cannot be estimated from the 
available data) in patients taking Glubrava. If you have a serious allergic reaction, including hives and 
swelling of the face, lips, tongue, or throat that may cause difficulty in breathing or swallowing stop 
taking this medicine and talk to your doctor immediately. 
 
The following side effects have been experienced by some patients taking Glubrava 
 
Very common (may affect more than 1 in 10 people) 
- stomach ache 
- feeling sick (nausea) 
- vomiting 
- diarrhoea 
- loss of appetite 
 
Common 
- weight gain 
- headache 
- respiratory infection 
- abnormal vision 
- joint pain 
- impotence 
- blood in urine 
- reduction in blood count (anaemia) 
- numbness 
- taste disturbance 
 



31 

Uncommon 
- inflammation of the sinuses (sinusitis) 
- gas 
- difficulty sleeping (insomnia) 
 
Very rare 
- decrease in amount of vitamin B12 in the blood 
- redness of the skin 
- itchy skin 
- raised and itchy rash (hives) 
 
Not known 
- inflammation of the liver (hepatitis) 
- liver does not work as well as it should (changes in liver enzymes) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Glubrava 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and the blister after “EXP”. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Glubrava contains 
- The active substances are pioglitazone and metformin hydrochloride. Each tablet contains 

15 mg of pioglitazone (as hydrochloride) and 850 mg of metformin hydrochloride. 
- The other ingredients are microcrystalline cellulose, povidone (K30), croscarmellose sodium 

magnesium stearate, hypromellose, macrogol 8000, talc and titanium dioxide (E171). 
 
What Glubrava looks like and contents of the pack 
The film-coated tablets (tablets) are white to off white, oblong, convex, embossed ’15 / 850’ on one 
face and ‘4833M’ on the other. They are supplied in aluminium/aluminium blister in packs of 14, 28, 
30, 50, 56, 60, 90, 98 or 180 tablets.  
 
Not all pack sizes may be marketed. 
 
Marketing authorisation holder:  
Takeda Pharma A/S, 
Dybendal Alle 10, 
2630 Taastrup, 
Denmark. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


32 

Manufacturer: 
Takeda Ireland Limited, Bray Business Park, Kilruddery, County Wicklow, Ireland  
Delpharm Novara S.r.l., Via Crosa, 86, I-28065 Cerano (NO), Italy  
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Takeda Belgium 
Tél/Tel: +32 2 464 06 11 
Takeda-belgium@takeda.com  
 

Lietuva 
Takeda UAB 
Tel: +370 521 09 070 
Lt-info@takeda.com  

България 
Такеда България 
Тел.: + 359 2 958 27 36;  + 359 2 958 15 29 
 

Luxembourg/Luxemburg 
Takeda Belgium 
Tél/Tel: +32 2 464 06 11 
Takeda-belgium@takeda.com  
 

Česká republika 
Takeda Pharmaceuticals Czech Republic s.r.o. 
Tel: + 420 234 722 722  

Magyarország 
Takeda Pharma Kft. 
Tel: +361 2707030 
 

Danmark 
Takeda Pharma A/S 
Tlf: +45 46 77 11 11 
 

Malta 
Takeda Italia S.p.A. 
Tel: +39 06 502601 
 

Deutschland 
Takeda GmbH 
Tel: 0800 825 3325 
medinfo@takeda.de  

Nederland 
Takeda Nederland bv 
Tel: +31 23 56 68 777 
 

Eesti 
Takeda Pharma AS 
Tel: +372 6177 669 
info@takeda.ee  
 

Norge  
Takeda AS 
Tlf: +47 6676 3030 
infonorge@ takeda.com 
 

Ελλάδα 
TAKEDA ΕΛΛΑΣ Α.Ε 
Τηλ: +30 210 6387800 
gr.info@takeda.com  
 

Österreich 
Takeda Pharma Ges.m.b.H 
Tel: +43(0)800 20 80 50 
 

España 
Takeda Farmacéutica España S.A. 
Tel: +34 917 14 99 00 
spain@takeda.com  

Polska 
Takeda Polska Sp. z o.o. 
Tel.: +48 22 608 13 00 
 
 

France 
Takeda France  
Tél: +33 1 46 25 16 16 
 

Portugal 
Takeda - Farmacêuticos Portugal, Lda. 
Tel: + 351 21 120 1457 

Hrvatska 
Takeda Pharmaceuticals Croatia d.o.o 
Tel: +385 1 377 88 96 
 

România 
Takeda Pharmaceuticals SRL 
Tel: +40 21 335 03 91 
 

Ireland 
Takeda Products Ireland Limited 
Tel: +353 (0) 1 6420021 
 

Slovenija 
Takeda GmbH Podružnica Slovenija 
Tel:+ 386 (0) 59 082 480 
 

mailto:Takeda%1Ebelgium@takeda.com
mailto:Lt%1Einfo@takeda.com
mailto:Takeda%1Ebelgium@takeda.com
mailto:medinfo@takeda.de
mailto:info@takeda.ee
mailto:gr.info@takeda.com
mailto:spain@takeda.com


33 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
vistor@vistor.is  
 

Slovenská republika 
Takeda Pharmaceuticals Slovakia s.r.o. 
Tel: +421 (2) 20 602 600 
 
 

Italia 
Takeda Italia S.p.A. 
Tel: +39 06 502601 
 

Suomi/Finland 
Takeda Oy 
Puh/Tel: +358 20 746 5000 
 

Κύπρος 
Takeda Pharma A/S 
Τηλ: +45 46 77 11 11 
 

Sverige 
Takeda Pharma AB 
Tel: +46 8 731 28 00 
infosweden@takeda.com  
 

Latvija 
Takeda Latvia SIA 
Tel: +371 67840082 
 

United Kingdom 
Takeda UK Ltd 
Tel: +44 (0)1628 537 900 
 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 

mailto:vistor@vistor.is
mailto:infosweden@takeda.com
http://www.ema.europa.eu/


34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 

OF THE MARKETING AUTHORISATION(S) 
 
 
 
 
 
 
 
 
 
 
 
 
 



35 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for glimepiride / pioglitazone 
hydrochloride, metformin / pioglitazone, pioglitazone, the scientific conclusions of CHMP are as 
follows:  
 
The MAH provided updates on new information related to the important identified and important 
potential risks as listed in the summary of safety concerns. The data presented during the current 
reporting period did not provide new information that would allow for further reduction, mitigation, or 
characterisation of these risks. Based on the data presented, the risk minimisation measures in the 
approved product information are considered adequate for the listed safety concerns. 
Given the accumulation of data since the implementation of the additional risk minimisation measures, 
the PRAC agreed with the MAH’s proposal to remove the additional risk minimisation measures. As a 
consequence, the conditions or restrictions with regards to the safe and effective use of the medicinal 
product should be updated to remove the additional risk minimisation measures. The RMP has been 
updated in accordance. 
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
 
Grounds for the variation to the terms of the Marketing Authorisation(s)  
 
On the basis of the scientific conclusions for glimepiride / pioglitazone hydrochloride, metformin / 
pioglitazone, pioglitazone the CHMP is of the opinion that the benefit-risk balance of the medicinal 
product(s) containing glimepiride / pioglitazone hydrochloride, metformin / pioglitazone, pioglitazone 
is unchanged subject to the proposed changes to the product information. 
 
The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 
 
 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)