Incresync

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Incresync 12.5 mg/30 mg film-coated tablets 
Incresync 25 mg/30 mg film-coated tablets 
Incresync 25 mg/45 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Incresync 12.5 mg/30 mg film-coated tablets 
Each tablet contains alogliptin benzoate and pioglitazone hydrochloride equivalent to 12.5 mg 
alogliptin and 30 mg pioglitazone. 
 
Excipient(s) with known effect 
Each tablet contains 121 mg of lactose (as monohydrate).  
 
Incresync 25 mg/30 mg film-coated tablets 
Each tablet contains alogliptin benzoate and pioglitazone hydrochloride equivalent to 25 mg alogliptin 
and 30 mg pioglitazone. 
 
Excipient(s) with known effect 
Each tablet contains 121 mg of lactose (as monohydrate). 
 
Incresync 25 mg/45 mg film-coated tablets 
Each tablet contains alogliptin benzoate and pioglitazone hydrochloride equivalent to 25 mg alogliptin 
and 45 mg pioglitazone. 
 
Excipient(s) with known effect 
Each tablet contains 105 mg of lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Incresync 12.5 mg/30 mg film-coated tablets 
Pale peach, round (approximately 8.7 mm in diameter), biconvex, film-coated tablets with both “A/P” 
and “12.5/30” printed in red ink on one side. 
 
Incresync 25 mg/30 mg film-coated tablets 
Peach, round (approximately 8.7 mm in diameter), biconvex, film-coated tablets with both “A/P” and 
“25/30” printed in grey ink on one side. 
 
Incresync 25 mg/45 mg film-coated tablets 
Red, round (approximately 8.7 mm in diameter), biconvex, film-coated tablets with both “A/P” and 
“25/45” printed in grey ink on one side. 
 
 



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4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Incresync is indicated as a second or third line treatment in adult patients aged 18 years and older with 
type 2 diabetes mellitus: 
 
• as an adjunct to diet and exercise to improve glycaemic control in adult patients (particularly 

overweight patients) inadequately controlled on pioglitazone alone, and for whom metformin is 
inappropriate due to contraindications or intolerance. 

 
• in combination with metformin (i.e. triple combination therapy) as an adjunct to diet and 

exercise to improve glycaemic control in adult patients (particularly overweight patients) 
inadequately controlled on their maximal tolerated dose of metformin and pioglitazone. 

 
In addition, Incresync can be used to replace separate tablets of alogliptin and pioglitazone in those 
adult patients aged 18 years and older with type 2 diabetes mellitus already being treated with this 
combination. 
 
After initiation of therapy with Incresync, 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, Incresync should be discontinued. In light of potential risks with prolonged pioglitazone 
therapy, prescribers should confirm at subsequent routine reviews that the benefit of Incresync is 
maintained (see section 4.4). 
 
4.2 Posology and method of administration 
 
Posology 
 
For the different dose regimens Incresync is available in strengths of 25 mg/30 mg, 25 mg/45 mg and 
12.5 mg/30 mg film-coated tablets. 
 
Adults (≥ 18 years old) 
The dose should be individualised on the basis of the patient’s current treatment regimen 
 
For patients intolerant to metformin or for whom metformin is contraindicated, inadequately 
controlled on pioglitazone alone, the recommended dose of Incresync is one tablet of 25 mg/30 mg or 
25 mg/45 mg once daily, depending on the dose of pioglitazone already being taken. 
 
For patients inadequately controlled on dual therapy with pioglitazone and a maximally tolerated 
dose of metformin, the dose of metformin should be maintained, and Incresync administered 
concomitantly. The recommended dose is one tablet of 25 mg/30 mg or 25 mg/45 mg once daily, 
depending on the dose of pioglitazone already being taken. 
 
Caution should be exercised when alogliptin is used in combination with metformin and a 
thiazolidinedione as an increased risk of hypoglycaemia has been observed with this triple therapy (see 
section 4.4). In case of hypoglycaemia, a lower dose of the thiazolidinedione or metformin may be 
considered. 
 
For patients switching from separate tablets of alogliptin and pioglitazone, both alogliptin and 
pioglitazone should be dosed at the daily dose already being taken. 
 
Maximum daily dose 
The maximum recommended daily dose of 25 mg alogliptin and 45 mg pioglitazone should not be 
exceeded. 
 



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Special populations 
Elderly (≥ 65 years old) 
No dose adjustment is necessary based on age (see section 4.4). However, dosing of alogliptin should 
be conservative in patients with advanced age due to the potential for decreased renal function in this 
population. 
 
Renal impairment 
For patients with mild renal impairment (creatinine clearance (CrCl) > 50 to ≤ 80 mL/min), no dose 
adjustment of Incresync is necessary (see section 5.2). 
 
For patients with moderate renal impairment (CrCl ≥ 30 to ≤ 50 mL/min), one-half of the 
recommended dose of alogliptin should be administered. Therefore, one tablet of 12.5 mg/30 mg once 
daily is recommended in patients with moderate renal impairment (see section 5.2). 
 
Incresync is not recommended for patients with severe renal impairment (CrCl < 30 mL/min) or 
end-stage renal disease requiring dialysis.  
 
Appropriate assessment of renal function is recommended prior to initiation of Incresync and 
periodically thereafter (see section 4.4). 
 
Hepatic impairment 
Incresync must not be used in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2). 
 
Paediatric population 
The safety and efficacy of Incresync in children and adolescents < 18 years old have not been 
established. No data are available. 
 
Method of administration  
 
Oral use. 
 
Incresync should be taken once daily with or without food. The tablets should be swallowed whole 
with water.  
 
If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be 
taken on the same day. 
 
4.3 Contraindications 
 
- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or 

history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic 
shock, and angioedema, to any dipeptidyl-peptidase-4 (DPP-4) inhibitor (see sections 4.4 
and 4.8) 

- Cardiac failure or history of cardiac failure (NYHA stages I to IV; see section 4.4) 
- Hepatic impairment (see section 4.4) 
- Diabetic ketoacidosis 
- Current bladder cancer or a history of bladder cancer (see section 4.4) 
- Uninvestigated macroscopic haematuria (see section 4.4) 
 
4.4 Special warnings and precautions for use 
 
General 
 
Incresync should not be used in patients with type 1 diabetes mellitus. Incresync is not a substitute for 
insulin in insulin-requiring patients. 
 



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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 pioglitazone therapy 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. 
Patients should be observed for signs and symptoms of heart failure, weight gain and oedema when 
pioglitazone is used in combination with insulin. Since insulin and pioglitazone are both associated 
with fluid retention, concomitant administration may increase the risk of oedema. Post marketing 
cases of peripheral oedema and cardiac failure have also been reported in patients with concomitant 
use of pioglitazone and nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 
inhibitors. Incresync 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 anti-diabetic 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 patients 
 
In light of age-related risks (especially bladder cancer, fractures and heart failure associated with the 
pioglitazone component), the balance of benefits and risks should be considered carefully both before 
and during Incresync treatment in the elderly.  
 
Bladder cancer  
 
Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical studies 
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 the medicinal product 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 Incresync treatment (risks include 
age, smoking history, exposure to some occupational or chemotherapy medicinal products e.g. 
cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria 
should be investigated before starting 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 hepatocellular dysfunction during post-marketing experience with 
pioglitazone (see section 4.8). Postmarketing reports of hepatic dysfunction including hepatic failure 
have been received for alogliptin. It is recommended, therefore, that patients treated with Incresync 
undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation 
of therapy in all patients. Therapy with Incresync 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.  
 



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Following initiation of therapy with Incresync, it is recommended that liver enzymes be monitored 
periodically based on clinical judgement. If ALT levels are increased to 3 x upper limit of normal 
during 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 Incresync should be guided by clinical judgement pending 
laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.  
 
Renal impairment 
 
As there is a need for dose adjustment of alogliptin in patients with moderate or severe renal 
impairment, or end-stage renal disease requiring dialysis, appropriate assessment of renal function is 
recommended prior to initiation of Incresync and periodically thereafter (see section 4.2).  
 
Incresync is not recommended for patients with severe renal impairment or end-stage renal disease 
requiring dialysis. No information is available on pioglitazone and alogliptin use in dialysed patients 
and, therefore, co-administered alogliptin plus pioglitazone should not be used in such patients (see 
sections 4.2 and 5.2).  
 
Weight gain 
 
In clinical studies 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. Part of 
the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a 
calorie-controlled diet.  
 
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) and to a 
lesser extent sulphonylurea- and insulin- (haemoglobin 1-2% and haematocrit 1-3.2% relative 
reductions) treated patients in comparative-controlled studies with pioglitazone.  
 
Use with other antihyperglycaemic medicinal products and hypoglycaemia 
 
Due to the increased risk of hypoglycaemia in combination with metformin, a lower dose of 
metformin or the pioglitazone component may be considered to reduce the risk of hypoglycaemia 
when this combination is used (see section 4.2). 
 
Combinations not studied 
 
The efficacy and safety of Incresync as triple therapy with a sulphonylurea has not been established 
and thus use is not recommended. 
 
Incresync should not be used in combination with insulin, as the safety and efficacy of this 
combination have not been established. 
 



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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 on Incresync report disturbances in visual acuity; an appropriate ophthalmological 
referral should be considered.  
 
Hypersensitivity reactions 
 
Hypersensitivity reactions, including anaphylactic reactions, angioedema and exfoliative skin 
conditions including Stevens-Johnson syndrome and erythema multiforme have been observed for 
DPP-4 inhibitors and have been spontaneously reported for alogliptin in the post-marketing setting. In 
clinical studies of alogliptin, anaphylactic reactions were reported with a low incidence.  
 
Acute pancreatitis 
 
Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. In a pooled 
analysis of the data from 13 studies, the overall rates of pancreatitis reports in patients treated with 
25 mg alogliptin, 12.5 mg alogliptin, active control or placebo were 2, 1, 1 or 0 events per 
1,000 patient years, respectively. In the cardiovascular outcomes study the rates of pancreatitis reports 
in patients treated with alogliptin or placebo were 3 or 2 events per 1,000 patient years, respectively. 
There have been spontaneously reported adverse reactions of acute pancreatitis in the post-marketing 
setting. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, 
severe abdominal pain, which may radiate to the back. If pancreatitis is suspected, Incresync should be 
discontinued; if acute pancreatitis is confirmed, Incresync should not be restarted. Caution should be 
exercised in patients with a history of pancreatitis. 
 
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 studies in over 8,100 pioglitazone- 
and 7,400 comparator-treated patients, on treatment for up to 3.5 years.  
 
Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated 
with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) 
versus comparator (1.5%).  
 
The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with 
pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed 
excess risk of fractures for women in this dataset on pioglitazone is, therefore, 0.8 fractures per 
100 patient years of use.  
 
In the 3.5 year cardiovascular risk 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. No increase in fracture rates was 
observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).  
 
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 
Incresync (see section 4.8).  
 
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, therefore, be made aware of the risk of pregnancy and if a patient wishes to become 
pregnant or if pregnancy occurs, Incresync treatment should be discontinued (see section 4.6).  



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Incresync 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).  
 
Incresync tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total 
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Co-administration of 25 mg alogliptin once daily and 45 mg pioglitazone once daily for 12 days in 
healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin, pioglitazone 
or their active metabolites. 
 
Specific pharmacokinetic drug interaction studies have not been performed with Incresync. The 
following section outlines the interactions observed with the individual components of Incresync 
(alogliptin/pioglitazone) as reported in their respective Summary of Product Characteristics. 
 
Interactions with pioglitazone 
 
Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported 
to result in a 3-fold increase in AUC for pioglitazone. Since there is a potential for an increase in 
dose-related adverse reactions, 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 for 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). 
 
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics 
or pharmacodynamics of digoxin, warfarin, phenprocoumon or metformin. Co-administration of 
pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. 
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.  
 
Effects of other medicinal products on alogliptin 
 
Alogliptin is primarily excreted unchanged in the urine and metabolism by the cytochrome (CYP) 
P450 enzyme system is negligible (see section 5.2). Interactions with CYP inhibitors are thus not 
expected and have not been shown. 
 
Results from clinical interaction studies also demonstrate that there are no clinically relevant effects of 
gemfibrozil (a CYP2C8/9 inhibitor), fluconazole (a CYP2C9 inhibitor), ketoconazole (a CYP3A4 
inhibitor), cyclosporine (a p-glycoprotein inhibitor), voglibose (an alpha-glucosidase inhibitor), 
digoxin, metformin, cimetidine, pioglitazone or atorvastatin on the pharmacokinetics of alogliptin. 
 



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Effects of alogliptin on other medicinal products 
 
In vitro studies suggest that alogliptin does not inhibit nor induce CYP 450 isoforms at concentrations 
achieved with the recommended dose of 25 mg alogliptin (see section 5.2). Interaction with substrates 
of CYP 450 isoforms are thus not expected and have not been shown. In studies in vitro, alogliptin 
was found to be neither a substrate nor an inhibitor of key transporters associated with disposition of 
the active substance in the kidney: organic anion transporter-1, organic anion transporter-3 or organic 
cationic transporter-2 (OCT2). Furthermore, clinical data do not suggest interaction with 
p-glycoprotein inhibitors or substrates. 
 
In clinical studies, alogliptin had no clinically relevant effect on the pharmacokinetics of caffeine, 
(R)-warfarin, pioglitazone, glyburide, tolbutamide, (S)-warfarin, dextromethorphan, atorvastatin, 
midazolam, an oral contraceptive (norethindrone and ethinyl oestradiol), digoxin, fexofenadine, 
metformin, or cimetidine, thus providing in vivo evidence of a low propensity to cause interaction with 
substrates of CYP1A2, CYP3A4, CYP2D6, CYP2C9, p-glycoprotein, and OCT2. 
 
In healthy subjects, alogliptin had no effect on prothrombin time or International Normalised Ratio 
(INR) when administered concomitantly with warfarin.  
 
Combination of alogliptin with other anti-diabetic medicinal products 
 
Results from alogliptin studies with metformin, pioglitazone (thiazolidinedione), voglibose 
(alpha-glucosidase inhibitor) and glyburide (sulphonylurea) have shown no clinically relevant 
pharmacokinetic interactions. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no data from the use of Incresync in pregnant women. Studies in animals with alogliptin 
plus pioglitazone as combination treatment have shown reproductive toxicity (slight augmentation of 
pioglitazone-related foetal growth retardation and foetal visceral variations, see section 5.3). Incresync 
should not be used during pregnancy.  
 
Risk related to alogliptin 
There are no data from the use of alogliptin in pregnant women. Animal studies do not indicate direct 
or indirect harmful effects with respect to reproductive toxicity (see section 5.3).  
 
Risk related to pioglitazone 
There are no adequate human data to determine the safety of pioglitazone during pregnancy. 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. 
The relevance of such a mechanism in humans is unclear. 
 
Breast-feeding 
 
No studies in lactating animals have been conducted with the combined active substances of 
Incresync. In studies performed with the individual active substances, both alogliptin and pioglitazone 
were excreted in the milk of lactating rats. It is unknown whether alogliptin and pioglitazone are 
excreted in human milk. A risk to the suckling child cannot be excluded. 
 
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 
Incresync therapy taking into account the benefit of breast-feeding for the child and the benefit of 
therapy for the woman. 
 



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Fertility 
 
The effect of Incresync on fertility in humans has not been studied. No adverse effects on fertility were 
observed in animal studies conducted with alogliptin (see section 5.3). In animal fertility studies 
conducted with pioglitazone there was no effect on copulation, impregnation or fertility index. 
 
4.7 Effects on ability to drive and use machines 
 
Incresync 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. Patients should 
be alerted to the risk of hypoglycaemia when Incresync is used in combination with other anti-diabetic 
medicinal products known to cause hypoglycaemia. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Acute pancreatitis is a serious adverse reaction and is attributed to the alogliptin component of 
Incresync (see section 4.4). Hypersensitivity reactions, including Stevens-Johnson syndrome, 
anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of 
Incresync (see section 4.4). Other reactions such as upper respiratory tract infections, sinusitis, 
headache, hypoglycaemia, nausea, weight increase and oedema may occur commonly (≥ 1/100 to 
< 1/10). 
 
Clinical studies conducted to support the efficacy and safety of Incresync involved the 
co-administration of alogliptin and pioglitazone as separate tablets. However, the results of 
bioequivalence studies have demonstrated that Incresync film-coated tablets are bioequivalent to the 
corresponding doses of alogliptin and pioglitazone co-administered as separate tablets. 
 
The information provided is based on a total of 3,504 patients with type 2 diabetes mellitus, including 
1,908 patients treated with alogliptin and pioglitazone, who participated in 4 phase 3 double-blind, 
placebo- or active-controlled clinical studies. These studies evaluated the effects of co-administered 
alogliptin and pioglitazone on glycaemic control and their safety as initial combination therapy, as 
dual therapy in patients initially treated with pioglitazone alone (with or without metformin or a 
sulphonylurea), and as add-on therapy to metformin. 
 
Tabulated list of adverse reactions 
 
The adverse reactions are listed by system organ class and 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 available data). 
 



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Table 1: Adverse reactions 
 

System organ class 
Adverse reaction 

Frequency of adverse reactions 

 Alogliptin Pioglitazone Incresync 
Infections and infestations    
upper respiratory tract infections common common common 
nasopharyngitis common   
sinusitis  uncommon common 
Neoplasms benign, malignant and unspecified 
(including cysts and polyps) 

   

bladder cancer  uncommon  
Immune system disorders    
hypersensitivity not known   
hypersensitivity and allergic reactions  not known  
Metabolism and nutrition disorders    
hypoglycaemia common  common 
Nervous system disorders    
headache common  common 
hypoaesthesia  common  
insomnia  uncommon  
Eye disorders    
visual disturbance  common  
macular oedema  not known  
Gastrointestinal disorders    
abdominal pain common  common 
gastroesophageal reflux disease common   
diarrhoea common   
dyspepsia   common 
nausea   common 
acute pancreatitis not known   
Hepatobiliary disorders    
hepatic dysfunction including hepatic failure not known   
Skin and subcutaneous tissue disorders    
pruritus common  common 
rash common   
exfoliative skin conditions including Stevens-
Johnson syndrome 

not known   

erythema multiforme not known   
angioedema not known   
urticaria not known   
Musculoskeletal and connective tissues 
disorders 

   

myalgia   common 
fracture bone  common  
General disorders and administration site 
conditions 

   

oedema peripheral   common 
weight increased   common 
Investigations    
weight increased  common  
alanine aminotransferase increased  not known  

 



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Description of selected adverse reactions 
 
Post-marketing spontaneous reports of hypersensitivity reactions in patients treated with pioglitazone 
include anaphylaxis, angioedema, and urticaria. 
 
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 as seen with other 
hypoglycaemic treatments.  
 
Oedema was reported in 6-9% of patients treated with pioglitazone over one year in controlled clinical 
studies. The oedema rates for comparator groups (sulphonylurea, metformin) were 2-5%. The reports 
of oedema were generally mild to moderate and usually did not require discontinuation of treatment.  
 
A pooled analysis was conducted of adverse reactions of bone fractures from randomised, 
comparator-controlled, double-blind clinical studies 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%) of pioglitazone-treated female patients experienced fractures 
compared to 23/905 (2.5%) of female patients treated with comparator. 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).  
 
In active comparator-controlled studies, mean weight increase with pioglitazone given as monotherapy 
was 2-3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In 
combination studies, pioglitazone added to metformin resulted in mean weight increase over one year 
of 1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups, addition of sulphonylurea to 
metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea a 
mean weight loss of 1.0 kg.  
 
In clinical studies 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. Rare 
cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing 
experience. Although in very rare cases, fatal outcome has been reported, causal relationship has not 
been established. 
 
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 
 
No data are available with regard to overdose of Incresync. 
 
Alogliptin 
 
The highest doses of alogliptin administered in clinical studies were single doses of 800 mg to healthy 
subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes mellitus 
(equivalent to 32 times and 16 times the recommended daily dose of 25 mg alogliptin, respectively).  
 

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


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Pioglitazone 
 
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.  
 
Hypoglycaemia may occur in combination with sulphonylureas or insulin.  
 
Management 
 
In the event of an overdose, appropriate supportive measures should be employed as dictated by the 
patient’s clinical status. 
 
Minimal quantities of alogliptin are removed by haemodialysis (approximately 7% of the substance 
was removed during a 3-hour haemodialysis session). Therefore, haemodialysis is of little clinical 
benefit in overdose. It is not known if alogliptin is removed by peritoneal dialysis. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Drugs used in diabetes; combinations of oral blood glucose lowering 
drugs. 
 
ATC code: A10BD09. 
 
Mechanism of action and pharmacodynamic effects 
 
Incresync combines two antihyperglycaemic medicinal products with complementary and distinct 
mechanisms of action to improve glycaemic control in patients with type 2 diabetes mellitus: 
alogliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, and pioglitazone, a member of the 
thiazolidinedione class. Studies in animal models of diabetes showed that concomitant treatment with 
alogliptin and pioglitazone produced both additive and synergistic improvements in glycaemic control, 
increased pancreatic insulin content and normalised pancreatic beta-cell distribution. 
 
Alogliptin 
Alogliptin is a potent and highly selective inhibitor of DPP-4, > 10,000-fold more selective for DPP-4 
than other related enzymes including DPP-8 and DPP-9. DPP-4 is the principal enzyme involved in 
the rapid degradation of the incretin hormones, glucagon-like peptide-1 (GLP-1) and GIP (glucose-
dependent insulinotropic polypeptide), which are released by the intestine and levels are increased in 
response to a meal. GLP-1 and GIP increases insulin biosynthesis and secretion from pancreatic beta 
cells, while GLP-1 also inhibits glucagon secretion and hepatic glucose production. Alogliptin 
therefore improves glycaemic control via a glucose-dependent mechanism, whereby insulin release is 
enhanced and glucagon levels are suppressed when glucose levels are high.  
 
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 following treatment with pioglitazone in 
patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction 
in both fasting and postprandial plasma insulin concentrations. 
 



14 

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 studies, 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 study 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 studies, 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 studies of up to two years duration, pioglitazone reduced total plasma triglycerides and free 
fatty acids, and increased HDL-cholesterol levels compared to placebo, metformin or gliclazide. 
Pioglitazone did not cause statistically significant increases in LDL-cholesterol levels compared to 
placebo whilst reductions were 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 hepatically synthesised triglycerides. These effects were independent of 
pioglitazone’s effects on glycaemia and were statistically significantly different to glibenclamide. 
 
Clinical efficacy 
 
Clinical studies conducted to support the efficacy of Incresync involved the co-administration of 
alogliptin and pioglitazone as separate tablets. However, the results of bioequivalence studies have 
demonstrated that Incresync film-coated tablets are bioequivalent to the corresponding doses of 
alogliptin and pioglitazone co-administered as separate tablets. 
 
The co-administration of alogliptin and pioglitazone has been studied as dual therapy in patients 
initially treated with pioglitazone alone (with or without metformin or a sulphonylurea) and as add-on 
therapy to metformin. 
 
Administration of 25 mg alogliptin to patients with type 2 diabetes mellitus produced peak inhibition 
of DPP-4 within 1 to 2 hours and exceeded 93% both after a single 25 mg dose and after 14 days of 
once-daily dosing. Inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. 
When the 4-hour postprandial glucose concentrations were averaged across breakfast, lunch and 
dinner, 14 days of treatment with 25 mg alogliptin resulted in a mean placebo-corrected reduction 
from baseline of -35.2 mg/dL. 
 
Both 25 mg alogliptin alone and in combination with 30 mg pioglitazone demonstrated significant 
decreases in postprandial glucose and postprandial glucagon whilst significantly increasing 
postprandial active GLP-1 levels at Week 16 compared to placebo (p < 0.05). In addition, 25 mg 
alogliptin alone and in combination with 30 mg pioglitazone produced statistically significant 
(p < 0.001) reductions in total triglycerides at Week 16 as measured by postprandial incremental 
AUC(0-8) change from baseline compared to placebo. 
 
A total of 3,504 patients with type 2 diabetes mellitus, including 1,908 patients treated with alogliptin 
and pioglitazone, participated in 4 phase 3 double-blind, placebo- or active-controlled clinical studies 
conducted to evaluate the effects of co-administered alogliptin and pioglitazone on glycaemic control 
and their safety. In these studies, 312 alogliptin/pioglitazone-treated patients were ≥ 65 years old. The 
studies included 1,269 patients with mild renal impairment and 161 patients with moderate renal 
impairment treated with alogliptin/pioglitazone.  
 



15 

Overall, treatment with the recommended daily dose of 25 mg alogliptin in combination with 
pioglitazone improved glycaemic control. This was determined by clinically relevant and statistically 
significant reductions in glycosylated haemoglobin (HbA1c) and fasting plasma glucose compared to 
control from baseline to study endpoint. Reductions in HbA1c were similar across different subgroups 
including renal impairment, age, gender and body mass index, while differences between races (e.g. 
White and non-White) were small. Clinically meaningful reductions in HbA1c compared to control 
were also observed regardless of baseline background medicinal product dose. Higher baseline HbA1c 
was associated with a greater reduction in HbA1c. Generally, the effects of alogliptin on body weight 
and lipids were neutral. 
 
Alogliptin as add-on therapy to pioglitazone 
The addition of 25 mg alogliptin once daily to pioglitazone therapy (mean dose = 35.0 mg, with or 
without metformin or a sulphonylurea) resulted in statistically significant improvements from baseline 
in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo (Table 2). 
Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg 
alogliptin regardless of whether patients were receiving concomitant metformin or sulphonylurea 
therapy. Significantly more patients receiving 25 mg alogliptin (49.2%) achieved target HbA1c levels 
of ≤ 7.0% compared to those receiving placebo (34.0%) at Week 26 (p = 0.004).  
 
Alogliptin as add-on therapy to pioglitazone with metformin 
The addition of 25 mg alogliptin once daily to 30 mg pioglitazone in combination with metformin 
hydrochloride therapy (mean dose = 1,867.9 mg) resulted in improvements from baseline in HbA1c at 
Week 52 that were both non-inferior and statistically superior to those produced by 45 mg 
pioglitazone in combination with metformin hydrochloride therapy (mean dose = 1,847.6 mg, 
Table 3). The significant reductions in HbA1c observed with 25 mg alogliptin plus 30 mg pioglitazone 
and metformin were consistent over the entire 52-week treatment period compared to 45 mg 
pioglitazone and metformin (p < 0.001 at all time points). In addition, mean change from baseline in 
fasting plasma glucose at Week 52 for 25 mg alogliptin plus 30 mg pioglitazone and metformin was 
significantly greater than that for 45 mg pioglitazone and metformin (p < 0.001). Significantly more 
patients receiving 25 mg alogliptin plus 30 mg pioglitazone and metformin (33.2%) achieved target 
HbA1c levels of ≤ 7.0% compared to those receiving 45 mg pioglitazone and metformin (21.3%) at 
Week 52 (p < 0.001).  
 

Table 2: Change in HbA1c (%) from baseline with alogliptin 25 mg at Week 26  
by placebo-controlled study (FAS, LOCF) 

Study Mean baseline 
HbA1c (%) (SD) 

Mean change from 
baseline in HbA1c 

(%)† (SE) 

Placebo-corrected 
change from baseline 

in HbA1c (%)† 
(2-sided 95% CI) 

Add-on combination therapy placebo-controlled studies 
Alogliptin 25 mg 
once daily with 
pioglitazone ± 
metformin or a 
sulphonylurea 
(n = 195) 

8.01 
(0.837) 

-0.80 
(0.056) 

-0.61* 
(-0.80, -0.41) 

FAS = full analysis set 
LOCF = last observation carried forward 
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values 
* p < 0.001 compared to placebo or placebo+combination treatment 
 
 



16 

Table 3: Change in HbA1c (%) from baseline with alogliptin 25 mg 
by active-controlled study (PPS, LOCF) 

Study Mean baseline 
HbA1c (%) (SD) 

Mean change from 
baseline in HbA1c 

(%)† (SE) 

Treatment-corrected 
change from baseline 

in HbA1c (%)† 
(1-sided CI) 

Add-on combination therapy studies 
Alogliptin 25 mg 
once daily with 
pioglitazone + 
metformin vs 
titrating 
pioglitazone + 
metformin 
 
Change at Week 26 
(n = 303) 
 
Change at Week 52 
(n = 303) 

 
 
 
 
 
 
 
 

8.25 
(0.820) 

 
8.25 

(0.820) 
 

 
 
 
 
 
 
 
 

-0.89 
(0.042) 

 
-0.70 

(0.048) 
 

 
 
 
 
 
 
 
 

-0.47* 
(-infinity, -0.35) 

 
-0.42* 

(-infinity, -0.28) 

PPS = per protocol set 
LOCF = last observation carried forward 
* Non inferiority and superiority statistically demonstrated 
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values 
 
 
Patients with renal impairment 
Incresync is not recommended for patients with severe renal impairment or end-stage renal disease 
requiring dialysis (see section 4.2).  
 
Elderly (≥ 65 years old) 
The efficacy and safety of the recommended doses of alogliptin and pioglitazone in a subgroup of 
patients with type 2 diabetes mellitus and ≥ 65 years old were reviewed and found to be consistent 
with the profile obtained in patients < 65 years old. 
 
Clinical safety 
 
Cardiovascular Safety 
In a pooled analysis of the data from 13 studies, the overall incidences of cardiovascular death, non 
fatal myocardial infarction and non-fatal stroke were comparable in patients treated with 25 mg 
alogliptin, active control or placebo. 
 
In addition, a prospective randomised cardiovascular outcomes safety study was conducted with 
5,380 patients with high underlying cardiovascular risk to examine the effect of alogliptin compared 
with placebo (when added to standard of care) on major adverse cardiovascular events (MACE) 
including time to the first occurrence of any event in the composite of cardiovascular death, nonfatal 
myocardial infarction and nonfatal stroke in patients with a recent (15 to 90 days) acute coronary 
event. At baseline, patients had a mean age of 61 years, mean duration of diabetes of 9.2 years, and 
mean HbA1c of 8.0%. 
 
The study demonstrated that alogliptin did not increase the risk of having a MACE compared to 
placebo [Hazard Ratio: 0.96; 1-sided 99% Confidence Interval: 0-1.16]. In the alogliptin group, 11.3% 
of patients experienced a MACE compared to 11.8% of patients in the placebo group. 
 



17 

Table 4. MACE Reported in cardiovascular outcomes study 

 Number of Patients (%) 

Alogliptin 
25 mg Placebo 

N = 2,701 N = 2,679 
Primary Composite Endpoint [First 
Event of CV Death, Nonfatal MI and 
Nonfatal Stroke] 

305 (11.3) 316 (11.8) 

 Cardiovascular Death* 89 (3.3) 111 (4.1) 
 Nonfatal Myocardial Infarction 187 (6.9) 173 (6.5) 
 Nonfatal Stroke 29 (1.1) 32 (1.2) 
*Overall there were 153 subjects (5.7%) in the alogliptin group and 
173 subjects (6.5%) in the placebo group who died (all-cause 
mortality) 

 
There were 703 patients who experienced an event within the secondary MACE composite endpoint 
(first event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent 
revascularization due to unstable angina). In the alogliptin group, 12.7% (344 subjects) experienced an 
event within the secondary MACE composite endpoint, compared with 13.4% (359 subjects) in the 
placebo group [Hazard Ratio = 0.95; 1-sided 99% Confidence Interval: 0-1.14]. 
 
In controlled clinical studies, 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. Heart failure has been reported rarely with marketing use of pioglitazone, but 
more frequently when pioglitazone was used in combination with insulin or in patients with a history 
of cardiac failure.  
 
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 anti-diabetic 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, angiotensin-converting-enzyme (ACE) inhibitors, 
angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, 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 incidences of oedema, weight 
gain and heart failure were increased. No increase in mortality from heart failure was observed. 
 
Hypoglycaemia 
In a pooled analysis of the data from 12 studies, the overall incidence of any episode of 
hypoglycaemia was lower in patients treated with 25 mg alogliptin than in patients treated with 
12.5 mg alogliptin, active-control or placebo (3.6%, 4.6%, 12.9% and 6.2%, respectively). The 
majority of these episodes were mild to moderate in intensity. The overall incidence of episodes of 
severe hypoglycaemia was comparable in patients treated with 25 mg alogliptin or 12.5 mg alogliptin, 



18 

and lower than the incidence in patients treated with active-control or placebo (0.1%, 0.1%, 0.4% and 
0.4%, respectively). In the prospective randomised controlled cardiovascular outcomes study, 
investigator reported events of hypoglycemia were similar in patients receiving placebo (6.5%) and 
patients receiving alogliptin (6.7%) in addition to standard of care. 

 
A clinical study of alogliptin as add-on therapy to pioglitazone demonstrated that there was no 
clinically relevant increase in hypoglycaemia rate compared to placebo. The incidence of 
hypoglycaemia was greater when alogliptin was used as triple therapy with pioglitazone and 
metformin (compared to active-control). This has also been observed with other DPP-4 inhibitors. 
 
Patients (≥ 65 years old) with type 2 diabetes mellitus are considered more susceptible to episodes of 
hypoglycaemia than patients < 65 years old. In a pooled analysis of the data from 12 studies, the 
overall incidence of any episode of hypoglycaemia was similar in patients ≥ 65 years old treated with 
25 mg alogliptin (3.8%) to that in patients < 65 years old (3.6%). 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Incresync in all subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The results of bioequivalence studies in healthy subjects demonstrated that Incresync film-coated 
tablets are bioequivalent to the corresponding doses of alogliptin and pioglitazone co-administered as 
separate tablets. 
 
Co-administration of 25 mg alogliptin once daily and 45 mg pioglitazone once daily for 12 days in 
healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin, pioglitazone 
or their active metabolites. 
 
Administration of Incresync with food resulted in no change in overall exposure to alogliptin or 
pioglitazone. Incresync may, therefore, be administered with or without food. 
 
The following section outlines the pharmacokinetic properties of the individual components of 
Incresync (alogliptin/pioglitazone) as reported in their respective Summary of Product Characteristics. 
 
Alogliptin 
 
The pharmacokinetics of alogliptin has been shown to be similar in healthy subjects and in patients 
with type 2 diabetes mellitus. 
 
Absorption 
The absolute bioavailability of alogliptin is approximately 100%. 
 
Administration with a high-fat meal resulted in no change in total and peak exposure to alogliptin. 
Alogliptin may, therefore, be administered with or without food.  
 
After administration of single, oral doses of up to 800 mg in healthy subjects, alogliptin was rapidly 
absorbed with peak plasma concentrations occurring 1 to 2 hours (median Tmax) after dosing. 
 
No clinically relevant accumulation after multiple dosing was observed in either healthy subjects or in 
patients with type 2 diabetes mellitus.  
 
Total and peak exposure to alogliptin increased proportionately across single doses of 6.25 mg up to 
100 mg alogliptin (covering the therapeutic dose range). The inter-subject coefficient of variation for 
alogliptin AUC was small (17%).  



19 

 
Distribution 
Following a single intravenous dose of 12.5 mg alogliptin to healthy subjects, the volume of 
distribution during the terminal phase was 417 L indicating that the active substance is well distributed 
into tissues.  
 
Alogliptin is 20-30% bound to plasma proteins. 
 
Biotransformation 
Alogliptin does not undergo extensive metabolism, 60-70% of the dose is excreted as unchanged 
active substance in the urine. 
 
Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, 
N-demethylated alogliptin, M-I (< 1% of the parent compound), and N-acetylated alogliptin, M-II 
(< 6% of the parent compound). M-I is an active metabolite and is a highly selective inhibitor of 
DPP-4 similar to alogliptin; M-II does not display any inhibitory activity towards DPP-4 or other 
DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited 
metabolism of alogliptin.  
 
In vitro studies indicate that alogliptin does not induce CYP1A2, CYP2B6 and CYP2C9 and does not 
inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at concentrations 
achieved with the recommended dose of 25 mg alogliptin. Studies in vitro have shown alogliptin to be 
a mild inducer of CYP3A4, but alogliptin has not been shown to induce CYP3A4 in studies in vivo.  
 
In studies in vitro, alogliptin was not an inhibitor of the following renal transporters; OAT1, OAT3 
and OCT2. 
 
Alogliptin exists predominantly as the (R)-enantiomer (> 99%) and undergoes little or no chiral 
conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at therapeutic doses.  
 
Elimination 
Alogliptin was eliminated with a mean terminal half-life (T1/2) of approximately 21 hours.  
 
Following administration of an oral dose of [14C] alogliptin, 76% of total radioactivity was eliminated 
in the urine and 13% was recovered in the faeces.  
 
The average renal clearance of alogliptin (170 mL/min) was greater than the average estimated 
glomerular filtration rate (approx. 120 mL/min), suggesting some active renal excretion. 
 
Time-dependency 
Total exposure (AUC(0-inf)) to alogliptin following administration of a single dose was similar to 
exposure during one dose interval (AUC(0-24)) after 6 days of once daily dosing. This indicates no 
time-dependency in the kinetics of alogliptin after multiple dosing. 
 
Special populations 
Renal impairment 
A single dose of 50 mg alogliptin was administered to 4 groups of patients with varying degrees of 
renal impairment (CrCl using the Cockcroft-Gault formula): mild (CrCl = > 50 to ≤ 80 mL/min), 
moderate (CrCl = ≥ 30 to ≤ 50 mL/min), severe (CrCl = < 30 mL/min) and end-stage renal disease on 
haemodialysis.  
 
An approximate 1.7-fold increase in AUC for alogliptin was observed in patients with mild renal 
impairment. However, as the distribution of AUC values for alogliptin in these patients was within the 
same range as control subjects, no dose adjustment of alogliptin for patients with mild renal 
impairment is necessary (see section 4.2).  
 



20 

In patients with moderate or severe renal impairment, or end-stage renal disease on haemodialysis, an 
increase in systemic exposure to alogliptin of approximately 2- and 4-fold was observed, respectively. 
(Patients with end-stage renal disease underwent haemodialysis immediately after alogliptin dosing. 
Based on mean dialysate concentrations, approximately 7% of the active substance was removed 
during a 3-hour haemodialysis session. Therefore, in order to maintain systemic exposures to 
alogliptin that are similar to those observed in patients with normal renal function, lower doses of 
alogliptin should be used in patients with moderate or severe renal impairment, or end-stage renal 
disease requiring dialysis (see above and section 4.2).  
 
Hepatic impairment 
Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% 
lower in patients with moderate hepatic impairment compared to control subjects. The magnitude of 
these reductions was not considered to be clinically relevant. Therefore, no dose adjustment of 
alogliptin is necessary for patients with mild to moderate hepatic impairment (Child-Pugh scores of 
5 to 9). Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh 
score > 9). 
 
Age, gender, race, body weight 
Age (65-81 years old), gender, race (white, black and Asian) and body weight did not have any 
clinically relevant effect on the pharmacokinetics of alogliptin. No dose adjustment is necessary (see 
section 4.2).  
 
Paediatric population 
The pharmacokinetics of alogliptin in children and adolescents < 18 years old has not been 
established. No data are available (see section 4.2). 
 
Pioglitazone 
 
Absorption 
Following oral administration, pioglitazone is rapidly absorbed and peak serum concentrations of 
unchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases of 
the serum 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 19 L.  
 
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 pioglitazone 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 3-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 or 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 
serum concentration of pioglitazone (see section 4.5). 
 



21 

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 serum elimination half-life of 
unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.  
 
Special populations 
Renal impairment 
In patients with renal impairment, serum 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 (see section 4.2).  
 
Hepatic impairment 
Total serum 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 (see 
section 4.2). 
 
Elderly (≥ 65 years old) 
Steady-state pharmacokinetics is similar in patients aged 65 years and over and young subjects (see 
section 4.2).  
 
Paediatric population 
The pharmacokinetics of pioglitazone in children and adolescents < 18 years old has not been 
established. No data are available (see section 4.2). 
 
Incresync 
 
Special populations 
Renal impairment 
For patients with moderate renal impairment, Incresync 12.5 mg/30 mg should be administered once 
daily. Incresync is not recommended for patients with severe renal impairment or end-stage renal 
disease requiring dialysis. No dose adjustment of Incresync for patients with mild renal impairment is 
necessary (see section 4.2). 
 
Hepatic impairment 
Due to its pioglitazone component, Incresync should not be used in patients with hepatic impairment 
(see section 4.2). 
 
5.3 Preclinical safety data 
 
Animal studies of up to 13-weeks duration have been conducted with the combined substances in 
Incresync. 
 
Concomitant treatment with alogliptin and pioglitazone did not produce new toxicities, nor did it 
exacerbate any pioglitazone-related findings. No effects on the toxicokinetics of either compound 
were observed. 
 
Combination treatment with alogliptin and pioglitazone to pregnant rats slightly augmented 
pioglitazone-related foetal effects of growth retardation and visceral variations, but did not induce 
embryo-foetal mortality or teratogenicity. 
 
The following data are findings from studies performed with alogliptin or pioglitazone individually. 
 



22 

Alogliptin 
 
Nonclinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology and toxicology. 
 
The no-observed-adverse-effect level (NOAEL) in the repeated dose toxicity studies in rats and dogs 
up to 26- and 39-weeks in duration, respectively, produced exposure margins that were approximately 
147- and 227-fold, respectively, the exposure in humans at the recommended daily dose of 25 mg 
alogliptin. 
 
Alogliptin was not genotoxic in a standard battery of in vitro and in vivo genotoxicity studies. 
 
Alogliptin was not carcinogenic in 2-year carcinogenicity studies conducted in rats and mice. Minimal 
to mild simple transitional cell hyperplasia was seen in the urinary bladder of male rats at the lowest 
dose used (27 times the human exposure) without establishment of a clear NOEL (no observed effect 
level). 
 
No adverse effects of alogliptin were observed upon fertility, reproductive performance, or early 
embryonic development in rats up to a systemic exposure far above the human exposure at the 
recommended dose. Although fertility was not affected, a slight, statistical increase in the number of 
abnormal sperm was observed in males at an exposure far above the human exposure at the 
recommended dose.  
 
Placental transfer of alogliptin occurs in rats. 
 
Alogliptin was not teratogenic in rats or rabbits with a systemic exposure at the NOAELs far above the 
human exposure at the recommended dose. Higher doses of alogliptin were not teratogenic but 
resulted in maternal toxicity, and were associated with delayed and/or lack of ossification of bones and 
decreased foetal body weights. 
 
In a pre- and postnatal development study in rats, exposures far above the human exposure at the 
recommended dose did not harm the developing embryo or affect offspring growth and development. 
Higher doses of alogliptin decreased offspring body weight and exerted some developmental effects 
considered secondary to the low body weight. 
 
Studies in lactating rats indicate that alogliptin is excreted in milk. 
 
No alogliptin-related effects were observed in juvenile rats following repeat-dose administration for 
4 and 8 weeks.  
 
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.  
 



23 

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, treatment with two other thiazolidinediones 
increased tumour multiplicity in the colon. The relevance of this finding is unknown. 
 
Environmental Risk Assessment (ERA) 
 
No environmental impact is anticipated from the clinical use of pioglitazone. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Mannitol 
Microcrystalline cellulose 
Hydroxypropylcellulose 
Croscarmellose sodium 
Magnesium stearate 
Lactose monohydrate 
 
Film-coating 
 
12.5 mg/30 mg 
film-coated tablets 

25 mg/30 mg 
film-coated tablets 

25 mg/45 mg 
film-coated tablets 

Hypromellose Hypromellose Hypromellose 
Talc Talc Talc 
Titanium dioxide 
(E171) 

Titanium dioxide 
(E171) 

Titanium dioxide 
(E171) 

Macrogol 8000 Macrogol 8000 Macrogol 8000 
Iron oxide red (E172) Iron oxide red (E172) Iron oxide red (E172) 
Iron oxide yellow 
(E172)  

Iron oxide yellow 
(E172)  

 

 
Printing ink 
 
12.5 mg/30 mg 
film-coated tablets 

25 mg/30 mg 
film-coated tablets 

25 mg/45 mg 
film-coated tablets 

Shellac Shellac Shellac 
Iron oxide red (E172) Iron oxide black 

(E172) 
Iron oxide black 
(E172) 

Carnauba wax   
Glycerol mono-oleate   
 



24 

6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions. Store in the 
original package in order to protect from moisture. 
 
6.5 Nature and contents of container  
 
Nylon/aluminium/polyvinyl chloride (PVC) blisters with push through aluminium lidding foil. Pack 
sizes of 10, 14, 28, 30, 56, 60, 90, 98 or 100 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark 
 
 



25 

8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/842/001 
EU/1/13/842/002 
EU/1/13/842/003 
EU/1/13/842/004 
EU/1/13/842/005 
EU/1/13/842/006 
EU/1/13/842/007 
EU/1/13/842/008 
EU/1/13/842/009 
EU/1/13/842/019 
EU/1/13/842/020 
EU/1/13/842/021 
EU/1/13/842/022 
EU/1/13/842/023 
EU/1/13/842/024 
EU/1/13/842/025 
EU/1/13/842/026 
EU/1/13/842/027 
EU/1/13/842/028 
EU/1/13/842/029 
EU/1/13/842/030 
EU/1/13/842/031 
EU/1/13/842/032 
EU/1/13/842/033 
EU/1/13/842/034 
EU/1/13/842/035 
EU/1/13/842/036 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 September 2013 
Date of latest renewal: 24 May 2018 
 
 
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/


26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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 

 
 



27 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Takeda Ireland Ltd. 
Bray Business Park  
Kilruddery 
Co Wicklow 
Ireland 
 
 
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. 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



30 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Incresync 25 mg/30 mg film-coated tablets 
 
alogliptin/pioglitazone 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 25 mg alogliptin (as benzoate) and 30 mg pioglitazone (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
90 film-coated tablets 
98 film-coated tablets 
100 film-coated 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 
 



31 

 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
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/1/13/842/019 10 film-coated tablets 
EU/1/13/842/020 14 film-coated tablets 
EU/1/13/842/021 28 film-coated tablets 
EU/1/13/842/022 30 film-coated tablets 
EU/1/13/842/023 56 film-coated tablets 
EU/1/13/842/024 60 film-coated tablets 
EU/1/13/842/025 90 film-coated tablets 
EU/1/13/842/026 98 film-coated tablets 
EU/1/13/842/027 100 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Incresync 25 mg/30 mg  
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



32 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



33 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Incresync 25 mg/30 mg tablets 
 
alogliptin/pioglitazone 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



34 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Incresync 25 mg/45 mg film-coated tablets 
 
alogliptin/pioglitazone  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 25 mg alogliptin (as benzoate) and 45 mg pioglitazone (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
90 film-coated tablets 
98 film-coated tablets 
100 film-coated 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 
 
 



35 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
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/1/13/842/028 10 film-coated tablets 
EU/1/13/842/029 14 film-coated tablets 
EU/1/13/842/030 28 film-coated tablets 
EU/1/13/842/031 30 film-coated tablets 
EU/1/13/842/032 56 film-coated tablets 
EU/1/13/842/033 60 film-coated tablets 
EU/1/13/842/034 90 film-coated tablets 
EU/1/13/842/035 98 film-coated tablets 
EU/1/13/842/036 100 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Incresync 25 mg/45 mg  
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 



36 

 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



37 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Incresync 25 mg/45 mg tablets 
 
alogliptin/pioglitazone  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



38 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Incresync 12.5 mg/30 mg film-coated tablets 
 
alogliptin/pioglitazone  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 12.5 mg alogliptin (as benzoate) and 30 mg pioglitazone (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
90 film-coated tablets 
98 film-coated tablets 
100 film-coated 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 



39 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
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/1/13/842/001 10 film-coated tablets 
EU/1/13/842/002 14 film-coated tablets 
EU/1/13/842/003 28 film-coated tablets 
EU/1/13/842/004 30 film-coated tablets 
EU/1/13/842/005 56 film-coated tablets 
EU/1/13/842/006 60 film-coated tablets 
EU/1/13/842/007 90 film-coated tablets 
EU/1/13/842/008 98 film-coated tablets 
EU/1/13/842/009 100 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Incresync 12.5 mg/30 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



40 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



41 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Incresync 12.5 mg/30 mg tablets 
 
alogliptin/pioglitazone  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Takeda  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



42 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



43 

Package leaflet: Information for the patient 
 

Incresync 12.5 mg/30 mg film-coated tablets 
Incresync 25 mg/30 mg film-coated tablets 
Incresync 25 mg/45 mg film-coated tablets 

alogliptin/pioglitazone 
 
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 Incresync is and what it is used for  
2. What you need to know before you take Incresync 
3. How to take Incresync 
4. Possible side effects  
5. How to store Incresync 
6. Contents of the pack and other information 
 
 
1. What Incresync is and what it is used for 
 
What Incresync is 
Incresync contains two different medicines called alogliptin and pioglitazone in one tablet:  
 
- alogliptin belongs to a group of medicines called DPP-4 inhibitors (dipeptidyl peptidase-4 

inhibitors). Alogliptin works to increase the levels of insulin in the body after a meal and 
decrease the amount of sugar in the body.  

- pioglitazone belongs to a group of medicines called thiazolidinediones. It helps your body make 
better use of the insulin it produces. 

 
Both of these groups of medicines are “oral anti-diabetics”. 
 
What Incresync is used for 
Incresync is used to lower blood sugar levels in adults with type 2 diabetes. Type 2 diabetes is also 
called non-insulin-dependent diabetes mellitus or NIDDM. 
 
Incresync is taken when your blood sugar cannot be adequately controlled by diet, exercise and other 
oral anti-diabetic medicines such as pioglitazone; or pioglitazone and metformin taken together. Your 
doctor will check whether Incresync is working 3 to 6 months after you start taking it. 
 
If you are already taking both alogliptin and pioglitazone as single tablets, Incresync can replace them 
in one tablet. 
 
It is important that you continue to follow the advice on diet and exercise that your nurse or doctor has 
given you. 
 
 



44 

2. What you need to know before you take Incresync 
 
Do not take Incresync: 
- if you are allergic to alogliptin, pioglitazone or any of the other ingredients of this medicine 

(listed in section 6). 
- if you have had a serious allergic reaction to any other similar medicines that you take to control 

your blood sugar. Symptoms of a serious allergic reaction may include; rash, raised red patches 
on your skin (hives), swelling of the face, lips, tongue, and throat that may cause difficulty in 
breathing or swallowing. Additional symptoms may include general itching and feeling of heat 
especially affecting the scalp, mouth, throat, palms of hands and soles of feet (Stevens-Johnson 
syndrome). 

- if you have heart failure or have had heart failure in the past. 
- if you have liver disease. 
- if you have diabetic ketoacidosis (a serious complication of poorly controlled diabetes). 

Symptoms include excessive thirst, frequent urination, loss of appetite, nausea or vomiting and 
rapid weight loss. 

- if you have or have ever had bladder cancer. 
- if you have blood in your urine that your doctor has not checked. Do not take Incresync and get 

your doctor to check your urine as soon as possible.  
 
Warnings and precautions  
Talk to your doctor or pharmacist before taking Incresync: 
- if you have type 1 diabetes (your body does not produce insulin). 
- if you are taking an anti-diabetic medicine known as sulphonylurea (e.g. glipizide, tolbutamide, 

glibenclamide) or insulin.  
- if you suffer from heart disease or fluid retention. If you take anti-inflammatory medicines 

which can also cause fluid retention and swelling, you must also tell your doctor. 
- if you are elderly and are taking insulin, because you may have an increased risk of heart 

problems. 
- if you have a problem with your liver or kidneys. Before you start taking this medicine you will 

have a blood sample taken to check your liver and kidney function. This check may be repeated 
at intervals. In case of kidney disease, your doctor may reduce the dose of Incresync. 

- if you have a special type of diabetic eye disease called macular oedema (swelling of the back 
of the eye). 

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

- if you have or have had a disease of the pancreas. 
 
Slight changes in cell counts may show up in blood tests. Your doctor may discuss the results with 
you.  
 
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 
Incresync is not recommended for children and adolescents under 18 years due to the lack of data in 
these patients.  
 
Other medicines and Incresync 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
In particular tell your doctor or pharmacist if you are taking any of the following: 
- gemfibrozil (used to lower cholesterol) 
- rifampicin (used to treat tuberculosis and other infections)  



45 

 
Your blood sugar will be checked and your dose of Incresync may need to be changed. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.  
 
There is no experience of using Incresync in pregnant women or during breast-feeding. Incresync 
should not be used during pregnancy or breast-feeding.  
 
Driving and using machines 
You may experience visual disturbances while taking this medicine. If this happens, do not drive or 
use any tools or machines. Taking Incresync in combination with other anti-diabetic medicines can 
cause low blood sugar levels (hypoglycaemia), which may affect your ability to drive and use 
machines. 
 
Incresync contains lactose  
If you have been told by your doctor that you have intolerance to some sugars, contact your doctor 
before taking Incresync. 
 
 
3. How to take Incresync 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Your doctor will tell you how much Incresync you need to take and if you need to change the amount 
of other medicines you take. 
 
The maximum recommended daily dose is one 25 mg/45 mg tablet. 
 
Incresync should be taken once daily. Swallow your tablet(s) whole with water. You can take this 
medicine with or without food. 
 
If you have kidney problems your doctor may prescribe you a reduced dose. 
 
If you are following a diabetic diet, you should continue with this while you are taking Incresync. 
  
Your weight should be checked at regular intervals; if your weight increases, tell your doctor.  
 
If you take more Incresync than you should 
If you take more tablets than you should, or if someone else or a child takes your medicine, contact or 
go to your nearest emergency centre straight away. Take this leaflet or some tablets with you so that 
your doctor knows exactly what you have taken.  
 
If you forget to take Incresync 
If you forget to take a dose, take it as soon as you remember it. Do not take a double dose to make up 
for a forgotten dose. 
 
If you stop taking Incresync 
Do not stop taking Incresync without consulting your doctor first. Your blood sugar levels may 
increase when you stop taking Incresync. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 



46 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
STOP taking Incresync and contact a doctor immediately if you notice any of the following 
serious side effects: 
 
Common (may affect up to 1 in 10 people): 
- Sudden and severe bone pain or immobility (particularly in women).  
 
Uncommon (may affect up to 1 in 100 people): 
- Symptoms of bladder cancer including blood in your urine, pain when urinating or a sudden 

need to urinate. 
 

Not known (frequency cannot be estimated from the available data): 
- An allergic reaction. The symptoms may include: a rash, hives, swallowing or breathing 

problems, swelling of your lips, face, throat or tongue and feeling faint.  
- A severe allergic reaction: skin lesions or spots on your skin that can progress to a sore 

surrounded by pale or red rings, blistering and/or peeling of the skin possibly with symptoms 
such as itching, fever, overall ill feeling, achy joints, vision problems, burning, painful or itchy 
eyes and mouth sores (Stevens-Johnson syndrome and Erythema multiforme).  

- Severe and persistent pain in the abdomen (stomach area) which might reach through to your 
back, as well as nausea and vomiting, as it could be a sign of an inflamed pancreas 
(pancreatitis).  

 
You should also discuss with your doctor if you experience the following side effects: 
 
Common: 
- Symptoms of low blood sugar (hypoglycaemia) may occur when Incresync is taken in 

combination with insulin or sulphonylureas (e.g. glipizide, tolbutamide, glibenclamide). 
Symptoms may include: trembling, sweating, anxiety, blurred vision, tingling lips, paleness, 
mood change or feeling confused. Your blood sugar could fall below the normal level, but can 
be increased again by taking sugar. It is recommended that you carry some sugar lumps, sweets, 
biscuits or sugary fruit juice. 

- Cold or flu-like symptoms such as sore throat, stuffy or blocked nose 
- Inflammation of the sinuses (sinusitis) 
- Itchy skin 
- Headache 
- Stomach ache 
- Diarrhoea 
- Indigestion, heartburn 
- Feeling sick 
- Muscle pain 
- Feeling numb in any part of your body 
- Blurred or distorted vision 
- Weight gain 
- Swollen or puffy hands or feet 
- Rash 
 
Uncommon: 
- Difficulty sleeping 
 
Not known: 
- Visual disturbances (caused by a condition called macular oedema). 
- Liver problems such as nausea or vomiting, stomach pain, unusual or unexplained tiredness, 

loss of appetite, dark urine or yellowing of your skin or the whites of your eyes. 
 



47 

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 Incresync 
 
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 blister after EXP. The 
expiry date refers to the last day of that month. 
 
This medicinal product does not require any special temperature storage conditions. Store in the 
original package in order to protect from moisture. 
 
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 Incresync contains  
- The active substances are alogliptin and pioglitazone. 
Each 25 mg/30 mg film-coated tablet contains alogliptin benzoate and pioglitazone hydrochloride 
equivalent to 25 mg alogliptin and 30 mg pioglitazone. 
- The other ingredients are mannitol, microcrystalline cellulose, hydroxypropylcellulose, 

croscarmellose sodium, magnesium stearate, lactose monohydrate, hypromellose, talc, titanium 
dioxide (E171), yellow iron oxide (E172), red iron oxide (E172), macrogol 8000, shellac and 
black iron oxide (E172). See section 2 “Incresync contains lactose”. 

Each 25 mg/45 mg film-coated tablet contains alogliptin benzoate and pioglitazone hydrochloride 
equivalent to 25 mg alogliptin and 45 mg pioglitazone. 
- The other ingredients are mannitol, microcrystalline cellulose, hydroxypropylcellulose, 

croscarmellose sodium, magnesium stearate, lactose monohydrate, hypromellose, talc, titanium 
dioxide (E171), red iron oxide (E172), macrogol 8000, shellac and black iron oxide (E172). See 
section 2 “Incresync contains lactose”. 

Each12.5 mg/30 mg film-coated tablet contains alogliptin benzoate and pioglitazone hydrochloride 
equivalent to 12.5 mg alogliptin and 30 mg pioglitazone. 
- The other ingredients are mannitol, microcrystalline cellulose, hydroxypropylcellulose, 

croscarmellose sodium, magnesium stearate, lactose monohydrate, hypromellose, talc, titanium 
dioxide (E171), yellow iron oxide (E172), red iron oxide (E172), macrogol 8000, shellac, 
carnauba wax and glycerol mono-oleate. See section 2 “Incresync contains lactose”. 

 
What Incresync looks like and contents of the pack 
- Incresync 25 mg/30 mg film-coated tablets (tablets) are peach, round (approximately 8.7 mm in 

diameter), biconvex, film-coated tablets, with both “A/P” and “25/30” printed in grey ink on 
one side. 

 
- Incresync 25 mg/45 mg film-coated tablets (tablets) are red, round (approximately 8.7 mm in 

diameter), biconvex, film-coated tablets, with both “A/P” and “25/45” printed in grey ink on 
one side. 

 
- Incresync 12.5 mg/30 mg film-coated tablets (tablets) are pale peach, round (approximately 

8.7 mm in diameter), biconvex, film-coated tablets, with both “A/P” and “12.5/30” printed in 
red ink on one side. 

 

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


48 

Incresync is available in blister packs containing 10, 14, 28, 30, 56, 60, 90, 98 or 100 tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Takeda Pharma A/S 
Dybendal Alle 10 
2630 Taastrup 
Denmark 
 
Manufacturer 
Takeda Ireland Limited 
Bray Business Park 
Kilruddery 
Co. Wicklow 
Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien/ 
Luxembourg/Luxemburg 
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 
 

Magyarország 
Takeda Pharma Kft. 
Tel: +361 2707030 

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

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

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

Nederland 
Takeda Nederland bv 
Tel: +31 23 56 68 777 
nl.medical.info@takeda.com 
 

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

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

Eesti 
Takeda Pharma AS 
Tel: +372 6177 669 
 

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

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

Polska 
Takeda Pharma sp. z o.o. 
tel. +48 22 608 13 00 
 



49 

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

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

France 
Takeda France S.A.S 
Tél: +33 1 46 25 16 16  
 

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

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

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

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

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

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

Suomi/Finland 
Takeda Oy 
Tel. +358 20 746 5000 
 

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

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

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

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

Latvija 
Takeda Latvia SIA 
Tel: +371 67840082 
 

 

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

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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