Cyero 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, Cyero 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 Cyero , 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, Cyero should be discontinued. In light of potential risks with prolonged pioglitazone
therapy, prescribers should confirm at subsequent routine reviews that the benefit of Cyero is
maintained (see section 4.4).

Posology
For the different dose regimens Cyero is available in strengths of 25 mg/15 mg and 25 mg/30 mg filmcoated
tablets.
Adults (≥ 18 years old)
The dose of Cyero 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 Cyero is one tablet of 25 mg/ 15mg or
25 mg/30 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 Cyero administered concomitantly. The
recommended dose is one tablet of 25 mg/ 15mg or 25 mg/30 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.
The maximum recommended daily dose of 25 mg alogliptin and 45 mg pioglitazone should not be
exceeded.

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 > 50 to ≤ 80 mL/min), no dose adjustment
of Cyero is necessary (see section 5.2).
Cyero 25 mg/15 mg or 25 mg/30 mg is not recommended for patients with moderate renal impairment
(see section 5.2).
Cyero is not recommended for patients with severe renal impairment (creatinine clearance
< 30 mL/min) or end-stage renal disease requiring dialysis.
Appropriate assessment of renal function is recommended prior to initiation of Cyero and periodically
thereafter (see section 4.4).
Hepatic impairment
Cyero 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 Cyero in children and adolescents < 18 years old have not been established.
No data are available.
Method of administration
Oral use.

Cyero 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.

 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)

General
Cyero should not be used in patients with type 1 diabetes mellitus. Cyero is not a substitute for insulin in
insulin-requiring patients.
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, including selective COX-2 inhibitors. Cyero 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 Cyero treatment in the elderly.
Bladder cancer
Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with
pioglitazone (19 cases from 12,506 patients, 0.15%) than in control groups (7 cases from 10,212 patients,
0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to 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. Available epidemiological data also
suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular
in patients treated for the longest durations and with the highest cumulative doses. A possible risk after
short term treatment with pioglitazone cannot be excluded.
Risk factors for bladder cancer should be assessed before initiating Cyero 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 functionThere 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 Cyero undergo
periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy
in all patients. Therapy with Cyero should not be initiated in patients with increased baseline liver
enzyme levels (ALT > 2.5 x upper limit of normal) or with any other evidence of liver disease.
Following initiation of therapy with Cyero, 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 Cyero 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 Cyero and periodically thereafter (see section 4.2).
Cyero is not recommended for patients with moderate or 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 trials with pioglitazone, there was evidence of dose-related weight gain, which may be due to
fat accumulation and, in some cases, associated with fluid retention. In some cases, weight increase may
be a symptom of cardiac failure, therefore weight should be closely monitored. 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 trials 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 Cyero as triple therapy with a sulphonylurea has not been established and thus
use is not recommended.
Cyero should not be used in combination with insulin, as the safety and efficacy of this combination have
not been established.

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 Cyero 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, Cyero should be discontinued; if acute
pancreatitis is confirmed, Cyero 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 trials 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 Cyero .
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, Cyero treatment should be discontinued (see section 4.6).
Cyero 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).
Cyero tablets contain lactose and, therefore, should not be administered to patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
 

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 Cyero. The
following section outlines the interactions observed with the individual components of Cyero
(alogliptin/pioglitazone) as reported in their respective Summary of Product Characteristics.
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.

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 drug disposition 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 (alphaglucosidase
inhibitor) and glyburide (sulphonylurea) have shown no clinically relevant pharmacokinetic
interactions.
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.

Pregnancy
Pregnancy Category C
There are no data from the use of Cyero 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). Cyero
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 Cyero . 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.
Cyero should not be administered to women who are breast-feeding.
Fertility
The effect of Cyero 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.

Alogliptin has no or negligible influence on the ability to drive and use machines. Pioglitazone 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 Cyero is used in combination with other anti-diabetic medicinal products known
to cause hypoglycaemia.

Summary of the safety profile
Clinical studies conducted to support the efficacy and safety of Cyero involved the co-administration of
alogliptin and pioglitazone as separate tablets. However, the results of bioequivalence studies have
demonstrated that Cyero 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.
The safety profile of co-administered alogliptin and pioglitazone was consistent with that of the individual
components as demonstrated in clinical trials for alogliptin and from the comprehensive data available for
pioglitazone. As such, the following section outlines the adverse reactions of the individual components
of Cyero (alogliptin/pioglitazone) as reported in their respective Summary of Product Characteristics.
Alogliptin

The information provided is based on a total of 9,405 patients with type 2 diabetes mellitus, including
3,750 patients treated with 25 mg alogliptin and 2,476 patients treated with 12.5 mg alogliptin, who
participated in one phase 2 or 12 phase 3 double-blind, placebo- or active-controlled clinical studies. In
addition, a cardiovascular outcomes study with 5,380 patients with type 2 diabetes mellitus and a recent
acute coronary syndrome event was conducted with 2,701 randomised to alogliptin and 2,679 randomised
to placebo. These studies evaluated the effects of alogliptin on glycaemic control and its safety as
monotherapy, as initial combination therapy with metformin or pioglitazone, and as add-on therapy to
metformin, or a sulphonylurea, or pioglitazone (with or without metformin or a sulphonylurea), or insulin
(with or without metformin).
In a pooled analysis of the data from 13 studies, the overall incidences of adverse events, serious adverse
events and adverse events resulting in discontinuation of therapy were comparable in patients treated with
25 mg alogliptin, 12.5 mg alogliptin, active-control or placebo. The most common adverse reaction in
patients treated with 25 mg alogliptin was headache.
The safety of alogliptin between the elderly (≥ 65 years old) and non-elderly (< 65 years old) was similar.
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).
Alogliptin
In the pooled pivotal phase 3 controlled clinical trials of alogliptin as monotherapy and as add-on
combination therapy involving 5,659 patients, the observed adverse reactions are listed below (Table 1).

Table 1: Adverse reactions observed in pooled pivotal phase 3 controlled clinical studies
System Organ Class
Adverse reaction                                Frequency of adverse reactions

Infections and infestations
Upper respiratory tract infections                 Common
Nasopharyngitis                                                  Common

Nervous system disorders
Headache                                                             Common        

Gastrointestinal disorders
Abdominal pain                                                     common
Gastroesophageal reflux disease                      common

Skin and subcutaneous tissue disorders
Pruritus                                                                  Common
Rash                                                                        Common

 

Alogliptin/pioglitazone
In pooled pivotal phase 3 controlled clinical trials of alogliptin as add-on therapy to pioglitazone
involving 3,504 patients, the observed adverse reactions are listed below (Table 2).

Table 2: Adverse reactions observed in pooled pivotal phase 3 controlled clinical studies
System Organ Class
Adverse reaction                                                         Frequency of adverse reactions
Infections and infestations
Upper respiratory tract infections                           Common
Sinusitis

Nervous system disorders
Headache                                                                        Common

Gastrointestinal disorders
Nausea                                                                           Common
Dyspepsia
Abdominal pain

Skin and subcutaneous tissue disorders
Pruritus                                                                          Common

Musculoskeletal and connective tissues disorders
Myalgia                                                                          Common

General disorders and administration site
conditions
Oedema peripheral                                                     Common
Weight increased

 

Alogliptin
Post-marketing experience
Table 3 shows additional adverse reactions which have been spontaneously reported post-marketing.
Table 3: Spontaneously reported alogliptin post-marketing adverse reactions
System Organ Class
Adverse reaction                                                               Frequency of adverse reactions
Immune system disorders
Hypersensitivity                                                                      Not known

Gastrointestinal disorders
Acute pancreatitis                                                                  Not known

Hepatobiliary disorders
Hepatic dysfunction including hepatic                             Not known

failure
Skin and subcutaneous tissue disorders                          Not known
Exfoliative skin conditions including
Stevens-Johnson syndrome
Erythema multiforme
Angioedema
Urticaria
 

Pioglitazone
Adverse reactions observed in double-blind studies with pioglitazone as monotherapy are listed below
(Table 4)
Table 4: Frequency of adverse reactions of pioglitazone
System Organ Class
Adverse reaction                                                                             Frequency of adverse reactions
Infections and infestations
Upper respiratory tract infection                                                Common
Sinusitis                                                                                             Uncommon


Neoplasms benign, malignant and unspecified
(including cysts and polyps)
Bladder cancer                                                                                  Uncommon

Immune System Disorders
Hypersensitivity and allergic reactions                                       Not known

Nervous system disorders
Hypoaesthesia                                                                                 Common
Insomnia                                                                                           Uncommon


Eye disorders
Visual disturbance                                                                           Common
Macular oedema                                                                             Not known


Musculoskeletal and connective tissue disorders
Fracture bone                                                                                  Common

Investigations 
Weight increased                                                                            Common
Alanine aminotransferase increased                                         Not known


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
trials. 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 trials in over 8,100 patients in the pioglitazone-treated
groups and 7,400 in the comparator-treated groups of up to 3.5 years duration. A higher rate of fractures
was observed in women taking pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture
rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
In the 3.5 year PROactive study, 44/870 (5.1%) 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%).
In active comparator-controlled trials, 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 trials, 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 trials with pioglitazone, the incidence of elevations of ALT greater than three times the upper
limit of normal was equal to placebo but less than that seen in metformin or sulphonylurea comparator
groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. 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
Pharmacovigilance and Drug Safety Centre (NPC) listed below:
To report any side effect(s):
 Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

No data are available with regard to overdose of Cyero.
Alogliptin
The highest doses of alogliptin administered in clinical trials 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).
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.

Pharmacotherapeutic group: Drugs used in diabetes; combinations of oral blood glucose lowering drugs.
ATC code: A10BD09.
Mechanism of action and pharmacodynamic effects
Cyero combines two antihyperglycaemic medications 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.
HOMA analysis shows that pioglitazone improves beta-cell function as well as increasing insulin
sensitivity. Two-year clinical studies have shown maintenance of this effect.
In one-year clinical trials, pioglitazone consistently gave a statistically significant reduction in the
albumin/creatinine ratio compared to baseline.

The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in type 2
diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was significantly
decreased while there was an increase in extra-abdominal fat mass. Similar changes in body fat
distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity. In most
clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol
levels were observed as compared to placebo with small, but not clinically significant, increases in
LDL-cholesterol levels.
In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty
acids, and increased HDL-cholesterol levels compared 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 Cyero involved the co-administration of
alogliptin and pioglitazone as separate tablets. However, the results of bioequivalence studies have
demonstrated that Cyero 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.

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 medication 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 5).
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 6). 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).
Patients with renal impairment
Cyero is not recommended for patients with moderate or 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 randomized 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.

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 trials, the incidence of reports of heart failure with pioglitazone treatment was the
same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in
combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular
disease, the incidence of serious heart failure was 1.6% higher with pioglitazone than with placebo when
added to therapy that included insulin. However, this did not lead to an increase in mortality in this study.
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, activecontrol
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, 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
randomized 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 trial 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 activecontrol).
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 Cyero in
all subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for
information on paediatric use).
 

The results of bioequivalence studies in healthy subjects demonstrated that Cyero 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 Cyero with food resulted in no change in overall exposure to alogliptin or pioglitazone.
Cyero may, therefore, be administered with or without food.
The following section outlines the pharmacokinetic properties of the individual components of Cyero
(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%).
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 drug 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 drug 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 (creatinine clearance (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).
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 drug 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.

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).
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).
Cyero
Special populations
Renal impairment
Cyero 25 mg/15 mg, 25 mg/30 mg or 25 mg/45 mg is not recommended for patients with moderate renal
impairment. Cyero is not recommended for patients with severe renal impairment or end-stage renal
disease requiring dialysis. No dose adjustment of Cyero for patients with mild renal impairment is
necessary (see section 4.2).
Hepatic impairment
Due to its pioglitazone component, Cyero should not be used in patients with hepatic impairment (see
section 4.2).

Animal studies of up to 13-weeks duration have been conducted with the combined substances in Cyero.
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.
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.
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
No environmental impact is anticipated from the clinical use of pioglitazone.

Active ingredients:
alogliptin and pioglitazone.
Inactive ingredients:
mannitol, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium
stearate, and lactose monohydrate; the tablets are film-coated with hypromellose, polyethylene glycol,
titanium dioxide, talc and ferric oxide (yellow and/or red) and are marked with red A1 or gray F1 printing
ink.

Not applicable.

3 years.

Do not store above 30 °C.

Primary Packaging Material: Blister packaging configuration is constructed of Aluminum cold
forming film and aluminum push-through lidding foil.
Secondary Packaging Material: Carton.
Pack sizes of 10, 14, 28, 30, 56, 60, 90, 98 or 100 film-coated tablets.
Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.