4.1.1 Monotherapy and Combination Therapy
ZYTERO PLUS is indicated as an adjunct to diet and exercise to improve glycemic control
in adults ( ≥ 18 years) with type 2 diabetes mellitus in multiple clinical settings when treatment with both alogliptin and metformin is appropriate.
4.1.2 Limitation of Use
ZYTERO PLUS should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

4.2.1 Posology
For the different dose regimens Zytero Plus is available in strengths of 12.5 mg/500 mg and
12.5 mg/1000 mg film-coated tablets
4.2.2 Recommendations for All Patients
• Healthcare providers should individualize the starting dose of ZYTERO PLUS based on the patient’s current regimen.
• ZYTERO PLUS should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. ZYTERO PLUS tablets
3
must not be split before swallowing.
• Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl.

4.2.3 Special populations
Elderly (≥ 65 years old)
No dose adjustment is necessary based on age. 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 ≥ 60 mL/min), no dose adjustment of Zytero Plus is necessary (see section 5.2).
As Zytero Plus contains metformin, it must not be used in patients with moderate or severe renal impairment or end-stage renal disease requiring dialysis (creatinine clearance < 60 mL/min) (see sections 4.3, 4.4 and 5.2).
Appropriate assessment of renal function is recommended prior to initiation of Zytero Plus and at regular intervals thereafter (see section 4.4).
Hepatic impairment
Zytero Plus should not be used in patients with hepatic impairment (see sections 4.3 and 5.2).
Paediatric population
The safety and efficacy of Zytero Plus in children and adolescents < 18 years old have not been established. No data are available.

Method of administration
Oral use.
Zytero Plus should be taken twice daily because of the pharmacokinetics of its metformin component. It should also be taken with meals to reduce the gastrointestinal adverse reactions associated with metformin. 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 at the same time. In that case, the missed dose should be skipped.

 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)  Diabetic ketoacidosis, diabetic pre-coma  Moderate and severe renal impairment and end-stage renal disease (creatinine clearance < 60 mL/min; see section 4.4)  Acute conditions with the potential to alter renal function such as: o dehydration o severe infection o shock  Acute or chronic disease which may cause tissue hypoxia (see section 4.4) such as: o cardiac or respiratory failure o recent myocardial infarction o shock  Hepatic impairment (see section 4.4)  Acute alcohol intoxication, alcoholism (see sections 4.4 and 4.5)

General
Zytero Plus should not be used in patients with type 1 diabetes mellitus. Zytero Plus is not a substitute for insulin in insulin-requiring patients.
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any conditions associated with hypoxia.
Diagnosis
A diagnosis of lactic acidosis must be considered in the event of non-specific symptoms such as muscle cramps and/or abdominal pain and/or severe asthenia. Lactic acidosis is further characterised by acidotic dyspnoea and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with Zytero Plus should be discontinued and the patient hospitalised immediately (see section 4.9).
Renal function

Alogliptin and metformin are substantially excreted by the kidney. The risk of metformin-related lactic acidosis increases with the degree of renal impairment, therefore, serum creatinine concentrations should be determined (and corresponding estimated glomerular filtration rate or creatinine clearance estimated) before initiating treatment and regularly thereafter:
 at least once a year in patients with normal renal function
 at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly patients
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).
Zytero Plus is not recommended for use in patients with moderate and severe renal impairment and end-stage renal disease (creatinine clearance < 60 mL/min)(see section 4.3).
Hepatic impairment
Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh score >9) and is, therefore, not recommended for use in such patients (see sections 4.2, 4.3 and 5.2).
Surgery

As Zytero Plus contains metformin, treatment should be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. Treatment should not usually be resumed earlier than
48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
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Administration of iodinated contrast agents
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Therefore, Zytero Plus should be discontinued prior to, or at the time of, the test and not reinstituted until
48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.5).

Use with other antihyperglycaemic medicinal products and hypoglycaemia
Insulin is known to cause hypoglycaemia. Therefore, a lower dose of insulin may be considered to reduce the risk of hypoglycaemia when this medicinal product is used in combination with Zytero Plus (see section 4.2).
Due to the increased risk of hypoglycaemia in combination with pioglitazone, a lower dose of pioglitazone may be considered to reduce the risk of hypoglycaemia when this drug is used in combination with Zytero Plus (see section 4.2).
Combinations not studied
Zytero Plus should not be used in combination with a sulphonylurea, as the safety and efficacy of this combination have not been fully established.
Change in clinical status of patients with previously controlled type 2 diabetes mellitus
As Zytero Plus contains metformin, any patient with type 2 diabetes mellitus previously well controlled on Zytero Plus who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, Zytero Plus must be stopped immediately and other appropriate corrective measures initiated.
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, Zytero Plus should be discontinued; if acute pancreatitis is confirmed, Zytero Plus should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Hepatic effects

Postmarketing reports of hepatic dysfunction including hepatic failure have been received. A causal relationship has not been established. Patients should be observed closely for possible liver

abnormalities. Obtain liver function tests promptly in patients with symptoms suggestive of liver injury. If an abnormality is found and an alternative etiology is not established, consider discontinuation of alogliptin treatment.

Co-administration of 100 mg alogliptin once daily and 1,000 mg metformin hydrochloride twice daily for 6 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin or metformin.
Specific pharmacokinetic drug interaction studies have not been performed with Zytero Plus . The following section outlines the interactions observed with the individual components of Zytero Plus (alogliptin/metformin) 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 studies with metformin, pioglitazone (thiazolidinedione), voglibose (alpha-glucosidase inhibitor) and glyburide (sulphonylurea) have shown no clinically relevant pharmacokinetic interactions.

Interactions with metformin
Combinations not recommended
Alcohol
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic impairment) due to the metformin component (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Cationic medicinal products
Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine (400 mg twice daily) increased metformin systemic exposure (area under the curve, AUC) by 50% and Cmax by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered.
Iodinated contrast agents
The intravascular administration of iodinated contrast agents may lead to renal failure resulting in metformin accumulation and a risk of lactic acidosis. Therefore, Zytero Plus should be discontinued prior to, or at the time of, the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see section 4.4).
Combination requiring precautions for use

Medicinal products with intrinsic hyperglycaemic activity
Glucocorticoids (given by systemic and local routes), beta-2-agonists and diuretics (see also
section 4.4) have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of Zytero Plus should be adjusted during therapy with the other medicinal product and upon its discontinuation.
ACE inhibitors
Angiotensin-converting-enzyme (ACE) inhibitors may decrease blood glucose levels. If necessary, the dose of Zytero Plus should be adjusted during therapy with the other medicinal product and upon its discontinuation.

Pregnancy
Pregnancy Category B
There are no data from the use of Zytero Plus in pregnant women. Studies in pregnant rats with alogliptin plus metformin as combination treatment have shown reproductive toxicity at approximately 5-20 times (for metformin and alogliptin respectively) the human exposure at the recommended dose.
Zytero Plus 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 metformin
A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (see section 5.3).
Breast-feeding
No studies in lactating animals have been conducted with the combined active substances of Zytero Plus . In studies performed with the individual active substances, both alogliptin and metformin were excreted in the milk of lactating rats. It is unknown whether alogliptin is excreted in human milk.
Metformin is excreted in human milk in small amounts. A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zytero Plus therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
The effect of Zytero Plus on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies conducted with alogliptin or with metformin (see section 5.3).

Zytero Plus has no or negligible influence on the ability to drive and use machines. However, patients should be alerted to the risk of hypoglycaemia especially when used in combination with insulin or pioglitazone.

Summary of the safety profile
Clinical studies conducted to support the efficacy and safety of Zytero Plus involved the co-administration of alogliptin and metformin as separate tablets. However, the results of
bioequivalence studies have demonstrated that Zytero Plus film-coated tablets are bioequivalent to the corresponding doses of alogliptin and metformin co-administered as separate tablets.
The information provided is based on a total of 7,150 patients with type 2 diabetes mellitus, including 4,201 patients treated with alogliptin and metformin, who participated in 7 phase 3 double-blind, placebo- or active-controlled clinical studies. These studies evaluated the effects of co-administered alogliptin and metformin on glycaemic control and their safety as initial combination therapy, as dual therapy in patients initially treated with metformin alone, and as add-on therapy to a thiazolidinedione or insulin.
The safety profile of co-administered alogliptin and metformin was consistent with that of the individual components as demonstrated in clinical trials for alogliptin and from the comprehensive data available for metformin. As such, the following section outlines the adverse reactions of the individual components of Zytero Plus (alogliptin/metformin) 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 a thiazolidinedione, and as add-on therapy to metformin, or a sulphonylurea, or a thiazolidinedione (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                                                         Common
Upper respiratory tract infections Nasopharyngitis

Nervous system disorders
Headache                                                                                        Common

Gastrointestinal disorders                                                          Common
Abdominal pain Gastroesophageal reflux disease

Skin and subcutaneous tissue disorders                                  Common
Pruritus Rash
 

Alogliptin/metformin
In the pooled pivotal phase 3 controlled clinical trials of alogliptin as add-on combination therapy to metformin, involving 7,151 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 Nasopharyngitis
Common Common

Nervous system disorders
Headache
Common

Gastrointestinal disorders Gastroenteritis Abdominal pain Diarrhoea Vomiting
Gastritis
Gastroesophageal reflux disease
Common Common Common Common Common Common

Skin and subcutaneous tissue disorders
Pruritus Rash
Common

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 failure
Not known

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

Metformin
Clinical trial data and post-marketing experience
Table 4 shows additional adverse reactions which have been reported from clinical trials and post- marketing.
Table 4: Frequency of metformin adverse reactions identified from clinical trial data
and post-marketing experience
System Organ Class
Adverse reaction
Frequency of adverse reactions
Metabolism and nutrition disorders
Lactic acidosis
Vitamin B12 deficiency
Very rare Very rare

Nervous system disorders
Metallic taste
Common

Gastrointestinal disorders Abdominal pain Diarrhoea
Loss of appetite Nausea Vomiting
Very common Very common Very common Very common Very common

Hepatobiliary disorders
Hepatitis
Liver function test abnormalities
Very rare Very rare

Skin and subcutaneous tissue disorders
Erythema Pruritus Urticaria
Very rare Very rare Very rare

Description of selected adverse reactions
Lactic acidosis: 0.03 cases/1000 patient-years (see section 4.4).

Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption and appears generally to be without clinical significance. However, it may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).
Gastrointestinal symptoms occur most frequently during initiation of therapy and resolve spontaneously in most cases. These may be prevented by taking metformin in 2 daily doses during or after meals.
Isolated cases of hepatitis or liver function test abnormalities resolving on discontinuation of metformin have been reported.
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 Zytero Plus . 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 total daily dose of 25 mg alogliptin, respectively).
Metformin
A large overdose of metformin or concomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital.

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 removing alogliptin in overdose. It is not known if alogliptin is removed by peritoneal dialysis.
The most effective method of removing lactate and metformin is haemodialysis.

Pharmacotherapeutic group: Drugs used in diabetes; combinations of oral blood glucose lowering drugs.
ATC code: A10BD13.
Mechanism of action and pharmacodynamic effects
Zytero Plus 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 metformin, a member of the biguanide class.
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.
Metformin

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and, therefore, does not produce hypoglycaemia.
Metformin may act via 3 mechanisms:
- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
- in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation.
- by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. It also increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies; metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.
Clinical efficacy
Clinical studies conducted to support the efficacy of Zytero Plus involved the co-administration of alogliptin and metformin as separate tablets. However, the results of bioequivalence studies have demonstrated that Zytero Plus film-coated tablets are bioequivalent to the corresponding doses of alogliptin and metformin co-administered as separate tablets.
The co-administration of alogliptin and metformin has been studied as dual therapy in patients initially treated with metformin alone, and as add-on therapy to a thiazolidinedione or insulin.
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 7,151 patients with type 2 diabetes mellitus, including 4,202 patients treated with alogliptin and metformin, participated in 7 phase 3 double-blind, placebo- or active-controlled clinical studies conducted to evaluate the effects of co-administered alogliptin and metformin on glycaemic control and their safety. In these studies, 696 alogliptin/metformin-treated patients were ≥ 65 years old.
Overall, treatment with the recommended total daily dose of 25 mg alogliptin in combination with metformin 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 treatment. 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 metformin
The addition of 25 mg alogliptin once daily to metformin hydrochloride therapy (mean
dose = 1,847 mg) 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). Significantly more patients receiving 25 mg alogliptin (44.4%) achieved target HbA1c levels of  7.0% compared to those receiving placebo (18.3%) at Week 26 (p<0.001).

The addition of 25 mg alogliptin once daily to metformin hydrochloride therapy (mean
dose = 1,835 mg) resulted in improvements from baseline in HbA1c at Week 52 and Week 104. At Week 52, the HbA1c reduction by 25 mg alogliptin plus metformin (-0.76%, Table 6) was similar to that produced by glipizide (mean dose = 5.2 mg) plus metformin hydrochloride therapy (mean
dose = 1,824 mg, -0.73%). At Week 104, the HbA1c reduction by 25 mg alogliptin plus metformin (- 0.72%, Table 6) was greater than that produced by glipizide plus metformin (-0.59%). Mean change from baseline in fasting plasma glucose at Week 52 for 25 mg alogliptin and metformin was significantly greater than that for glipizide and metformin (p<0.001). By Week 104, mean change from baseline in fasting plasma glucose for 25 mg alogliptin and metformin was -3.2 mg/dL compared with 5.4 mg/dL for glipizide and metformin. More patients receiving 25 mg alogliptin and metformin (48.5%) achieved target HbA1c levels of ≤ 7.0% compared to those receiving glipizide and metformin (42.8%) (p=0.004).
Co-administration of 12.5 mg alogliptin and 1,000 mg metformin hydrochloride twice daily resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to either 12.5 mg alogliptin twice daily alone or 1,000 mg metformin hydrochloride twice daily alone. Significantly more patients receiving 12.5 mg alogliptin and 1.000 mg metformin hydrochloride twice daily (59.5%) achieved target HbA1c levels of < 7.0% compared to those receiving either 12.5 mg alogliptin twice daily alone (20.2%, p<0.001) or 1,000 mg metformin hydrochloride twice daily alone (34.3%, p<0.001) at Week 26.
Alogliptin as add-on therapy to metformin with a thiazolidinedione
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).
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 FPG 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).
Alogliptin as add-on therapy to metformin with insulin
The addition of 25 mg alogliptin once daily to insulin therapy (mean dose = 56.5 IU, with or without metformin) resulted in statistically significant improvements from baseline in HbA1c and FPG 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 therapy. More patients receiving 25 mg alogliptin (7.8%) achieved target HbA1c levels of  7.0% compared to those receiving placebo (0.8%) at Week 26.

Elderly (≥ 65 years old)
The efficacy and safety of the recommended doses of alogliptin and metformin 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 alogliptiThere 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].
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, 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.
In a clinical trial of alogliptin as mono-therapy, the incidence of hypoglycaemia was similar to that of placebo, and lower than placebo in another trial as add-on to a sulphonylurea.
Higher rates of hypoglycaemia were observed with triple therapy with a thiazolidinedione and metformin and in combination with insulin, as 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 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 Zytero Plus 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 Zytero Plus film-coated tablets are bioequivalent to the corresponding doses of alogliptin and metformin co-administered as separate tablets.
Co-administration of 100 mg alogliptin once daily and 1,000 mg metformin hydrochloride twice daily for 6 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin or metformin.
Administration of Zytero Plus with food resulted in no change in total exposure (AUC) to alogliptin or metformin. However, mean peak plasma concentrations of alogliptin and metformin were decreased by 13% and 28% when Zytero Plus was administered with food, respectively. There was no change in the time to peak plasma concentration (Tmax) for alogliptin, but there was a delayed Tmax for metformin of 1.5 hours. These changes are not likely to be clinically significant (see below).
Zytero Plus should be taken twice daily because of the pharmacokinetics of its metformin component. It should also be taken with meals to reduce the gastrointestinal undesirable effects associated with metformin (see section 4.2).
The pharmacokinetics of Zytero Plus in children and adolescents < 18 years old has not been established. No data are available (see section 4.2).
The following section outlines the pharmacokinetic properties of the individual components of Zytero Plus (alogliptin/metformin) 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 (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 and above).
Metformin
Absorption
After an oral dose of metformin, the maximum plasma concentration (Cmax) is reached in approximately 2.5 hours (Tmax). Absolute bioavailability of a 500 mg or 850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.
At the recommended metformin doses and dosing schedules, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 microgram/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 microgram/mL even at maximum doses.
Food slightly delays and decreases the extent of the absorption of metformin. Following oral administration of an 850 mg metformin hydrochloride tablet, the peak plasma concentration was 40% lower, AUC was decreased by 25% and the time to peak plasma concentration (Tmax) was prolonged by 35 minutes. The clinical relevance of these findings is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276 L.

Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination
Renal clearance of metformin is > 400 mL/min indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and, thus, the elimination half-life is prolonged leading to increased levels of metformin in the plasma.
Zytero Plus
Special populations
Renal impairment
Due to its metformin component, Zytero Plus should not be used in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis (see section 4.2).
Hepatic impairment
Zytero Plus should not be used in patients with hepatic impairment (see section 4.2).

Concomitant treatment with alogliptin and metformin did not produce new toxicities and no effects on the toxicokinetics of either compound were observed.
In rats no treatment-related foetal abnormalities occurred following concomitant administration at exposure margins of approximately 28- to 29-fold for alogliptin and 2- to 2.5-fold for metformin at the maximum recommended human dose of 25 mg/day and 2000 mg/day, respectively. The combination revealed teratogenic potential in small numbers of foetuses (microphthalmia, small eye bulge and cleft palate) at higher doses of metformin (exposure margins of approximately 20-fold and 5- to 6-fold the maximum recommended human dose for alogliptin and metformin, respectively).
The following data are findings from studies performed with alogliptin or metformin 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 total 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.
Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction.

Mannitol Microcrystalline cellulose Povidone
Crospovidone Magnesium stearate
The tablets are film-coated with hypromellose 2910 Talc
Titanium dioxide Ferric oxide yellow

Not applicable.

3 years.

Do not store above 30 °C.

Primary Packaging Material: The packaging configuration for blister packs is constructed of aluminum forming material and aluminum lidding material.
Secondary Packaging Material: Carton.
Pack sizes of 10, 14, 20, 28, 56, 60, 98, 112, 120, 180, 196, 196 (2x98 multipack) or 200 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.