Vipdomet - summary of medicine characteristics

NAME OF THE MEDICINAL PRODUCT

Vipdomet 12.5 mg/850 mg film-coated tablets

Vipdomet 12.5 mg/1,000 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Vipdomet 12.5 mg/850 mg film-coated tablets

Each tablet contains alogliptin benzoate equivalent to 12.5 mg alogliptin and 850 mg metformin hydrochloride.

Vipdomet 12.5 mg/1,000 mg film-coated tablets

Each tablet contains alogliptin benzoate equivalent to 12.5 mg alogliptin and 1000 mg metformin hydrochloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Vipdomet 12.5 mg/850 mg film-coated tablets

Light yellow, oblong (approximately 21.0 mm long by 10.1 mm wide), biconvex, film-coated tablets with “12.5/850” debossed on one side and “322M” debossed on the other side.

Vipdomet 12.5 mg/1,000 mg film-coated tablets

Pale yellow, oblong (approximately 22.3 mm long by 10.7 mm wide), biconvex, film-coated tablets with “12.5/1000” debossed on one side and “322M” debossed on the other side.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Vipdomet is indicated in the treatment of 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, inadequately

controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of alogliptin and metformin.

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

exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and pioglitazone.

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

improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control.

4.2 Posology and method of administration

Posology

For the different dose regimens Vipdomet is available in strengths of 12.5 mg/850 mg and 12.5 mg/1,000 mg film-coated tablets.

Adults (>18 years old) with normal renal, function (glomerular, filtration rate (GFR)>90 mL/min) The dose should be individualised on the basis of the patient’s current treatment regimen.

For patients inadequately controlled on the maximal tolerated dose ofmetformin hydrochloride alone , the recommended dose is one tablet of 12.5 mg/850 mg or 12.5 mg/1,000 mg twice daily, corresponding to 25 mg alogliptin plus 1,700 mg or 2,000 mg metformin hydrochloride daily, depending on the dose of metformin hydrochloride already being taken.

For patients inadequately controlled on dual therapy with a maximal tolerated dose of metformin and pioglitazone , the dose of pioglitazone should be maintained, and Vipdomet administered concomitantly; alogliptin should be dosed at 12.5 mg twice daily (25 mg total daily dose) and metformin hydrochloride at a similar dose (either 850 mg or 1,000 mg twice daily) to that 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 metformin (as dual therapy or as part of triple therapy with insulin), both alogliptin and metformin should be dosed at the total daily dose already being taken; the individual dose of alogliptin should be halved as it will be taken twice daily whilst the dosing of metformin should remain unchanged.

For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin , the dose of Vipdomet should provide alogliptin dosed at 12.5 mg twice daily (25 mg total daily dose) and a dose of metformin similar to the dose already being taken.

A lower dose of insulin may be considered to reduce the risk of hypoglycaemia.

Maximum daily dose

The maximum recommended daily dose of 25 mg alogliptin should not be exceeded.

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

A GFR should be assessed before initiation of treatment with metformin containing medicinal products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g every 3–6 months.

The maximum daily dose of metformin should preferably be divided into 2–3 daily doses. Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin in patients with GFR<60 mL/min.

If no adequate strength of Vipdomet is available, individual monocomponents should be used instead of the fixed dose combination.

GFR mL/min	Metformin	Alogliptin*
60–89	Maximum daily dose is 3,000 mg Dose reduction may be considered in relation to declining renal function.	No dose adjustment Maximum daily dose is 25 mg
45–59	Maximum daily dose is 2,000 mg The starting dose is at most half of the maximum dose.	Maximum daily dose is 12.5 mg
30–44	Maximum daily dose is 1,000 mg. The starting dose is at most half of the maximum dose.	Maximum daily dose is 12.5 mg
<30	Metformin is contra-indicated	Maximum daily dose is 6.25 mg

* Alogliptin dose adjustment is based on a pharmacokinetic study where kidney function was assessed using creatinine clearance (CrCl) levels estimated from the Cockcroft-Gault equation.

Hepatic impairment

Vipdomet 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 Vipdomet in children and adolescents <18 years old have not been established. No data are available.

Method of administration

Oral use.

Vipdomet 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.

4.3 Contraindications

• – Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or

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

• – Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

• – Diabetic pre-coma

• – Severe renal failure (GFR <30 mL/min)

• – Acute conditions with the potential to alter renal function such as:

• – dehydration

• – severe infection

• – shock

–     Acute or chronic disease which may cause tissue hypoxia (see section 4.4) such as:

• – cardiac or respiratory failure

• – recent myocardial infarction

• – shock

• – Hepatic impairment (see section 4.4)

• – Acute alcohol intoxication, alcoholism (see sections 4.4 and 4.5)

4.4 Special warnings and precautions for use

General

Vipdomet should not be used in patients with type 1 diabetes mellitus. Vipdomet is not a substitute for insulin in insulin-requiring patients.

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever, heat, reduced fluid intake) Vipdomet should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs)) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking Vipdomet and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruva­te ratio.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast media may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Vipdomet should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.5.

Renal function

GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with GFR<30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).

Surgery

As Vipdomet contains metformin it must be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.

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).

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 Vipdomet (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 medicinal product is used in combination with Vipdomet (see section 4.2).

Combinations not studied

Vipdomet 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 Vipdomet contains metformin, any patient with type 2 diabetes mellitus previously well controlled on Vipdomet 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, Vipdomet 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, Vipdomet should be discontinued; if acute pancreatitis is confirmed, Vipdomet 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.

Bullous Pemphigoid

There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including alogliptin. If bullous pemphigoid is suspected, alogliptin should be discontinued.

4.5 Interaction with other medicinal products and other forms of interaction

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

Interactions with metformin

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Vipdomet must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.4.

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.

Combination requiring , precautions , for use

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, angiotensincon­verting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

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 Vipdomet should be adjusted during therapy with the other medicinal product and upon its discontinuation.

ACE inhibitors

ACE inhibitors may decrease blood glucose levels. If necessary, the dose of Vipdomet should be adjusted during therapy with the other medicinal product and upon its discontinuation.

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 disposition of the active substance in the kidney: organic anion transporter-1, organic anion transporter-3 or organic cationic transporter-2 (OCT2). Furthermore, clinical data do not suggest interaction with p-glycoprotein inhibitors or substrates.

In clinical studies, alogliptin had no clinically relevant effect on the pharmacokinetics of caffeine, ®-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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Vipdomet in pregnant women. Studies in pregnant rats with alogliptin plus metformin as combination treatment have shown reproductive toxicity (see section 5.3) at approximately 5–20 times (for metformin and alogliptin respectively) the human exposure at the recommended dose.

Vipdomet 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 Vipdomet. 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 Vipdomet therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of Vipdomet 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).

4.7 Effects on ability to drive and use machines

Vipdomet 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.

4.8 Undesirable effects

Summary of the safety profile

Acute pancreatitis is a serious adverse reaction and is attributed to the alogliptin component of Vipdomet (see section 4.4). Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of Vipdomet (see section 4.4). Lactic acidosis is a serious adverse reaction, which may occur very rarely (<1/10,000), and is attributed to the metformin component of Vipdomet (see section 4.4). Other reactions such as upper respiratory tract infections, nasopharyngitis, headache, gastroenteritis, abdominal pain, diarrhoea, vomiting, gastritis, gastroesophageal reflux disease, pruritus, rash, hypoglycaemia may occur commonly (> 1/100 to < 1/10) (see section 4.4) which are attributed to Vipdomet.

Clinical studies conducted to support the efficacy and safety of Vipdomet involved the co-administration of alogliptin and metformin as separate tablets. However, the results of bioequivalence studies have demonstrated that Vipdomet 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.

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).

Table 1: Adverse reactions

System organ class Adverse reaction	Frequency of adverse reactions
	Alogliptin	Metformin	Vipdomet
Infections and infestations
upper respiratory tract infections	common		common
nasopharyngitis	common		common
Immune system disorders
hypersensitivity	not known
Metabolism and nutrition disorders
lactic acidosis		very rare
vitamin B12 deficiency		very rare
hypoglycaemia	common		common
Nervous system disorders
headache	common		common
metallic taste		common
Gastrointestinal disorders
gastroenteritis			common
abdominal pain	common	very common	common
diarrhoea	common	very common	common
vomiting		very common	common
gastritis			common
gastroesophageal reflux disease	common		common
loss of appetite		very common
nausea		very common
acute pancreatitis	not known
Hepatobiliary disorders
hepatitis		very rare
Liver function test abnormalities		very rare
hepatic dysfunction including hepatic failure	not known
Skin and subcutaneous tissue disorders
pruritus	common	very rare	common
rash	common		common
erythema		very rare
exfoliative skin conditions including Stevens-Johnson syndrome	not known
erythema multiforme	not known
angioedema	not known
urticaria	not known	very rare
bullous pemphigoid	not known
Renal and urinary disorders
interstitial nephritis	not known

Description of selected adverse reactions

Lactic acidosis: 0.03 cases/1,000 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 reporting system listed in Appendix V.

4.9 Overdose

No data are available with regard to overdose of Vipdomet.

Alogliptin

The highest doses of alogliptin administered in clinical studies were single doses of 800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes mellitus (equivalent to 32 times and 16 times the recommended 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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes; combinations of oral blood glucose lowering drugs.

ATC code: A10BD13.

Mechanism of action and pharmacodynamic effects

Vipdomet combines two antihyperglycaemic medicinal products with complementary and distinct mechanisms of action to improve glycaemic control in patients with type 2 diabetes mellitus: alogliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, and 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 Vipdomet involved the co-administration of alogliptin and metformin as separate tablets. However, the results of bioequivalence studies have demonstrated that Vipdomet 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 2). Significantly more patients receiving 25 mg alogliptin (44.4%) achieved target HbAlc 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 3) 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 3) 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 HbAlc 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 2). Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg alogliptin regardless of whether patients were receiving concomitant metformin or sulphonylurea therapy. Significantly more patients receiving 25 mg alogliptin (49.2%) achieved target HbA1c levels of <7.0% compared to those receiving placebo (34.0%) at Week 26 (p=0.004).

The addition of 25 mg alogliptin once daily to 30 mg pioglitazone in combination with metformin hydrochloride therapy (mean dose = 1,867.9 mg) resulted in improvements from baseline in HbA1c at Week 52 that were both non-inferior and statistically superior to those produced by 45 mg pioglitazone in combination with metformin hydrochloride therapy (mean dose = 1,847.6 mg, Table 3). The significant reductions in HbA1c observed with 25 mg alogliptin plus 30 mg pioglitazone and metformin were consistent over the entire 52-week treatment period compared to 45 mg pioglitazone and metformin (p<0.001 at all time points). In addition, mean change from baseline in 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 2). 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.

Table 2: Change in HbAlc (%) from baseline with alogliptin 25 mg at Week 26 by placebo-controlled study (FAS, LOCF)
Study	Mean baseline HbAlc (%) (SD)	Mean change from baseline in HbAlc (%)f(SE)	Placebo-corrected change from baseline in HbAlc (%)f (2-sided 95% CI)
Add-on combination therapy placebo-controlled studies
Alogliptin 25 mg once daily with metformin (n=203)	7.93 (0.799)	–0.59 (0.054)	–0.48* (-0.67, –0.30)
Alogliptin 25 mg once daily with a sulphonylurea (n=197)	8.09 (0.898)	–0.52 (0.058)	–0.53* (-0.73, –0.33)
Alogliptin 25 mg once daily with a thiazolidinedione ± metformin or a sulphonylurea (n=195)	8.01 (0.837)	–0.80 (0.056)	–0.61* (-0.80, –0.41)
Alogliptin 25 mg once daily with insulin +metformin (n=126)	9.27 (1.127)	–0.71 (0.078)	–0.59* (-0.80, –0.37)
FAS = full analysis set LOCF = last observation carried forward ' Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values * p<0.001 compared to placebo or placebo+combination treatment

Table 3: Change in HbAlc (%) from baseline with alogliptin 25 mg by active-controlled study (PPS, LOCF)
Study	Mean baseline HbAlc (%) (SD)	Mean change from baseline in HbAlc (%)f(SE)	Treatment-corrected change from baseline in HbAlc (%)f (1-sided CI)
Add-on combination therapy studies
Alogliptin 25 mg once daily with metformin vs a sulphonylurea + metformin Change at Week 52 (n=382) Change at Week 104 (n=382)	7.61 (0.526) 7.61 (0.526)	–0.76 (0.027) –0.72 (0.037)	–0.03 (-infinity, 0.059) –0.13* (-infinity, –0.006)
Alogliptin 25 mg once daily with a thiazolidinedione + metformin vs a titrating thiazolidinedione + metformin Change at Week 26 (n=303) Change at Week 52 (n=303)	8.25 (0.820) 8.25 (0.820)	–0.89 (0.042) –0.70 (0.048)	–0.47* (-infinity, –0.35) –0.42*
PPS = per protocol set LOCF = last observation carried forward Non inferiority and superiority statistically demonstrated ' Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values

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 randomised cardiovascular outcomes safety study was conducted with 5,380 patients with high underlying cardiovascular risk to examine the effect of alogliptin compared with placebo (when added to standard of care) on major adverse cardiovascular events (MACE) including time to the first occurrence of any event in the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke in patients with a recent (15 to 90 days) acute coronary event. At baseline, patients had a mean age of 61 years, mean duration of diabetes of 9.2 years, and mean HbA1c of 8.0%.

The study demonstrated that alogliptin did not increase the risk of having a MACE compared to placebo [Hazard Ratio: 0.96; 1-sided 99% Confidence Interval: 0–1.16]. In the alogliptin group, 11.3% of patients experienced a MACE compared to 11.8% of patients in the placebo group.

Table 4. MACE Reported in cardiovascular outcomes study
	Number of Patients (%)
	Alogliptin 25 mg	Placebo
	N=2,7O1	N=2,679
Primary Composite Endpoint [First Event of CV Death, Nonfatal MI and Nonfatal Stroke]	305 (11.3)	316 (11.8)
Cardiovascular Death	89 (3.3)	111 (4.1)
Nonfatal Myocardial Infarction	187 (6.9)	173 (6.5)
Nonfatal Stroke	29 (1.1)	32 (1.2)
*Overall there were 153 subjects (5.7%) in the alogliptin group and 173 subjects (6.5%) in the placebo group who died (all-cause mortality)

There were 703 patients who experienced an event within the secondary MACE composite endpoint (first event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent revascularization due to unstable angina). In the alogliptin group, 12.7% (344 subjects) experienced an event within the secondary MACE composite endpoint, compared with 13.4% (359 subjects) in the placebo group [Hazard Ratio = 0.95; 1-sided 99% Confidence Interval: 0–1.14].

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 randomised controlled cardiovascular outcomes study, investigator reported events of hypoglycemia were similar in patients receiving placebo (6.5%) and patients receiving alogliptin (6.7%) in addition to standard of care.

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 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 Vipdomet in all subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The results of bioequivalence studies in healthy subjects demonstrated that Vipdomet 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 Vipdomet 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 Vipdomet 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).

Vipdomet 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 Vipdomet 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 Vipdomet (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 active substance is well distributed into tissues.

Alogliptin is 20–30% bound to plasma proteins.

Biotransformation

Alogliptin does not undergo extensive metabolism, 60–70% of the dose is excreted as unchanged active substance in the urine.

Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N-demethylated alogliptin, M-I (< 1% of the parent compound), and N-acetylated alogliptin, M-II (< 6% of the parent compound). M-I is an active metabolite and is a highly selective inhibitor of DPP-4 similar to alogliptin; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.

In vitro studies indicate that alogliptin does not induce CYP1A2, CYP2B6 and CYP2C9 and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at concentrations achieved with the recommended dose of 25 mg alogliptin. Studies in vitro have shown alogliptin to be a mild inducer of CYP3A4, but alogliptin has not been shown to induce CYP3A4 in studies in vivo.

In studies in vitro , alogliptin was not an inhibitor of the following renal transporters; OAT1, OAT3 and OCT2.

Alogliptin exists predominantly as the ®-enantiomer (>99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at therapeutic doses.

Elimination

Alogliptin was eliminated with a mean terminal half-life (T1/2) of approximately 21 hours.

Following administration of an oral dose of [14C] alogliptin, 76% of total radioactivity was eliminated in the urine and 13% was recovered in the faeces.

The average renal clearance of alogliptin (170 mL/min) was greater than the average estimated glomerular filtration rate (approx. 120 mL/min), suggesting some active renal excretion.

Time-dependency

Total exposure (AUC(0-inf)) to alogliptin following administration of a single dose was similar to exposure during one dose interval (AUC(0–24)) after 6 days of once daily dosing. This indicates no time-dependency in the kinetics of alogliptin after multiple dosing.

Special , populations

Renal impairment

A single dose of 50 mg alogliptin was administered to 4 groups of patients with varying degrees of renal impairment (CrCl using the Cockcroft-Gault formula): mild (CrCl = >50 to <80 mL/min), moderate (CrCl = >30 to <50 mL/min), severe (CrCl = <30 mL/min) and end-stage renal disease on haemodialysis.

An approximate 1.7-fold increase in AUC for alogliptin was observed in patients with mild renal impairment. However, as the distribution of AUC values for alogliptin in these patients was within the same range as control subjects, no dose adjustment of alogliptin for patients with mild renal impairment is necessary (see section 4.2).

In patients with moderate or severe renal impairment, or end-stage renal disease on haemodialysis, an increase in systemic exposure to alogliptin of approximately 2– and 4-fold was observed, respectively. (Patients with end-stage renal disease underwent haemodialysis immediately after alogliptin dosing. Based on mean dialysate concentrations, approximately 7% of the active substance was removed during a 3-hour haemodialysis session.) Therefore, in order to maintain systemic exposures to alogliptin that are similar to those observed in patients with normal renal function, lower doses of alogliptin should be used in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis (see above and section 4.2).

Hepatic impairment

Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment compared to control subjects. The magnitude of these reductions was not considered to be clinically relevant. Therefore, no dose adjustment of alogliptin is necessary for patients with mild to moderate hepatic impairment (Child-Pugh scores of 5 to 9). Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh score>9).

Age, gender, race, body weight

Age (65–81 years old), gender, race (white, black and Asian) and body weight did not have any clinically relevant effect on the pharmacokinetics of alogliptin. No dose adjustment is necessary (see section 4.2).

Paediatric population

The pharmacokinetics of alogliptin in children and adolescents <18 years old has not been established. No data are available (see section 4.2 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 studies, 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.

Vipdomet

Special , populations

Renal impairment

Due to its metformin component, Vipdomet should not be used in patients with severe renal impairment, or end-stage renal disease requiring dialysis (see section 4.2).

Hepatic impairment

Vipdomet should not be used in patients with hepatic impairment (see section 4.2).

5.3 Preclinical safety data

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 2,000 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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Mannitol

Microcrystalline cellulose

Povidone K30

Crospovidone Type A

Magnesium stearate

Film-coating

Hypromellose

Talc

Titanium dioxide (E171)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Polychlorotri­fluoroethylene (PCTFE)/polyvinyl chloride (PVC) blisters with push through aluminium lidding foil. Pack sizes of 10, 14, 20, 28, 56, 60, 98, 112, 120, 180, 196, 200 or multipacks containing 196 (2 packs of 98) film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Takeda Pharma A/S

Delta Park 45

2665 Vallensbaek Strand

Denmark

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/843/001–026

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 September 2013

Date of latest renewal: 24 May 2018