4.1. Therapeutic indications

Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride 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 of metformin 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 Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride 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

Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride in children and adolescents < 18 years old have not been established. No data are available.

Method of administration

Oral use.

Alogliptin/Metformin Hydrochloride 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:

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)

4.4. Special warnings and precautions for use

General

Alogliptin/Metformin Hydrochloride should not be used in patients with type 1 diabetes mellitus. Alogliptin/Metformin Hydrochloride 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) Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride 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.

Patients with known or suspected mitochondrial diseases

In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.

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. Alogliptin/Metformin Hydrochloride 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 4.4).

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 Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride (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 Alogliptin/Metformin Hydrochloride (see section 4.2).

Combinations not studied

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

Vitamin B12 deficiency

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. If vitamin B12 deficiency is suspected (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated, with appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.

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 Alogliptin/Metformin Hydrochloride. The following section outlines the interactions observed with the individual components of Alogliptin/Metformin Hydrochloride 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

Alogliptin/Metformin Hydrochloride 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, angiotensin-converting 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 Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride 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, (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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Alogliptin/Metformin Hydrochloride 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.

Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride. 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 Alogliptin/Metformin Hydrochloride therapy taking into account the benefit of breast‑feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of Alogliptin/Metformin Hydrochloride 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

Alogliptin/Metformin Hydrochloride 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 Alogliptin/Metformin Hydrochloride (see section 4.4). Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of Alogliptin/Metformin Hydrochloride (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 Alogliptin/Metformin Hydrochloride (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 Alogliptin/Metformin Hydrochloride.

Clinical studies conducted to support the efficacy and safety of Alogliptin/Metformin Hydrochloride involved the co‑administration of alogliptin and metformin as separate tablets. However, the results of bioequivalence studies have demonstrated that Alogliptin/Metformin Hydrochloride 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

Alogliptin/Metformin Hydrochloride

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 decrease/deficiency*

common

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

* see section 4.4 for further information

Description of selected adverse reactions

Lactic acidosis: 0.03 cases/1 000 patient‑years (see section 4.4).

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 Yellow Card Scheme at Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the GooglePlay or Apple App Store.

4.9. Overdose

No data are available with regard to overdose of Alogliptin/Metformin Hydrochloride.

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.