Vipdomet 12.5 mg/1000 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.

Film-coated tablet (tablet).

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.

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.

Posology

For the different dose regimens Vipdomet is available in strengths of 12.5 mg/850 mg and 12.5 mg/1000 mg film-coated tablets

Adults (≥ 18 years old)

The dose of Vipdomet 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 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 1000 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.

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

For patients with mild renal impairment (creatinine clearance ≥ 60 mL/min), no dose adjustment of Vipdomet is necessary (see section 5.2).

As Vipdomet 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 Vipdomet and at regular intervals thereafter (see section 4.4).

Hepatic impairment

Vipdomet should not be used in patients with hepatic impairment (see sections 4.3 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.

• 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

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 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 Vipdomet 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).

Vipdomet 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 Vipdomet 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-eva luated and found to be normal.

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, Vipdomet 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-eva luated 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 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 drug 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 eva luated promptly for evidence of ketoacidosis or lactic acidosis. eva luation 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.