VIPIDIA Film-coated tablet Ref.[6139] Active ingredients: Alogliptin

General

Vipidia should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Vipidia is not a substitute for insulin in insulin-requiring patients.

Use with other antihyperglycaemic medicinal products and hypoglycaemia

Due to the increased risk of hypoglycaemia in combination with a sulphonylurea, insulin or combination therapy with thiazolidinedione plus metformin, a lower dose of these medicinal products may be considered to reduce the risk of hypoglycaemia when these medicinal products are used in combination with alogliptin (see section 4.2).

Combinations not studied

Alogliptin has not been studied in combination with sodium glucose co-transporter 2 (SGLT-2) inhibitors or glucagon like peptide 1 (GLP-1) analogues nor formally as triple therapy with metformin and a sulphonylurea.

Renal impairment

As there is a need for dose adjustment in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis, appropriate assessment of renal function is recommended prior to initiation of alogliptin therapy and periodically thereafter (see section 4.2).

Experience in patients requiring renal dialysis is limited. Alogliptin has not been studied in patients undergoing peritoneal dialysis (see sections 4.2 and 5.2).

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 and 5.2).

Cardiac failure

Experience of alogliptin use in clinical studies in patients with congestive heart failure of New York Heart Association (NYHA) functional class III and IV is limited and caution is warranted in these patients.

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, Vipidia should be discontinued; if acute pancreatitis is confirmed, Vipidia 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.

Vipidia contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

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 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.

Pregnancy

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). As a precautionary measure, it is preferable to avoid the use of alogliptin during pregnancy.

Breast-feeding

It is unknown whether alogliptin is excreted in human milk. Animal studies have shown excretion of alogliptin in milk (see section 5.3). A risk to the suckling child cannot be excluded.

A decision on whether to discontinue breast-feeding or to discontinue alogliptin therapy should be made taking into account the benefit of breast-feeding for the child and the benefit of alogliptin therapy for the woman.

Fertility

The effect of alogliptin on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies (see section 5.3).

Vipidia 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 combined with a sulphonylurea, insulin or combination therapy with thiazolidinedione plus metformin.

Summary of the safety profile

The information provided is based on a total of 9,405 patients with type 2 diabetes mellitus, including 3,750 patients treated with 25 mg alogliptin and 2,476 patients treated with 12.5 mg alogliptin, who participated in one phase 2 or 12 phase 3 double-blind, placebo- or active-controlled clinical studies. In addition, a cardiovascular outcomes study with 5,380 patients with type 2 diabetes mellitus and a recent acute coronary syndrome event was conducted with 2,701 randomised to alogliptin and 2,679 randomised to placebo. These studies evaluated the effects of alogliptin on glycaemic control and its safety as monotherapy, as initial combination therapy with metformin or a thiazolidinedione, and as add-on therapy to metformin, or a sulphonylurea, or a thiazolidinedione (with or without metformin or a sulphonylurea), or insulin (with or without metformin).

In a pooled analysis of the data from 13 studies, the overall incidences of adverse events, serious adverse events and adverse events resulting in discontinuation of therapy were comparable in patients treated with 25 mg alogliptin, 12.5 mg alogliptin, active control or placebo. The most common adverse reaction in patients treated with 25 mg alogliptin was headache.

The safety of alogliptin between the elderly (≥65 years old) and non-elderly (< 65 years old) was similar.

Tabulated list of adverse reactions

The adverse reactions are listed by system organ class and frequency. Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

In the pooled pivotal phase 3 controlled clinical studies of alogliptin as monotherapy and as add-on combination therapy involving 5,659 patients, the observed adverse reactions are listed below (Table 1).

Table 1. Adverse reactions:

Paediatric population

In a clinical trial with alogliptin in paediatric patients with type 2 diabetes mellitus aged 10 to 17 years, the profile of adverse reactions was comparable to that observed in adults.

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.

Not applicable.