Alogliptin

Alogliptin is a potent and highly selective inhibitor of dipeptidyl peptidase 4 (DPP-4), with more than 10,000-fold selectivity for DPP-4 over related enzymes such as DPP-8 and DPP-9. DPP-4 is the main enzyme that rapidly degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which the gut releases in response to a meal.

Mechanism of Action

• Incretin protection: blocking DPP-4 raises the levels of active GLP-1 and GIP after a meal. DrugBank also reports lower postprandial glucagon and higher postprandial active GLP-1 than with placebo.
• Insulin and glucagon: GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells, and GLP-1 also inhibits glucagon secretion and hepatic glucose production.
• Glucose-dependent effect: insulin release is enhanced and glucagon suppressed mainly when glucose levels are high, so glycaemic control improves through a glucose-dependent mechanism.
• Degree of inhibition: in patients with type 2 diabetes, a 25 mg dose produced peak DPP-4 inhibition within 1 to 2 hours, above 93% after a single dose and after 14 days of once-daily dosing. Inhibition was still above 81% at 24 hours after 14 days of dosing.

Pharmacokinetics

• Absorption: rapid, with an absolute bioavailability of about 100%. Peak plasma concentrations occur 1 to 2 hours after dosing (median). A high-fat meal does not change exposure, so the tablets can be taken with or without food. Exposure rises in proportion to the dose between 6.25 and 100 mg, there is no clinically relevant accumulation with repeated dosing, and the kinetics do not change over time.
• Distribution: the volume of distribution after a single intravenous 12.5 mg dose was 417 L, showing good distribution into tissues. Alogliptin is 20–30% bound to plasma proteins.
• Metabolism: limited. Two minor metabolites were found: N-demethylated alogliptin (M-I, below 1% of the parent compound), an active DPP-4 inhibitor, and N-acetylated alogliptin (M-II, below 6%), which is inactive. CYP2D6 and CYP3A4 contribute to this limited metabolism. The drug exists predominantly as the (R)-enantiomer (more than 99%), with little or no conversion in the body.
• Elimination: mean terminal half-life about 21 hours. 60–70% of the dose is excreted unchanged in the urine; after a radiolabelled dose, 76% of the radioactivity was recovered in urine and 13% in faeces. Renal clearance (170 mL/min) exceeds the estimated glomerular filtration rate (about 120 mL/min), which suggests some active renal excretion.
• Special populations: in renal impairment, exposure was about 1.7-fold higher in mild impairment (within the range of controls, so no dose change) and about 2- to 4-fold higher in moderate or severe impairment and in end-stage renal disease on haemodialysis, which is why lower doses are used; about 7% of the dose was removed in a 3-hour haemodialysis session. Moderate hepatic impairment lowered total exposure by about 10% and peak exposure by about 8%, which is not clinically relevant. Age (65–81 years), gender, race and body weight had no clinically relevant effect. In children aged 10 to 17 years with type 2 diabetes, mean exposure was modestly lower than in adults (less than 25% difference).

• Type 2 diabetes mellitus: in adults aged 18 years and older, to improve glycaemic control in combination with other glucose-lowering medicinal products, including insulin, when these together with diet and exercise do not provide adequate glycaemic control. The SmPC points to its sections 4.4, 4.5 and 5.1 for the data on the different combinations.

Alogliptin is also marketed in two EU fixed-dose combinations, Vipdomet (with metformin) and Incresync (with pioglitazone); their indications and doses are set out in their own SmPCs.

• Hypersensitivity to alogliptin or to any of the excipients.
• History of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock and angioedema, to any dipeptidyl peptidase-4 (DPP-4) inhibitor.

In a pooled analysis of 13 studies, the overall incidences of adverse events, serious adverse events and adverse events leading to discontinuation were comparable with alogliptin 25 mg, alogliptin 12.5 mg, active control and placebo. The most common adverse reaction with 25 mg was headache, and safety was similar in patients aged 65 years and older and in younger patients. The reactions below are those listed in the SmPC from pooled phase 3 studies of alogliptin as monotherapy and add-on therapy (5,659 patients).

Common (≥1/100 to <1/10): upper respiratory tract infection, nasopharyngitis, hypoglycaemia, headache, abdominal pain, gastro-oesophageal reflux disease, diarrhoea, pruritus, rash.

Not known: hypersensitivity, acute pancreatitis, hepatic dysfunction including hepatic failure, exfoliative skin conditions (including Stevens-Johnson syndrome), erythema multiforme, angioedema, urticaria, bullous pemphigoid, interstitial nephritis.

No reactions are listed as very common, uncommon or rare. The important serious reactions are acute pancreatitis (persistent, severe abdominal pain that may radiate to the back), serious hypersensitivity reactions (anaphylaxis, angioedema, Stevens-Johnson syndrome), bullous pemphigoid and hepatic failure. In a trial in children aged 10 to 17 years with type 2 diabetes, the profile of adverse reactions was comparable with that in adults.

Alogliptin is excreted mainly unchanged in the urine and its metabolism by cytochrome P450 enzymes is negligible, so interactions with CYP inhibitors are not expected.

• Effect of other medicines on alogliptin: gemfibrozil, fluconazole, ketoconazole, ciclosporin, voglibose, digoxin, metformin, cimetidine, pioglitazone and atorvastatin had no clinically relevant effect on alogliptin exposure.
• Effect of alogliptin on other medicines: in vitro it neither inhibits nor induces CYP isoforms at the concentrations reached with 25 mg, and it is neither a substrate nor an inhibitor of the renal transporters OAT1, OAT3 or OCT2. In clinical studies it had no clinically relevant effect on caffeine, warfarin, pioglitazone, glibenclamide, tolbutamide, dextromethorphan, atorvastatin, an oral contraceptive (norethisterone and ethinylestradiol), digoxin, fexofenadine, metformin, cimetidine or a CYP3A4 probe substrate. This shows a low potential to interact with substrates of CYP1A2, CYP3A4, CYP2D6, CYP2C9, P-glycoprotein and OCT2.
• Other glucose-lowering medicines: a sulphonylurea, insulin, or a thiazolidinedione plus metformin increase the risk of hypoglycaemia when combined with alogliptin, so a lower dose of these medicines may be considered.
• Food: alogliptin can be taken with or without food.

Vipidia is a once-daily tablet added to the patient’s other glucose-lowering treatment. It is taken with or without food and swallowed whole with water.

Recommended Dose

• 25 mg once daily (one 25 mg tablet) as add-on therapy to metformin, a thiazolidinedione, a sulphonylurea or insulin, or as triple therapy with metformin and a thiazolidinedione or insulin. The 12.5 mg and 6.25 mg tablets provide the reduced doses used in renal impairment.
• With metformin and/or a thiazolidinedione: the dose of these medicines is maintained and Vipidia is given at the same time.
• With a sulphonylurea or insulin: a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia.
• With metformin plus a thiazolidinedione: an increased risk of hypoglycaemia was observed with this triple therapy, so caution is needed. If hypoglycaemia occurs, a lower dose of the thiazolidinedione or metformin may be considered.

Special Populations

• Elderly (65 years and older): no dose adjustment based on age, but dosing should be conservative in advanced age because kidney function may be reduced.
• Renal impairment: mild (creatinine clearance above 50 to 80 mL/min), no adjustment. Moderate (≥30 to ≤50 mL/min): 12.5 mg once daily, half the recommended dose. Severe (below 30 mL/min) or end-stage renal disease requiring dialysis: 6.25 mg once daily, one quarter of the recommended dose, which may be given regardless of the timing of dialysis. Experience in dialysis is limited and peritoneal dialysis has not been studied. Renal function should be assessed before treatment and periodically afterwards.
• Hepatic impairment: no adjustment in mild to moderate impairment (Child-Pugh score 5 to 9). Not studied in severe impairment (Child-Pugh score above 9), so not recommended.
• Children and adolescents: safety and efficacy below 18 years have not been established and no dose can be recommended. Alogliptin should not be used in the paediatric population because of lack of efficacy.

Missed Dose

Take the missed dose as soon as it is remembered. A double dose must not be taken on the same day.

Type 1 Diabetes and Ketoacidosis

Vipidia should not be used in type 1 diabetes or to treat diabetic ketoacidosis. It is not a substitute for insulin in patients who need insulin.

Hypoglycaemia With Other Medicines

The risk of hypoglycaemia is increased in combination with a sulphonylurea, insulin, or a thiazolidinedione plus metformin, so lower doses of those medicines may be considered. Alogliptin has not been studied together with SGLT-2 inhibitors or GLP-1 analogues, nor formally as triple therapy with metformin and a sulphonylurea.

Kidney, Liver and Heart

• Renal impairment: dose adjustment is needed in moderate or severe impairment and in end-stage renal disease, so renal function is assessed before starting and periodically afterwards.
• Hepatic impairment: not recommended in severe impairment, which has not been studied.
• Cardiac failure: experience in NYHA functional class III and IV congestive heart failure is limited, and caution is warranted.

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic reactions, angioedema and exfoliative skin conditions such as Stevens-Johnson syndrome and erythema multiforme, have been observed with DPP-4 inhibitors and spontaneously reported for alogliptin after marketing. Anaphylactic reactions were reported at a low incidence in clinical studies.

Acute Pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of acute pancreatitis. In a pooled analysis of 13 studies, pancreatitis was reported at 2, 1, 1 and 0 events per 1,000 patient-years with alogliptin 25 mg, alogliptin 12.5 mg, active control and placebo; in the cardiovascular outcomes study the rates were 3 with alogliptin and 2 with placebo. Patients should be told that the characteristic symptom is persistent, severe abdominal pain that may radiate to the back. If pancreatitis is suspected, Vipidia is stopped; if it is confirmed, it must not be restarted. Caution is needed in patients with a history of pancreatitis.

Liver Effects

Post-marketing reports of hepatic dysfunction, including hepatic failure, have been received; a causal relationship has not been established. Patients should be observed closely, liver function tests should be obtained promptly if symptoms suggest liver injury, and discontinuation should be considered if an abnormality is found and no other cause is established.

Bullous Pemphigoid

Bullous pemphigoid has been reported after marketing in patients taking DPP-4 inhibitors, including alogliptin. If it is suspected, alogliptin should be discontinued.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data from use in pregnant women. Animal studies do not indicate direct or indirect harmful effects on reproduction. As a precaution, it is preferable to avoid alogliptin during pregnancy.
• Breastfeeding: it is unknown whether alogliptin passes into human milk. Animal studies showed excretion in milk, so a risk to the suckling child cannot be excluded. A decision is made on whether to stop breastfeeding or alogliptin, weighing the benefit of breastfeeding for the child and of treatment for the woman.
• Fertility: the effect on fertility in humans has not been studied. No adverse effects on fertility were seen in animals.

Sodium

Each tablet contains less than 1 mmol sodium (23 mg), that is to say it is essentially sodium-free.

Effect on Driving

Alogliptin has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia, especially when it is combined with a sulphonylurea, insulin, or a thiazolidinedione plus metformin.

Vipidia tablets need no special storage conditions. They are supplied in PCTFE/PVC blisters with push-through aluminium foil, in packs of 10, 14, 28, 30, 56, 60, 84, 90, 98 or 100 tablets; not all pack sizes may be marketed. Keep out of the sight and reach of children.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx): a medicinal product subject to medical prescription. Alogliptin tablets are taken at home by the patient, so they are supplied to the patient or to the treating clinic on prescription. No cold chain is needed.