Vildagliptin

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4), described in the SmPC as a member of the islet enhancer class. After a dose it rapidly and completely inhibits DPP-4 activity, which raises the fasting and after-meal levels of the incretin hormones GLP-1 and GIP.

Mechanism of Action

• DPP-4 inhibition: DPP-4 normally cuts and inactivates the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) soon after the gut releases them. Vildagliptin blocks it, so more active incretin remains in the blood.
• Beta cells: higher incretin levels make beta cells more sensitive to glucose and improve glucose-dependent insulin secretion. In studies, 50–100 mg daily improved markers of beta-cell function, including the proinsulin-to-insulin ratio and the response to a meal tolerance test.
• Alpha cells: higher GLP-1 also makes alpha cells more sensitive to glucose, so that glucagon secretion is more appropriate to the glucose level.
• Glucose output: the greater insulin-to-glucagon ratio during hyperglycaemia lowers fasting and after-meal glucose production by the liver, and so lowers blood glucose.
• Normal glucose: in people with normal glucose levels vildagliptin does not stimulate insulin secretion or lower glucose. The delay in gastric emptying that raised GLP-1 is known to cause is not seen with vildagliptin.

Pharmacokinetics

• Absorption: rapidly absorbed when fasting, with peak plasma levels at 1.7 hours. Food delays the peak to 2.5 hours and lowers Cmax by 19% but does not change the overall exposure (AUC), so tablets can be taken with or without food. Absolute bioavailability is 85%.
• Distribution: plasma protein binding is low (9.3%), and vildagliptin distributes equally between plasma and red blood cells. The volume of distribution at steady state after intravenous dosing is 71 litres, suggesting distribution outside the blood vessels.
• Metabolism: metabolism is the main route of elimination (69% of the dose). The major metabolite (LAY151) is pharmacologically inactive; it is the hydrolysis product of the cyano group and accounts for 57% of the dose. It is followed by a glucuronide and the amide hydrolysis products (4% of the dose). The kidney may be a major site of hydrolysis, and DPP-4 contributes in part. CYP450 enzymes do not metabolise vildagliptin to any quantifiable extent, and in vitro it neither inhibits nor induces them.
• Elimination: after a radiolabelled oral dose, about 85% was excreted in urine and 15% in faeces; unchanged vildagliptin in urine accounted for 23% of the dose. After intravenous dosing, total plasma clearance is 41 L/h and renal clearance 13 L/h, and the mean half-life is about 2 hours (about 3 hours after an oral dose).
• Special populations: the dose is adjusted in moderate or severe renal impairment, and vildagliptin is not used in hepatic impairment (see Administration and Dosage). No dose adjustment is needed in elderly patients.

Vildagliptin is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus:

• Monotherapy: in patients in whom metformin is inappropriate because of contraindications or intolerance.
• Combination therapy: in combination with other medicines for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control (the SmPC gives the available data on the different combinations).

The fixed-dose combination of vildagliptin with metformin (Eucreas, Icandra, Zomarist) is a separate medicinal product with its own product information.

• Hypersensitivity to vildagliptin or to any of the excipients.

Safety data come from 5,451 patients who received vildagliptin 100 mg daily (50 mg twice daily) in double-blind, placebo-controlled trials of at least 12 weeks. Most reactions were mild and transient and did not require stopping treatment, and no link was found with age, ethnicity, duration of exposure or daily dose. Hypoglycaemia has been reported when vildagliptin is combined with a sulphonylurea or insulin, and the risk of acute pancreatitis has been reported.

Very common (≥1/10): nasopharyngitis.

Common (≥1/100 to <1/10): upper respiratory tract infection, dizziness, headache, tremor, blurred vision, constipation, nausea, gastro-oesophageal reflux disease, diarrhoea, abdominal pain (including upper), vomiting, hyperhidrosis, rash, pruritus, dermatitis, arthralgia, myalgia, asthenia, peripheral oedema.

Uncommon (≥1/1,000 to <1/100): hypoglycaemia, flatulence, urticaria, erectile dysfunction, fatigue, chills, abnormal liver function tests, weight increase.

Rare (≥1/10,000 to <1/1,000): pancreatitis.

Not known (post-marketing experience): hepatitis, exfoliative and bullous skin lesions including bullous pemphigoid, cutaneous vasculitis.

Rare cases of hepatic dysfunction, including hepatitis, have been reported. They were generally without symptoms, and liver tests returned to normal after treatment was stopped.

Vildagliptin has a low potential for interactions. It is not a substrate of cytochrome P450 enzymes and does not inhibit or induce them, so it is not likely to interact with medicines that are substrates, inhibitors or inducers of these enzymes.

• ACE inhibitors: there may be an increased risk of angioedema in patients taking an ACE inhibitor at the same time.
• Medicines that weaken the glucose-lowering effect: as with other oral antidiabetic medicines, the effect may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.
• Sulphonylureas: the risk of hypoglycaemia rises, and a lower dose of the sulphonylurea may be considered.
• Other oral antidiabetics: studies with pioglitazone, metformin and glibenclamide showed no clinically relevant pharmacokinetic interactions.
• Digoxin and warfarin: no clinically relevant pharmacokinetic interactions in healthy subjects, although this has not been established in the target population.
• Amlodipine, ramipril, valsartan and simvastatin: no clinically relevant pharmacokinetic interactions in healthy subjects.
• Food: vildagliptin can be taken with or without a meal.

Vildagliptin is taken by mouth, with or without a meal.

Recommended Dose

• 100 mg daily, as 50 mg in the morning and 50 mg in the evening, when used as monotherapy, with metformin, with a thiazolidinedione, with metformin and a sulphonylurea, or with insulin (with or without metformin).
• 50 mg once daily in the morning when used in dual combination with a sulphonylurea; in this group 100 mg daily was no more effective than 50 mg once daily. A lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.
• Doses above 100 mg are not recommended.
• The safety and efficacy of vildagliptin as triple oral therapy with metformin and a thiazolidinedione have not been established.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no adjustment in mild impairment (creatinine clearance 50 mL/min or more). In moderate or severe impairment, or end-stage renal disease, the dose is 50 mg once daily.
• Hepatic impairment: vildagliptin should not be used, including in patients whose ALT or AST before treatment is more than 3 times the upper limit of normal.
• Children and adolescents: not recommended below 18 years; safety and efficacy have not been established and no data are available.

Missed Dose

Take a missed dose as soon as it is remembered. Do not take a double dose on the same day.

General

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

Liver Function

Liver function tests should be done before starting treatment to establish the baseline, then every three months during the first year and periodically afterwards. A patient whose transaminases rise should have a second test to confirm the finding and then frequent tests until the values return to normal. If an increase in AST or ALT of 3 times the upper limit of normal or more persists, stopping vildagliptin is recommended. Patients who develop jaundice or other signs of liver dysfunction should stop it. After withdrawal and normalisation of the tests, treatment should not be restarted.

Renal Impairment

Experience in end-stage renal disease on haemodialysis is limited, so vildagliptin should be used with caution in these patients.

Cardiac Failure

In a trial in patients with NYHA functional class I–III heart failure, vildagliptin did not change left-ventricular function or worsen existing congestive heart failure compared with placebo. Experience in class III is limited and the results are inconclusive. There is no experience in class IV, and use is not recommended.

Skin Disorders

Skin lesions, including blistering and ulceration, appeared on the extremities of monkeys in non-clinical studies. They were not more frequent in clinical trials, although experience in patients with diabetic skin complications was limited, and bullous and exfoliative skin lesions have been reported after marketing. Monitoring for blistering or ulceration is recommended as part of routine diabetic care.

Acute Pancreatitis

Vildagliptin has been associated with acute pancreatitis. Patients should be told its characteristic symptom, persistent severe abdominal pain. If pancreatitis is suspected, vildagliptin should be stopped, and if it is confirmed, vildagliptin should not be restarted. Caution is needed in patients with a history of acute pancreatitis.

Hypoglycaemia

Sulphonylureas are known to cause hypoglycaemia, so patients taking vildagliptin with a sulphonylurea may be at risk. A lower dose of the sulphonylurea may be considered.

Lactose and Sodium

Each tablet contains 47.82 mg of lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. Each tablet also contains less than 1 mmol (23 mg) of sodium, that is, it is essentially ‘sodium-free’.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data in pregnant women, and animal studies showed reproductive toxicity at high doses. The risk for humans is unknown, so vildagliptin should not be used during pregnancy.
• Breastfeeding: it is unknown whether vildagliptin passes into human milk; it does in animals. It should not be used during breastfeeding.
• Fertility: no studies on human fertility have been done.

Effect on Driving

No studies on the effects on the ability to drive and use machines have been performed. Patients who feel dizzy should avoid driving or using machines.

Store the tablets in the original package to protect them from moisture. No special temperature is required and no refrigeration is needed. The tablets come in aluminium/aluminium (PA/Al/PVC//Al) blisters, in packs of 7, 14, 28, 30, 56, 60, 90, 112, 180 or 336 tablets and multipacks of 336 (3 packs of 112); not all pack sizes may be marketed. Some generics state no special storage conditions; follow the labelling of the product supplied.

3 years.

Prescription only (Rx): the medicinal product is subject to medical prescription (Annex II B) and is not restricted to specialists. Vildagliptin is taken at home, so it is supplied to the patient or the treating clinic on prescription.