Sitagliptin

Sitagliptin is an oral glucose-lowering medicine that inhibits dipeptidyl peptidase-4 (DPP-4), the enzyme that quickly inactivates the incretin hormones released from the gut. Keeping these hormones active for longer improves the insulin and glucagon responses to glucose.

Mechanism of Action

• DPP-4 inhibition: sitagliptin blocks DPP-4, which slows the inactivation of the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
• Incretin effect: incretins are released throughout the day and rise after meals as part of normal glucose control. With more active incretin present, insulin synthesis and release increase and glucagon release decreases, in a manner that depends on the glucose concentration.
• Result: better blood glucose control, shown as a lower glycosylated haemoglobin (HbA1c).

Pharmacokinetics

• Absorption: rapidly absorbed; after a 100 mg dose the median time to peak is 1 to 4 hours. Absolute bioavailability is about 87%. A high-fat meal has no effect, so the tablets can be taken with or without food. AUC rises in proportion to dose, whereas Cmax rises more than proportionally and the 24-hour level less than proportionally.
• Distribution: volume of distribution at steady state about 198 litres after a single 100 mg intravenous dose; binding to plasma proteins is low (38%).
• Metabolism: a minor pathway. About 79% of the dose is excreted unchanged in the urine. Six metabolites were found at trace levels and are not expected to add to DPP-4 inhibition. The limited metabolism is mainly by CYP3A4, with a contribution from CYP2C8. In vitro, sitagliptin does not inhibit CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6 and does not induce CYP3A4 or CYP1A2.
• Elimination: within one week of a radiolabelled oral dose, about 87% was found in urine and 13% in faeces. The terminal half-life is about 12.4 hours, with minimal accumulation on repeated dosing. Renal clearance is about 350 mL/min; elimination involves active tubular secretion, and sitagliptin is a substrate of human organic anion transporter-3 (hOAT-3), whose clinical relevance has not been established.
• Special populations: because the kidneys remove sitagliptin, the dose is lowered when the glomerular filtration rate falls below 45 mL/min (see Administration and Dosage). Severe hepatic impairment is not expected to change its pharmacokinetics, since elimination is mainly renal.

For adults with type 2 diabetes mellitus, sitagliptin is indicated to improve glycaemic control:

• Monotherapy: in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate because of contraindications or intolerance.
• Dual oral therapy in combination with:
  • metformin, when diet and exercise plus metformin alone do not provide adequate glycaemic control;
  • a sulphonylurea, when diet and exercise plus the maximal tolerated dose of a sulphonylurea alone do not provide adequate control and metformin is inappropriate because of contraindications or intolerance;
  • a PPAR gamma agonist (a thiazolidinedione), when use of a PPAR gamma agonist is appropriate and diet and exercise plus the PPAR gamma agonist alone do not provide adequate control.
• Triple oral therapy in combination with:
  • a sulphonylurea and metformin, when diet and exercise plus dual therapy with these medicines do not provide adequate control;
  • a PPAR gamma agonist and metformin, when use of a PPAR gamma agonist is appropriate and diet and exercise plus dual therapy with these medicines do not provide adequate control.
• Add-on to insulin (with or without metformin), when diet and exercise plus a stable dose of insulin do not provide adequate glycaemic control.

Fixed-dose combinations of sitagliptin with metformin (Janumet, Velmetia, Efficib, Ristfor) and with ertugliflozin (Steglujan) are separate medicinal products with their own product information.

• Hypersensitivity to sitagliptin or to any of the excipients (see the warnings on hypersensitivity reactions).

Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia was reported when sitagliptin was combined with a sulphonylurea (4.7%–13.8%) or with insulin (9.6%). The frequencies below come from placebo-controlled studies of monotherapy and from post-marketing experience.

Common (≥1/100 to <1/10): hypoglycaemia, headache.

Uncommon (≥1/1,000 to <1/100): dizziness, constipation, pruritus.

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

Not known: hypersensitivity reactions including anaphylactic responses, interstitial lung disease, vomiting, acute pancreatitis, fatal and non-fatal haemorrhagic and necrotising pancreatitis, angioedema, rash, urticaria, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome, bullous pemphigoid, arthralgia, myalgia, back pain, arthropathy, impaired renal function, acute renal failure.

Pruritus and the reactions of unknown frequency were identified through post-marketing surveillance. Whatever their cause, upper respiratory tract infection and nasopharyngitis were reported in at least 5% of treated patients and more often than with control; osteoarthritis and pain in an extremity were also more frequent with sitagliptin.

Clinical data suggest that the risk of clinically meaningful interactions with co-administered medicines is low.

• Digoxin: sitagliptin 100 mg daily for 10 days raised the digoxin AUC by about 11% and Cmax by about 18%. No change in the digoxin dose is recommended, but patients at risk of digoxin toxicity should be monitored.
• Ciclosporin (a potent P-glycoprotein inhibitor): a single 600 mg dose raised the AUC and Cmax of a single 100 mg dose of sitagliptin by about 29% and 68%. This was not considered clinically meaningful, and meaningful interactions are not expected with other P-glycoprotein inhibitors.
• Potent CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin): metabolism plays a larger part in clearing sitagliptin in severe renal impairment and end-stage renal disease, so these inhibitors could change its levels in such patients. This has not been assessed in a clinical study.
• OAT3 inhibitors: sitagliptin is a substrate of P-glycoprotein and OAT3. Probenecid inhibited OAT3 transport in vitro; the risk of a meaningful interaction is considered low, and OAT3 inhibitors have not been tested in vivo.
• Metformin: repeated 1,000 mg twice-daily doses with 50 mg of sitagliptin did not meaningfully change sitagliptin levels, and sitagliptin did not meaningfully change those of metformin.
• Other medicines: sitagliptin did not meaningfully alter the levels of glibenclamide, simvastatin, warfarin, oral contraceptives or a thiazolidinedione. It does not inhibit or induce CYP450 enzymes in vitro and may be a mild inhibitor of P-glycoprotein in vivo.
• Sulphonylurea or insulin: the hypoglycaemia risk rises, and a lower dose of these medicines may be considered.
• Food: sitagliptin can be taken with or without food.

Sitagliptin is taken by mouth once daily, with or without food. Generic tablets may be made with a different salt (for example, sitagliptin malate in one nationally authorised generic) at the same sitagliptin strength; follow the product information of the product supplied.

Recommended Dose

• 100 mg once daily.
• With metformin and/or a PPAR gamma agonist, the dose of those medicines is kept and sitagliptin is added 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.

Renal Impairment

Check the conditions of use in renal impairment of any other glucose-lowering medicine used with sitagliptin. Renal function should be assessed before starting and periodically afterwards.

• Mild (GFR 60 to under 90 mL/min) or moderate with GFR 45 to under 60 mL/min: no adjustment.
• Moderate with GFR 30 to under 45 mL/min: 50 mg once daily.
• Severe (GFR 15 to under 30 mL/min) or end-stage renal disease (GFR under 15 mL/min), including haemodialysis or peritoneal dialysis: 25 mg once daily, given without regard to the timing of dialysis.

Special Populations

• Hepatic impairment: no adjustment in mild to moderate impairment. Sitagliptin has not been studied in severe hepatic impairment, so care is needed.
• Elderly: no adjustment based on age.
• Children and adolescents: sitagliptin should not be used at 10 to 17 years of age because of insufficient efficacy; it has not been studied below 10 years.

Missed Dose

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

General

Sitagliptin must not be used in patients with type 1 diabetes or to treat diabetic ketoacidosis.

Acute Pancreatitis

DPP-4 inhibitors have been associated with acute pancreatitis. Patients should be told its characteristic symptom: persistent, severe abdominal pain. Pancreatitis resolved after stopping sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, sitagliptin and other potentially suspect medicines should be stopped, and if it is confirmed, sitagliptin should not be restarted. Caution is needed in patients with a history of pancreatitis.

Hypoglycaemia With Other Glucose-Lowering Medicines

In trials of monotherapy and of combinations with medicines not known to cause hypoglycaemia (metformin and/or a PPAR gamma agonist), hypoglycaemia with sitagliptin was as frequent as with placebo. It has been seen with a sulphonylurea or insulin, so a lower dose of these may be considered.

Renal Impairment

Sitagliptin is excreted by the kidneys. Lower doses are recommended when the GFR is below 45 mL/min and in end-stage renal disease needing dialysis, to give plasma levels similar to those in patients with normal kidney function.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, angioedema and exfoliative skin conditions such as Stevens-Johnson syndrome, have been reported after marketing. They began within the first 3 months, some after the first dose. If one is suspected, sitagliptin must be stopped, other possible causes assessed and an alternative diabetes treatment started.

Bullous Pemphigoid

Bullous pemphigoid has been reported after marketing in patients taking DPP-4 inhibitors, including sitagliptin. If it is suspected, sitagliptin must be stopped.

Sodium

Each tablet 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 sitagliptin should not be used during pregnancy.
• Breastfeeding: it is unknown whether sitagliptin passes into human milk; it does in animals. It should not be used during breastfeeding.
• Fertility: animal data do not suggest an effect on male or female fertility; human data are lacking.

Effect on Driving

Sitagliptin has no or negligible influence on the ability to drive and use machines, but dizziness and somnolence have been reported. Patients should also be alert to the risk of hypoglycaemia when it is combined with a sulphonylurea or insulin.

Store below 25 °C. No refrigeration is needed. The tablets come in opaque blisters (PVC/PE/PVDC and aluminium), in packs of 14, 28, 30, 56, 84, 90 or 98 tablets and 50 × 1 tablets in perforated unit-dose blisters (not all pack sizes may be marketed). Some generics state different storage conditions, for example no special conditions; follow the labelling of the product supplied.

2 years.

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