Linagliptin + Metformin

Oral
Type 2 diabetes mellitus

Severe (GFR <30 mL/min): Contraindicated.

Contraindicated.

Should be taken with food.

Diabetic pre-coma, acute or chronic metabolic acidosis (e.g. diabetic ketoacidosis, lactic acidosis), alcoholism or acute alcohol intoxication, acute or chronic disease that may cause hypoxia (e.g. cardiac or resp failure, recent MI, shock), conditions which may alter renal function (e.g. severe infection, dehydration). Intravascular admin of iodinated contrast agents.  Hepatic and severe renal impairment (GFR <30 mL/min).

Patient w/ CHF, history of pancreatitis, and those who are exposed to stress (e.g. infection, fever, trauma, surgery). Not intended for the treatment of diabetic ketoacidosis or type 1 DM. Renal impairment (GFR 30-45 mL/min). Pregnancy and lactation.

Significant: Hypoglycaemia, severe arthralgia, bullous pemphigoid, vit B12 deficiency. Rarely, serious hypersensitivity reactions (e.g. anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity).
GI: Diarrhoea, decreased appetite, nausea, pancreatitis, vomiting, constipation.
Resp: Nasopharyngitis, cough.
Genitourinary: UTI.
Endocrine: Hyperlipidaemia, hypertriglyceridaemia, wt gain.
Musculoskeletal: Back pain, pain in extremity.
Dermatologic: Pruritus.
Potentially Fatal: Lactic acidosis, acute pancreatitis.

PO: B

Monitor glycosylated Hb (HbA_1c), serum glucose, hepatic and renal function, haematologic parameters prior to initiation of therapy and periodically thereafter. Monitor signs or symptoms of pancreatitis.

Concomitant cationic drugs that interfere w/ renal tubular transport systems (e.g. ranolazine, vandetanib, dolutegravir, cimetidine) may increase metformin levels. Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, OCs, sympathomimetics, phenytoin, niacin, Ca channel blockers and isoniazid may produce hyperglycaemia which may lead to loss of glycaemic control. Increased risk of lactic acidosis w/ topiramate or other carbonic anhydrase inhibitors (e.g. zonisamide, acetazolamide, dichlorphenamide). Plasma concentration of linagliptin may be decreased by strong inducers of P-glycoprotein (e.g. rifampicin) and may be increased by strong P-glycoprotein inhibitors (e.g. ritonavir). Linagliptin may increase risk of hypoglycaemia when used in combination w/ sulfonylureas or insulin.

Food decreases the extent and slightly delays absorption of metformin. Alcohol may potentiate the effect of metformin on lactate metabolism. Reduced serum level w/ St John’s wort.

Description:
Mechanism of Action: Linagliptin inhibits dipeptidylpeptidase-4 (DPP-4), an enzyme that inactivates incretin hormones. Inhibition of DPP-4 results in an increase in the levels of incretin hormones [e.g. glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] which regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic β-cells and decreasing glucagon secretion from pancreatic α-cells, leading to reduced hepatic glucose production. Metformin is a biguanide antidiabetic agent that reduces hepatic glucose production by decreasing gluconeogenesis and glycogenolysis, decreases intestinal absorption of glucose and enhances insulin sensitivity by increasing peripheral utilisation and uptake of glucose.
Pharmacokinetics:
Absorption: Linagliptin: Rapidly absorbed from the GI tract. Absolute bioavailability: Approx 30%. Time to peak plasma concentration: W/in approx 1.5 hr. Metformin: Slowly and incompletely absorbed from the GI tract. Reduced if taken w/ food. Absolute bioavailability: Approx 50-60%. Time to peak plasma concentration: 2.5 hr.
Distribution: Linagliptin: Extensively distributed to body tissues. Plasma protein binding: Concentration dependent: 99% (low concentration); 70-80% (high concentration). Volume of distribution: Approx 1110 L. Metformin: Partitions into erythrocytes; concentrates in kidney, liver, and GI tract. Crosses the placenta and enters breast milk in small amounts. Volume of distribution: 654 ± 358 L.
Excretion: Linagliptin: Mainly via faeces (approx 80%, as unchanged drug); urine (5%, as unchanged drug). Elimination half-life: Approx 12 hr. Metformin: Via urine (90% as unchanged drug). Plasma elimination half-life: Approx 2 hr.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 10096344, Linagliptin. https://pubchem.ncbi.nlm.nih.gov/compound/Linagliptin. Accessed Oct. 23, 2023.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 4091, Metformin. https://pubchem.ncbi.nlm.nih.gov/compound/Metformin. Accessed Feb. 27, 2023.

Store at 25°C. Protect from moisture.

Antidiabetic Agents

A10BD11 - metformin and linagliptin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.

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Anon. Linagliptin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/08/2017.

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Buckingham R (ed). Linagliptin. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/08/2017.

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Jentadueto Tablet, Film Coated (Boehringer Ingelheim Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 01/08/2017.

Jentadueto XR Tablet, Film Coated, Extended Release (Boehringer Ingelheim Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 01/08/2017.