linagliptin/metformin

Adult Dosing

Type 2 diabetes mellitus

For patients currently not treated with metformin

Initial dose: 2.5 mg/500 mg PO bid
Max: 2.5 mg/1000 mg bid

For patients already treated with metformin

Initial dose: 2.5 mg linagliptin and the current metformin dose PO bid; e.g. if treated with metformin 1000 mg bid, start with 2.5 mg/1000 mg PO bid
Max: 2.5 mg/1000 mg bid

Notes:

Individualize dosage on the basis of both efficacy and tolerability
Administer dose with meals
Perform dose escalation gradually to reduce the GI side effects associated with metformin use
Patients already undergoing therapy with linagliptin and metformin individual components may be switched to linagliptin/metformin combination containing the same doses of each component
When co-administered with an insulin secretagogue such as a sulfonylurea, a lower dosage of insulin secretagogue may be considered to reduce the risk of hypoglycemia

Pediatric Dosing

Safety and effectiveness in pediatric patients have not been established

[Outline]

Adult Dosing
Pediatric Dosing

As an adjunct to diet and exercise for improving glycemic control in adults with type 2 diabetes mellitus when therapy with both linagliptin and metformin is appropriate

Notes:

Has not been indicated in patients with type 1 diabetes or for treatment of diabetic ketoacidosis
Has not been evaluated in combination with insulin
Has not been evaluated in patients with a history of pancreatitis

Hypersensitivity to any of the ingredients of the product
Type 1 diabetes mellitus
Acute or chronic metabolic acidosis including diabetic ketoacidosis
Renal impairment

Metformin accumulation may cause a rare, but serious, complication called lactic acidosis. This risk increases in patients with sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute CHF
Lactic acidosis often has a subtle onset and is accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and abdominal distress
Low pH, increased anion gap, and elevated blood lactate are the laboratory abnormalities associated with lactic acidosis
In case of suspected lactic acidosis, discontinue therapy and promptly hospitalize the patient

Renal Dose Adjustment

Renal impairment: Contraindicated

Hepatic Dose Adjustment

Hepatic impairment: Avoid use

See Supplemental Patient Information

Accumulation of metformin may cause a rare, but fatal, complication called lactic acidosis. Patients with sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute CHF are at a greater risk for developing lactic acidosis [US Black Box Warning]
Lactic acidosis may also occur in association with certain pathophysiologic conditions, including diabetes mellitus, and in presence of significant tissue hypoperfusion and hypoxemia
Lab abnormalities include elevated blood lactate levels (>5 mmol/L), low blood pH, electrolyte disturbances with an increased anion gap, and an elevated lactate/pyruvate ratio [US Black Box Warning]
Diabetic patients with significant renal impairment, including intrinsic renal disorder and renal hypoperfusion, often in the setting of multiple concurrent medical/surgical problems and multiple concurrent medications are more prone to lactic acidosis
The risk of lactic acidosis increases with the patient's age and degree of renal impairment. Periodically monitor renal function in patients receiving this combination drug, particularly in geriatric patients. Avoid therapy unless measurement of creatinine clearance demonstrates that renal function is not reduced. Withdraw therapy in the presence of any condition associated with hypoxemia, dehydration, or sepsis
Avoid therapy in patients with clinical or laboratory evidence of hepatic impairment
Temporarily discontinue treatment prior to any intravascular radiocontrast study and for any surgical procedure that necessitates restricted intake of food or fluids. Withhold therapy for 48 hours subsequent to the procedure and reinstitute only after renal function is confirmed to be normal
The risk of metformin-induced lactic acidosis may be exacerbated with topiramate, which is used in epilepsy and migraine prophylaxis
Lactic acidosis is manifested by nonspecific symptoms including malaise, myalgias, respiratory distress, increasing somnolence, and abdominal distress [US Black Box Warning]
Severe acidosis may be associated with hypothermia, hypotension, and resistant bradyarrhythmias. Educate patients to recognize and promptly report these symptoms. Discontinue therapy until lactic acidosis is ruled out, if such symptoms occur
Gastrointestinal symptoms may occur in association with lactic acidosis or other serious disease
Fasting venous plasma lactate levels above the upper limit of normal but <5 mmol/L in patients receiving therapy do not necessarily signify impending lactic acidosis, and may occur as a result of poorly controlled diabetes /obesity, vigorous physical activity, or technical issues in sample handling
Suspect lactic acidosis in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis including ketonuria and ketonemia. Discontinue therapy immediately and promptly institute supportive measures in patients with lactic acidosis [US Black Box Warning]
Postmarketing cases of acute pancreatitis, with fatalities have been reported in patients receiving linagliptin/metformin. Discontinue therapy and initiate appropriate management upon suspicion of pancreatitis
Renal impairment increases the risk of metformin accumulation, thereby increasing the risk of lactic acidosis. Therapy is therefore contraindicated in patients with renal impairment
Assess renal function and confirm it to be normal before therapy initiation and regularly thereafter. Continue linagliptin as a single entity tablet at the same total daily dose of 5 mg if this combination drug is discontinued due to evidence of renal impairment
Exercise caution when using linagliptin/metformin concomitantly with drugs that may affect renal function or result in marked hemodynamic change or may interfere with metformin disposition
When co-administered with an insulin secretagogue such as a sulfonylurea, a lower dosage of insulin secretagogue may be considered to reduce the risk of hypoglycemia
Elderly, alcoholic, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are at a greater risk of hypoglycemia
Metformin may cause reductions in vitamin B12 levels, which is very rarely associated with anemia; this may be reversed by discontinuation of therapy or vitamin B12 supplementation. Monitor hematologic parameters and vitamin B12 levels regularly during therapy. Appropriately investigate and manage any apparent abnormalities
Alcohol may augment the effect of metformin on lactate metabolism. Caution patients against excessive intake of alcohol during therapy
Cardiovascular collapse resulting from acute CHF, acute MI, and other conditions characterized by hypoxemia has been associated with lactic acidosis and may cause prerenal azotemia. Discontinue therapy if any such symptoms occur
Lack of conclusive evidence exists for macrovascular risk reduction associated with linagliptin or metformin or any other antidiabetic drug

Cautions: Use cautiously in

Risk of hypoglycemia
CHF
Concomitant use with beta-adrenergic blockers
Co-administration with glucose-lowering agents
Concomitant use of cationic drugs

Supplemental Patient Information

Advise patients to remain alert to signs and symptoms of lactic acidosis and promptly notify any unexplained symptoms to their physician
Educate patients about the importance of adherence to dietary instructions, regular exercise program, regular monitoring of blood glucose, HbA1c, renal function and hematologic parameters
Caution patients against excessive alcohol intake, either acute or chronic, while receiving linagliptin/metformin therapy

Pregnancy Category:B

Breastfeeding: Because no information is available regarding linagliptin use during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Low levels of metformin are detectable in the serum of breastfed infants. Metformin levels in milk are relatively constant during maternal metformin use and infants receive <0.5% of the maternal weight-adjusted dosage. Use cautiously when nursing newborn/premature infants and those with renal impairment. This information is based upon LactMed database (available at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT last accessed 09 February 2012). As per manufacturer's data, due to the potential risk of hypoglycemia in breastfed infants, a decision should be made whether to discontinue nursing or to discontinue the drug analyzing the importance of the drug to the mother.

CNS: Headache, asthenia
METABOLIC: Hypoglycemia
RESP: Nasopharyngitis
GI: Diarrhea, nausea, vomiting, flatulence, indigestion, abdominal discomfort

Linagliptin

Hypoglycemic agent; inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme which degrades the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), resulting in increased levels of active incretin hormones. It stimulates the release of insulin in a glucose-dependent manner and decreases the glucagon levels in the circulation
Absolute bioavailability is 30%
Metabolized minimally in the liver; CYP450: 3A4 substrate
Excretion: 90% unchanged; feces (80%) and urine (5%)
Half-life: 12 hrs

Metformin

Anti-hyperglycemic agent; decreases glucose production in liver and glucose absorption from GI tract. Also, increases peripheral glucose uptake and utilization, thereby improving insulin sensitivity
Absolute bioavailability: 50-60%
Not metabolized
Excreted in urine (90% unchanged)
Half-life:

Plasma: 6.2 hrs
Blood: 17.6 hrs