Linamet tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both Linagliptin and Metformin is appropriate.
Linamet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Linamet has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Linamet.
US-FDA Pregnancy Category B
There are no adequate and well controlled studies in pregnant women or its individual components, and some clinical data is available for Metformin which indicate that the risk for major malformations was not increased when Metformin is taken during the first trimester in pregnancy. In addition, metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, Linamet should be used during pregnancy only if clearly needed. Linamet was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations.
No studies in lactating animals have been conducted with the combined components of Linamet.
Safety and effectiveness of Linamet in pediatric patients under 18 years of age have not been established.
Linagliptin is minimally excreted by the kidney; however, Metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, Linamet should be used with caution as age increases.
Studies characterizing the pharmacokinetics of Linagliptin and Metformin after administration of Linamet in renally impaired patients have not been performed. Since Metformin is contraindicated in patients with renal impairment, use of Linamet is also contraindicated in patients with renal impairment (e.g., serum creatinine â‰¥1.5 mg/dL [males] or â‰¥1.4 mg/dL [females], or abnormal creatinine clearance).
Under steady-state conditions, Linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. In patients with moderate renal impairment under steady- state conditions, mean exposure of Linagliptin increased (AUCÏ„,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of Linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUC by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose.
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of Metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Studies characterizing the pharmacokinetics of Linagliptin and Metformin after administration of Linamet in hepatically impaired patients have not been performed. However, use of Metformin alone in patients with hepatic impairment has been associated with some cases of lactic acidosis. Therefore, use of Linamet is not recommended in patients with hepatic impairment.
In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUCÏ„,ss) of Linagliptin was approximately 25% lower and Cmax, ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of Linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of Linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.
No pharmacokinetic studies of Metformin have been conducted in patients with hepatic impairment.
Body Mass Index (BMI)/Weight
BMI/Weight had no clinically meaningful effect on the pharmacokinetics of Linagliptin based on a population pharmacokinetic analysis.
Gender had no clinically meaningful effect on the pharmacokinetics of Linagliptin based on a population pharmacokinetic analysis.
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of Metformin was comparable in males and females.
Studies characterizing the pharmacokinetics of Linagliptin and Metformin after administration of Linamet in geriatric patients have not been performed. Based on the Metformin component, Linamet treatment should not be initiated in patients â‰¥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Age did not have a clinically meaningful impact on the pharmacokinetics of Linagliptin based on a population pharmacokinetic analysis.
Limited data from controlled pharmacokinetic studies of Metformin in healthy elderly subjects suggest that total plasma clearance of Metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in Metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Studies characterizing the pharmacokinetics of Linagliptin and Metformin after administration of Linamet in pediatric patients have not yet been performed.
In vitro Assessment of Drug Interactions
Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.
Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, Linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.
In vivo Assessment of Drug Interactions
Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to Linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to Linagliptin is strongly recommended. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp, and OCT. No dose adjustment of Linagliptin is recommended based on results of the described pharmacokinetic studies.
Dosage & Administration
LINAMET should be given twice daily with meals. Dose escalation should be gradual to reduce thegastrointestinal (GI) side effects associated with metformin use. For available dosage forms and strengths.
Recommended starting dose:
- In patients currently not treated with metformin, initiate treatment with 2.5 mg linagliptin/500 mg metformin hydrochloride twice daily.
- In patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of metformin taken at each of the two daily meals (e.g., a patient on metformin 1000 mg twice daily would be started on 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily with meals).
- Patients already treated with linagliptin and metformin individual components may be switched to LINAMET containing the same doses of each component.
- No studies have been performed specifically examining the safety and efficacy of LINAMET in patients previously treated with other oral antihyperglycemic agents and switched to LINAMET. Any change in therapy of type 2 diabetes mellitus should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
When LINAMET is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
Lactic acidosis: Warn against excessive alcohol use. LINAMET is not recommended in hepatic impairment or hypoxic states and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter.
- There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue LINAMET.
- Temporarily discontinue LINAMET in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids.
- Hypoglycemia: When used with an insulin secretagogue (e.g.sulfonylurea (SU)) or insulin, consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
- There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of LINAMET) including anaphylaxis, angioedema, and exfoliative skin conditions. In such cases, promptly discontinue LINAMET, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
- Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually.
- Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint npain and discontinue drug if appropriate.
- Macrovascular outcomes: No conclusive evidence of macrovascular risk reduction with LINAMET or any other antidiabetic drug.