Linagliptin and Metformin Hydrochloride

5 WARNINGS AND PRECAUTIONS Lactic acidosis: See boxed warning ( 5.1 ) Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue linagliptin and metformin hydrochloride. ( 5.2 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating linagliptin and metformin hydrochloride ( 5.3 ) Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with linagliptin and metformin hydrochloride. If hypersensitivity reactions occur discontinue linagliptin and metformin hydrochloride, treat promptly, and monitor until signs and symptoms resolve. ( 5.4 ) Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.5 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.6 ) Bullous pemphigoid : There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue linagliptin and metformin hydrochloride. ( 5.7 ) Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of linagliptin and metformin hydrochloride in patients who have known risk factors for heart failure. Monitor for signs and symptoms. ( 5.8 )

5.1 Lactic Acidosis Metformin There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of linagliptin and metformin hydrochloride. In linagliptin and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue linagliptin and metformin hydrochloride and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.2 ) and Clinical Pharmacology (12.3 )] :

• Before initiating linagliptin and metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR).
• Linagliptin and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ].
• Initiation of linagliptin and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 .
• Obtain an eGFR at least annually in all patients taking linagliptin and metformin hydrochloride. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking linagliptin and metformin hydrochloride whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. Drug Interactions: The concomitant use of linagliptin and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7 )]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5 )]. Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop linagliptin and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart linagliptin and metformin hydrochloride if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Linagliptin and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue linagliptin and metformin hydrochloride. Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving linagliptin and metformin hydrochloride. Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of linagliptin and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.

5.2 Pancreatitis Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14.2 )], acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue linagliptin and metformin hydrochloride and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using linagliptin and metformin hydrochloride.

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when linagliptin and metformin hydrochloride is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1 )] . Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with linagliptin and metformin hydrochloride.

5.4 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue linagliptin and metformin hydrochloride, assess for other potential causes for the event, and institute alternative treatment for diabetes mellitus. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with linagliptin and metformin hydrochloride.

5.5 Vitamin B 12 Deficiency In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on linagliptin and metformin hydrochloride and manage any abnormalities [see Adverse Reactions (6.1 )] .

5.6 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.7 Bullous Pemphigoid Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.2 )] , and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving linagliptin and metformin hydrochloride. If bullous pemphigoid is suspected, linagliptin and metformin hydrochloride should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

5.8 Heart Failure An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of linagliptin and metformin hydrochloride prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of linagliptin and metformin hydrochloride.

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Lactic Acidosis [see Warnings and Precautions (5.1 )]
• Pancreatitis [see Warnings and Precautions (5.2 )]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3 )]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4 )]
• Vitamin B 12 Deficiency [see Warnings and Precautions (5.5 )]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.6 )]
• Bullous Pemphigoid [see Warnings and Precautions (5.7 )]
• Heart Failure [see Warnings and Precautions (5.8 )] Most common adverse reactions (incidence ≥5% and more often than placebo) were nasopharyngitis and diarrhea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Linagliptin/Metformin The safety of concomitantly administered linagliptin (daily dosage 5 mg) and metformin (mean daily dosage of approximately 1,800 mg) has been evaluated in 2,816 patients with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials. Three placebo-controlled trials with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 trial was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse reactions which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo+ metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design trial, adverse reactions reported in ≥5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1. Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Trial Adverse Reactions Placebo (%) n =72 Li n a g li pt in M o n o th er a py (%) n =142 M e tf or m i n M o n o th er a py (%) n =291 C o m b i n a t io n of Li n a g li pt i n with Metformin(%) n =286 Nasopharyngitis 1.4 5.6 2.7 6.3 Diarrhea 2.8 3.5 3.8 6.3 Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis. Linagliptin Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7% vs 6.1%), diarrhea (3.3% vs 3%), and cough (2.1% vs 1.4%). Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Metformin The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. Other Adverse Reactions Hypoglycemia Linagliptin/Metformin In a 24-week factorial design trial, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. The incidence of hypoglycemia with plasma glucose <54 mg/dL was 8.1% in the linagliptin group (N=792) compared to 5.3% in the placebo group (N=263) when administered in combination with metformin and sulfonylurea in a 24-week trial. Linagliptin The incidence of severe hypoglycemia (requiring assistance) was 1.7% in the linagliptin group (N=631) compared to 1.1% in the placebo group (N=630) when administered in combination with basal insulin in a 52-week trial. Laboratory Test Abnormalities in Clinical Trials of Linagliptin or Metformin Linagliptin Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group). Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively. Increase in Amylase: In a cardiovascular safety trial comparing linagliptin versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively. The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.2 )]. Metformin Decrease in Vitamin B 12 : In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients .

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Linagliptin

• Gastrointestinal Disorders: Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1 )] , mouth ulceration, stomatitis
• Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
• Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia
• Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid, rash Metformin
• Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy ( 8.3 ) Geriatric Use: Assess renal function more frequently ( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment ( 8.7 )

8.1 Pregnancy Risk Summary The limited data with linagliptin and metformin hydrochloride and linagliptin use in pregnant women are not sufficient to inform a linagliptin and metformin hydrochloride-associated or linagliptin-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defector miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed when the combination of linagliptin and metformin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see Data]. The estimated background risk of major birth defects is 6% to10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20% to 25% in women with HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Linagliptin and metformin, the components of linagliptin and metformin hydrochloride, were coadministered to pregnant Wistar Han rats during the period of organogenesis. No adverse developmental outcome was observed at doses similar to the maximum recommended clinical dose, based on exposure. At higher doses associated with maternal toxicity, the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations at ≥9-times a 2,000 mg clinical dose, based on exposure. Linagliptin No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of approximately 2- and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

8.2 Lactation Risk Summary There is limited information regarding the presence of linagliptin and metformin hydrochloride or its components (linagliptin or metformin) in human milk, the effects on the breastfed infant, or the effects on milk production. However, linagliptin is present in rat milk. Limited published studies report that metformin is present in human milk [see Data]. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for linagliptin and metformin hydrochloride and any potential adverse effects on the breastfed child from linagliptin and metformin hydrochloride or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

8.4 Pediatric Use Safety and effectiveness of linagliptin and metformin hydrochloride have not been established in pediatric patients. "Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Jentadueto® (Linagliptin; Metformin hydrochloride) Tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information." 8.5 Geriatric Use Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney [see Warnings and Precautions (5.1 ) and Clinical Pharmacology (12.3) ] . Linagliptin In linagliptin studies, 1,085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients. Metformin Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Contraindications (4 ), Warnings and Precautions (5.1 ), and Clinical Pharmacology (12.3 )] .

8.6 Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Linagliptin and metformin hydrochloride is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Dosage and Administration (2.2 ), Contraindications (4 ), Warnings and Precautions (5.1 ), and Clinical Pharmacology (12.3 )]. In the linagliptin treatment arm of the CARMELINA trial [see Clinical Studies (14.2)], 2,200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73 m 2 ). Approximately 20% of the population had eGFR ≥45 to <60 mL/min/1.73 m 2 , 28% of the population had eGFR ≥30 to <45 mL/min/1.73 m 2 and 15% had eGFR <30 mL/min/1.73 m 2 . The overall incidence of adverse reactions were generally similar between the linagliptin and placebo treatment arms.

8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Linagliptin and metformin hydrochloride is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1) ].

12.1 Mechanism of Action Linagliptin and Metformin Hydrochloride Linagliptin and metformin hydrochloride contains: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a biguanide. Linagliptin Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.2 Pharmacodynamics Linagliptin Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures. Cardiac Electrophysiology In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100 mg dose. At the 100 mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5 mg dose.

12.3 Pharmacokinetics Linagliptin and Metformin Hydrochloride Administration of linagliptin 2.5 mg/metformin HCl 1,000 mg fixed-dose combination with food resulted in no change in overall exposure of linagliptin. There was no change in metformin AUC; however, mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time-to-peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely to be clinically significant. Absorption Linagliptin The absolute bioavailability of linagliptin is approximately 30%. Following oral administration, plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. However, the prolonged elimination does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and C max and AUC increased by a factor of 1.3 at steady-state compared with the first dose. Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes mellitus. Metformin HCl The absolute bioavailability of a metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Distribution Linagliptin The mean apparent volume of distribution at steady-state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1,110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent decreasing from about 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment. Metformin HCl The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin HCl tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Elimination Linagliptin : Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min. Metformin HCl: Metformin has a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Metabolism Linagliptin : Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. Metformin HCl: Intravenous single-dose studies in normal subjects demonstrate that metformin does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Excretion Linagliptin : Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Metformin HCl: Following oral administration, approximately 90% of the absorbed drug is excreted via the renal route within the first 24 hours. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Specific Populations Renal Impairment Linagliptin and metformin hydrochloride: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of linagliptin and metformin hydrochloride in renally impaired patients have not been performed. Linagliptin : 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 (AUC τ,ss by 71% and C max 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 C max by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose. These findings were further supported by the results of population pharmacokinetic analyses. Metformin HCl: In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4 ) and Warnings and Precautions (5.1 )]. Hepatic Impairment Linagliptin and metformin hydrochloride: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of linagliptin and metformin hydrochloride in hepatically impaired patients have not been performed [see Warnings and Precautions (5.1 )]. Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUCτ,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 C max,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 AUC 0-24 and approximately 23% lower C max compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition. Metformin HCl: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Effects of Age, Body Mass Index (BMI), Gender, and Race Linagliptin : Based on the population pharmacokinetic analysis, age, BMI, gender, and race do not have a clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (8.5)]. Metformin HCl: 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. 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 C max 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. No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin HCl in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Caucasians (n=249), Blacks (n=51), and Hispanics (n=24). Drug Interactions Pharmacokinetic drug interaction studies with linagliptin and metformin hydrochloride have not been performed; however, such studies have been conducted with the individual components of linagliptin and metformin hydrochloride. Linagliptin 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 [see Drug Interactions (7 )]. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp, and organic cationic transporter (OCT). Table 3 describes the effect of coadministered drugs on systemic exposure of linagliptin. Table 3 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s i n g of Linagliptin* Geometric Mean Ratio ( r a t i o with/without coadministered drug) N o effect=1.0 AUC † Cmax Metformin 850 mg TID 10 mg QD 1.20 1.03 Glyburide 1.75 mg# 5 mg QD 1.02 1.01 Pioglitazone 45 mg QD 10 mg QD 1.13 1.07 Ritonavir** 200 mg BID 5 mg# 2.01 2.96 Rifampin 600 mg QD 5 mg QD 0.60 0.56 *Multiple dose (steady-state) unless otherwise noted **For information regarding clinical recommendations [see Drug Interactions (7 )]. # Single dose † AUC=AUC(0 to 24 hours) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments QD=once daily BID=twice daily TID=three times daily Table 4 describes the effect of linagliptin on systemic exposure of coadministered drugs. Table 4 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s i n g of Linagliptin* Geometric Mean Ratio(ratio with/without coadministered drug) N o effect=1.0 AUC† C m a x Metformin 850 mg TID 10 mg QD metformin 1.01 0.89 Glyburide 1.75 mg# 5 mg QD glyburide 0.86 0.86 Pioglitazone 45 mg QD 10 mg QD pioglitazone metabolite M-III metabolite M-IV 0.94 0.98 1.04 0.86 0.96 1.05 Digoxin 0.25 mg QD 5 mg QD digoxin 1.02 0.94 Simvastatin 40 mg QD 10 mg QD simvastatin simvastatin acid 1.34 1.33 1.10 1.21 Warfarin 10 mg# 5 mg QD R-warfarin S-warfarin INR PT 0.99 1.03 0.93** 1.03** 1.00 1.01 1.04** 1.15** Ethinylestradiol and levonorgestrel ethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD 5 mg QD ethinylestradiol levonorgestrel 1.01 1.09 1.08 1.13 * Multiple dose (steady-state) unless otherwise noted # Single dose † AUC = AUC(INF) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments **AUC=AUC(0 to 168) and C max =E max for pharmacodynamic end points INR = International Normalized Ratio PT = Prothrombin Time QD = once daily TID = three times daily Metformin HCl Table 5 describes the effect of coadministered drugs on plasma metformin systemic exposure. Table 5 Effect of Coadministered Drugs on Plasma Metformin Systemic Exposure Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s ing of Metformin* Geometric Mean Ratio(ratio with/without coadministered drug) N o effect=1.0 AUC † C m a x Glyburide 5 mg 850 mg metformin 0.91‡ 0.93‡ Furosemide 40 mg 850 mg metformin 1.09‡ 1.22‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05‡ 1.07‡ Cationic d r u g s eliminated by renal tubular secretion may reduce metformin elimination [see D rug Interactions (7)]. Cimetidine 400 mg 850 mg metformin 1.40 1.61 C ar b o n i c anhydrase inhibitors may cause metabolic acidosis [see Drug Interactions (7)] . Topiramate** 100 mg 500 mg metformin 1.25 1.17 * All metformin and coadministered drugs were given as single doses † AUC = AUC(INF) ‡ Ratio of arithmetic means **At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC(0-12hours) Table 6 describes the effect of metformin on coadministered drug systemic exposure. Table 6 Effect of Metformin on Coadministered Drug Systemic Exposure Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s ing of Metformin* Geometric Mean Ratio ( r a t i o with/without metformin) N o effect=1.0 AUC † C m a x Glyburide 5 mg 850 mg glyburide 0.78‡ 0.63‡ Furosemide 40 mg 850 mg furosemide 0.87‡ 0.69‡ Nifedipine 10 mg 850 mg nifedipine 1.10§ 1.08 Propranolol 40 mg 850 mg propranolol 1.01§ 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶ Cimetidine 400 mg 850 mg cimetidine 0.95§ 1.01 * All metformin and coadministered drugs were given as single doses † AUC = AUC(INF) unless otherwise noted ‡ Ratio of arithmetic means, p-value of difference <0.05 § AUC (0 to24 hours) reported ¶ Ratio of arithmetic means

Linagliptin and Metformin Hydrochloride Administration of linagliptin 2.5 mg/metformin HCl 1,000 mg fixed-dose combination with food resulted in no change in overall exposure of linagliptin. There was no change in metformin AUC; however, mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time-to-peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely to be clinically significant. Absorption Linagliptin The absolute bioavailability of linagliptin is approximately 30%. Following oral administration, plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. However, the prolonged elimination does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and C max and AUC increased by a factor of 1.3 at steady-state compared with the first dose. Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes mellitus. Metformin HCl The absolute bioavailability of a metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Distribution Linagliptin The mean apparent volume of distribution at steady-state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1,110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent decreasing from about 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment. Metformin HCl The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin HCl tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Elimination Linagliptin : Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min. Metformin HCl: Metformin has a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Metabolism Linagliptin : Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. Metformin HCl: Intravenous single-dose studies in normal subjects demonstrate that metformin does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Excretion Linagliptin : Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Metformin HCl: Following oral administration, approximately 90% of the absorbed drug is excreted via the renal route within the first 24 hours. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Specific Populations Renal Impairment Linagliptin and metformin hydrochloride: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of linagliptin and metformin hydrochloride in renally impaired patients have not been performed. Linagliptin : 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 (AUC τ,ss by 71% and C max 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 C max by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose. These findings were further supported by the results of population pharmacokinetic analyses. Metformin HCl: In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4 ) and Warnings and Precautions (5.1 )]. Hepatic Impairment Linagliptin and metformin hydrochloride: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of linagliptin and metformin hydrochloride in hepatically impaired patients have not been performed [see Warnings and Precautions (5.1 )]. Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUCτ,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 C max,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 AUC 0-24 and approximately 23% lower C max compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition. Metformin HCl: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Effects of Age, Body Mass Index (BMI), Gender, and Race Linagliptin : Based on the population pharmacokinetic analysis, age, BMI, gender, and race do not have a clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (8.5)]. Metformin HCl: 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. 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 C max 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. No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin HCl in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Caucasians (n=249), Blacks (n=51), and Hispanics (n=24). Drug Interactions Pharmacokinetic drug interaction studies with linagliptin and metformin hydrochloride have not been performed; however, such studies have been conducted with the individual components of linagliptin and metformin hydrochloride. Linagliptin 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 [see Drug Interactions (7 )]. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp, and organic cationic transporter (OCT). Table 3 describes the effect of coadministered drugs on systemic exposure of linagliptin. Table 3 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s i n g of Linagliptin* Geometric Mean Ratio ( r a t i o with/without coadministered drug) N o effect=1.0 AUC † Cmax Metformin 850 mg TID 10 mg QD 1.20 1.03 Glyburide 1.75 mg# 5 mg QD 1.02 1.01 Pioglitazone 45 mg QD 10 mg QD 1.13 1.07 Ritonavir** 200 mg BID 5 mg# 2.01 2.96 Rifampin 600 mg QD 5 mg QD 0.60 0.56 *Multiple dose (steady-state) unless otherwise noted **For information regarding clinical recommendations [see Drug Interactions (7 )]. # Single dose † AUC=AUC(0 to 24 hours) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments QD=once daily BID=twice daily TID=three times daily Table 4 describes the effect of linagliptin on systemic exposure of coadministered drugs. Table 4 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s i n g of Linagliptin* Geometric Mean Ratio(ratio with/without coadministered drug) N o effect=1.0 AUC† C m a x Metformin 850 mg TID 10 mg QD metformin 1.01 0.89 Glyburide 1.75 mg# 5 mg QD glyburide 0.86 0.86 Pioglitazone 45 mg QD 10 mg QD pioglitazone metabolite M-III metabolite M-IV 0.94 0.98 1.04 0.86 0.96 1.05 Digoxin 0.25 mg QD 5 mg QD digoxin 1.02 0.94 Simvastatin 40 mg QD 10 mg QD simvastatin simvastatin acid 1.34 1.33 1.10 1.21 Warfarin 10 mg# 5 mg QD R-warfarin S-warfarin INR PT 0.99 1.03 0.93** 1.03** 1.00 1.01 1.04** 1.15** Ethinylestradiol and levonorgestrel ethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD 5 mg QD ethinylestradiol levonorgestrel 1.01 1.09 1.08 1.13 * Multiple dose (steady-state) unless otherwise noted # Single dose † AUC = AUC(INF) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments **AUC=AUC(0 to 168) and C max =E max for pharmacodynamic end points INR = International Normalized Ratio PT = Prothrombin Time QD = once daily TID = three times daily Metformin HCl Table 5 describes the effect of coadministered drugs on plasma metformin systemic exposure. Table 5 Effect of Coadministered Drugs on Plasma Metformin Systemic Exposure Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s ing of Metformin* Geometric Mean Ratio(ratio with/without coadministered drug) N o effect=1.0 AUC † C m a x Glyburide 5 mg 850 mg metformin 0.91‡ 0.93‡ Furosemide 40 mg 850 mg metformin 1.09‡ 1.22‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05‡ 1.07‡ Cationic d r u g s eliminated by renal tubular secretion may reduce metformin elimination [see D rug Interactions (7)]. Cimetidine 400 mg 850 mg metformin 1.40 1.61 C ar b o n i c anhydrase inhibitors may cause metabolic acidosis [see Drug Interactions (7)] . Topiramate** 100 mg 500 mg metformin 1.25 1.17 * All metformin and coadministered drugs were given as single doses † AUC = AUC(INF) ‡ Ratio of arithmetic means **At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC(0-12hours) Table 6 describes the effect of metformin on coadministered drug systemic exposure. Table 6 Effect of Metformin on Coadministered Drug Systemic Exposure Coad m i n i stered Drug Do s i n g of Coadministered Drug* Do s ing of Metformin* Geometric Mean Ratio ( r a t i o with/without metformin) N o effect=1.0 AUC † C m a x Glyburide 5 mg 850 mg glyburide 0.78‡ 0.63‡ Furosemide 40 mg 850 mg furosemide 0.87‡ 0.69‡ Nifedipine 10 mg 850 mg nifedipine 1.10§ 1.08 Propranolol 40 mg 850 mg propranolol 1.01§ 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶ Cimetidine 400 mg 850 mg cimetidine 0.95§ 1.01 * All metformin and coadministered drugs were given as single doses † AUC = AUC(INF) unless otherwise noted ‡ Ratio of arithmetic means, p-value of difference <0.05 § AUC (0 to24 hours) reported ¶ Ratio of arithmetic means