Linagliptin And Metformin Hydrochloride

1 INDICATIONS AND USAGE JENTADUETO XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . JENTADUETO XR is a combination of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1 ) Limitations of Use Not recommended in patients with type 1 diabetes mellitus ( 1 ) Has not been studied in patients with a history of pancreatitis ( 1 ) Limitations of Use JENTADUETO XR is not recommended in patients with type 1 diabetes mellitus. JENTADUETO XR 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 JENTADUETO XR [see Warnings and Precautions (5.2) ].

2 DOSAGE AND ADMINISTRATION Individualize the starting dosage of JENTADUETO XR based on the patient's current regimen ( 2.1 ) The maximum recommended dosage is 5 mg linagliptin/2,000 mg metformin HCl once daily ( 2.1 ) Take orally once daily with a meal, with gradual dose escalation to reduce the gastrointestinal effects due to metformin ( 2.1 ) Swallow whole; do not split, crush, dissolve, or chew ( 2.1 ) Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 ) Do not use in patients with eGFR below 30 mL/min/1.73 m 2 Initiation is not recommended in patients with eGFR between 30 - 45 mL/min/1.73 m 2 Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 Discontinue if eGFR falls below 30 mL/min/1.73 m 2 JENTADUETO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.3 ) 2.1 Recommended Dosage and Administration The dosage of JENTADUETO XR should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended total daily dosage of linagliptin 5 mg and metformin hydrochloride (HCl) 2,000 mg. JENTADUETO XR should be given orally once daily with a meal. Dosage escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with metformin use. Recommended starting dosage: In patients currently not treated with metformin HCl, initiate JENTADUETO XR treatment with 5 mg linagliptin/1,000 mg metformin HCl extended-release once daily with a meal. In patients already treated with metformin HCl, start JENTADUETO XR with 5 mg of linagliptin total daily dosage and a similar total daily dosage of metformin HCl once daily with a meal. In patients already treated with linagliptin and metformin HCl or JENTADUETO, switch to JENTADUETO XR containing 5 mg of linagliptin total daily dosage and a similar total daily dosage of metformin HCl once daily with a meal. JENTADUETO XR should be swallowed whole. The tablets must not be split, crushed, dissolved, or chewed. JENTADUETO XR 5 mg linagliptin/1,000 mg metformin HCl extended-release tablet should be taken as a single tablet once daily. Patients using 2.5 mg linagliptin/1,000 mg metformin HCl extended-release tablets should take two tablets together once daily. 2.2 Recommended Dosing in Renal Impairment Assess renal function prior to initiation of JENTADUETO XR and periodically thereafter. JENTADUETO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 . Initiation of JENTADUETO XR in patients with an eGFR between 30-45 mL/min/1.73 m 2 is not recommended. In patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73 m 2 , assess benefit/risk of continuing therapy. Discontinue JENTADUETO XR if the patient's eGFR later falls below 30 mL/min/1.73 m 2 [see Contraindications (4) and Warnings and Precautions (5.1) ]. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue JENTADUETO XR 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 liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart JENTADUETO XR if renal function is stable [see Warnings and Precautions (5.1) ].

6 ADVERSE REACTIONS 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 Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 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 Linagliptin Monotherapy (%) n=142 Metformin Monotherapy (%) n=291 Combination of Linagliptin 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 (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), 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 antidiabetic 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. In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%), and nausea (6.7% vs 4.2%). 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 1.0% 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

12.3 Pharmacokinetics JENTADUETO XR Administration of JENTADUETO XR with a high-fat meal resulted in up to 7% to 22% decrease in overall exposure (AUC 0-72 ) of linagliptin; this effect is not clinically relevant. For metformin extended-release, high-fat meals increased systemic exposure (AUC 0-tz ) by approximately 54% to 71% relative to fasting, while C max is increased up to 11%. Meals prolonged T max by approximately 3 hours. 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 Following a single oral dose of 1,000 mg (2 × 500 mg tablets) metformin extended-release after a meal, the time to reach maximum plasma metformin concentration (T max ) is achieved at approximately 7 to 8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2 × 500 mg tablets) dosing provides equivalent systemic exposure, as measured by AUC, and up to 35% higher C max of metformin relative to the immediate-release given as 500 mg twice daily. Single oral doses of metformin extended-release from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and C max . Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T max by approximately 3 hours but C max was not affected. 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 [ 14 C] 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 JENTADUETO XR: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of JENTADUETO XR 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 JENTADUETO XR: Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of JENTADUETO XR 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 (AUC τ,ss ) of linagliptin was approximately 25% lower and C max,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUC ss 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 JENTADUETO XR have not been performed; however, such studies have been conducted with the individual components of JENTADUETO XR (linagliptin and metformin HCl). 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 Coadministered Drug Dosing of Coadministered Drug* Dosing of Linagliptin* Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.0 AUC † C max *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 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 Table 4 describes the effect of linagliptin on systemic exposure of coadministered drugs. Table 4 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs Coadministered Drug Dosing of Coadministered Drug* Dosing of Linagliptin* Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.0 AUC † C max * 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(0-168) and C max =E max for pharmacodynamic end points INR = International Normalized Ratio PT=Prothrombin Time QD=once daily TID=three times daily Metformin 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 0.94 0.86 metabolite M-III 0.98 0.96 metabolite M-IV 1.04 1.05 Digoxin 0.25 mg QD 5 mg QD digoxin 1.02 0.94 Simvastatin 40 mg QD 10 mg QD simvastatin 1.34 1.10 simvastatin acid 1.33 1.21 Warfarin 10 mg # 5 mg QD R-warfarin 0.99 1.00 S-warfarin 1.03 1.01 INR 0.93** 1.04** PT 1.03** 1.15** Ethinylestradiol and levonorgestrel ethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD 5 mg QD ethinylestradiol 1.01 1.08 levonorgestrel 1.09 1.13 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 Coadministered Drug Dosing of Coadministered Drug* Dosing of Metformin* Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.0 AUC † C max *All metformin and coadministered drugs were given as single doses † AUC=AUC(INF) ≠metformin HCl extended-release tablets 500 mg ‡Ratio of arithmetic means **At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC(0-12 hours) Glyburide 5 mg 500 mg ≠ metformin 0.98‡ 0.99‡ 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 drugs eliminated by renal tubular secretion may reduce metformin elimination [see Drug Interactions (7) ]. Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Drug Interactions (7) ] . Topiramate** 100 mg 500 mg metformin 1.25 1.17 Table 6 describes the effect of metformin on coadministered drug systemic exposure. Table 6 Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dosing of Coadministered Drug* Dosing of Metformin* Geometric Mean Ratio (ratio with/without metformin) No effect=1.0 AUC † C max *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(0-24 hours) reported ¶Ratio of arithmetic means Glyburide 5 mg 500 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§ 0.94 Ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶ Cimetidine 400 mg 850 mg cimetidine 0.95§ 1.01