Linagliptin and metformin hydrochloride

1 INDICATIONS AND USAGE Linagliptin and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Linagliptin and metformin hydrochloride tablets are not recommended in patients with type 1 diabetes mellitus. Linagliptin and metformin hydrochloride tablets have 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 linagliptin and metformin hydrochloride tablets [see Warnings and Precautions (5.2 )]. Linagliptin and metformin hydrochloride tablets are 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 )

2 DOSAGE AND ADMINISTRATION • Individualize the starting dosage of linagliptin and metformin hydrochloride tablets based on the patient's current regimen ( 2.1 ) • The maximum recommended dosage is 2.5 mg linagliptin/1,000 mg metformin HCl twice daily ( 2.1 ) • Take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal effects due to metformin ( 2.1 ) • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 ) o Do not use in patients with eGFR below 30 mL/min/1.73 m 2 o Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 o Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 o Discontinue if eGFR falls below 30 mL/min/1.73 m 2 • Linagliptin and metformin hydrochloride tablets 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 linagliptin and metformin hydrochloride tablets should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dosage of 2.5 mg linagliptin/1,000 mg metformin hydrochloride (HCl), taken orally twice daily. Linagliptin and metformin hydrochloride tablets should be given twice daily with meals. 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 treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily. • In patients already treated with metformin HCl, start with 2.5 mg linagliptin and the current dosage of metformin HCl taken at each of the two daily meals (e.g., a patient on metformin HCl 1,000 mg twice daily would be started on 2.5 mg linagliptin/1,000 mg metformin HCl twice daily with meals). • Patients already treated with linagliptin and metformin HCl individual components may be switched to linagliptin and metformin hydrochloride tablets containing the same dosages of each component. 2.2 Recommended Dosing in Renal Impairment Assess renal function prior to initiation of linagliptin and metformin hydrochloride tablets and periodically thereafter. Linagliptin and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 . Initiation of linagliptin and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m 2 is not recommended. In patients taking linagliptin and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess benefit /risk of continuing therapy. Discontinue linagliptin and metformin hydrochloride tablets 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 linagliptin and metformin hydrochloride tablets 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 linagliptin and metformin hydrochloride tablets if renal function is stable [ see Warnings and Precautions (5.1 ) ].

3 DOSAGE FORMS AND STRENGTHS Linagliptin and metformin hydrochloride tablets are a combination of linagliptin and metformin hydrochloride available as: 2.5 mg linagliptin/500 mg metformin hydrochloride tablets are yellow, oval, biconvex film-coated tablets debossed with "500" on one side and "LM" on the other side 2.5 mg linagliptin/850 mg metformin hydrochloride tablets are orange, oval, biconvex film-coated tablets debossed with "850" on one side and "LM" on the other side 2.5 mg linagliptin/1,000 mg metformin hydrochloride tablets are pink, oval, biconvex film-coated tablets debossed with "1,000" on one side and "LM" on the other side Tablets: 2.5 mg linagliptin/500 mg metformin hydrochloride ( 3 ) 2.5 mg linagliptin/850 mg metformin hydrochloride ( 3 ) 2.5 mg linagliptin/1,000 mg metformin hydrochloride ( 3 )

4 CONTRAINDICATIONS Linagliptin and metformin hydrochloride are contraindicated in patients with: • severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1 )] . • acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1 )]. • hypersensitivity to linagliptin, metformin, or any of the excipients in linagliptin and metformin hydrochloride, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin [see Warnings and Precautions (5.4 ) and Adverse Reactions (6.1 )] . Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 ) Hypersensitivity to linagliptin, metformin, or any of the excipients in linagliptin and metformin hydrochloride ( 4 )

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 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 re …

7 DRUG INTERACTIONS Table 2 describes clinically relevant interactions with linagliptin and metformin hydrochloride. Table 2 Clinically Relevant Interactions with linagliptin and metformin hydrochloride Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with linagliptin and metformin hydrochloride may increase the risk of lactic acidosis. Intervention Consider more frequent monitoring of these patients. Drugs that Reduce Metformin Clearance Clinical Impact Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3 )]. Intervention Consider the benefits and risks of concomitant use. Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention Warn patients against excessive alcohol intake while receiving linagliptin and metformin hydrochloride. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when linagliptin and metformin hydrochloride is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Intervention Coadministration of linagliptin and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. Intervention When such drugs are administered to a patient receiving linagliptin and metformin hydrochloride, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving linagliptin and metformin hydrochloride, the patient should be observed closely for hypoglycemia. Inducers of P-glycoprotein or CYP3A4 Enzymes Clinical Impact Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Intervention Use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer. Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring. ( 7 ) Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use. (7 ) Alcohol: Can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7 ) Strong P-glycoprotein/CYP3A4 Inducer: Efficacy may be reduced when administered in combination (e.g., rifampin). Use of alternative treatments is strongly recommended. ( 7 )

8 USE IN SPECIFIC POPULATIONS 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 …

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.

11 DESCRIPTION Linagliptin and metformin hydrochloride tablets for oral use contain: linagliptin and metformin hydrochloride. Linagliptin Linagliptin is an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. The chemical name of linagliptin is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]- The molecular formula is C 25 H 28 N 8 O 2 and the molecular weight is 472.54 g/mol. The structural formula is: Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca.1 mg/mL). Metformin Hydrochloride Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a biguanide. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.63 g/mol. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is: Linagliptin and Metformin Hydrochloride Tablets Linagliptin and metformin hydrochloride tablets are available for oral administration as tablets containing: • 2.5 mg linagliptin and 500 mg metformin hydrochloride (equivalent to 389.93 mg of metformin) • 2.5 mg linagliptin and 850 mg metformin hydrochloride (equivalent 662.88 mg of metformin) • 2.5 mg linagliptin and 1,000 mg metformin hydrochloride (equivalent to 779.86 mg of metformin) Each film-coated tablet of linagliptin and metformin hydrochloride tablets contains the following inactive ingredients: colloidal silicon dioxide, copovidone, corn starch, hypromellose, magnesium stearate, meglumine, povidone, propylene glycol, titanium dioxide, talc, yellow iron oxide (2.5 mg/500 mg; 2.5 mg/850 mg) and/or red iron oxide (2.5 mg/850 mg; 2.5 mg/1,000 mg). lina-met-tabs-structure1 lina-met-tabs-structure2

10 OVERDOSAGE In the event of an overdose with linagliptin and metformin hydrochloride, consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations. Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1 )]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

16 HOW SUPPLIED/STORAGE AND HANDLING Linagliptin and metformin hydrochloride tablets 2.5 mg/500 mg are yellow, oval, biconvex film-coated tablets debossed with “500” on one side and “LM” on the other side, and are supplied as follows: Bottles of 60 (NDC 72205-407-01) Bottles of 180 (NDC 72205-407-02) Linagliptin and metformin hydrochloride tablets 2.5 mg/850 mg are orange, oval, biconvex film-coated tablets debossed with “850” on one side and “LM” on the other side, and are supplied as follows: Bottles of 60 (NDC 72205-408-01) Bottles of 180 (NDC 72205-408-02) Linagliptin and metformin hydrochloride tablets 2.5 mg/1,000 mg are pink, oval, biconvex film-coated tablets debossed with “1000” on one side and “LM” on the other side, and are supplied as follows: Bottles of 60 (NDC 72205-409-01) Bottles of 180 (NDC 72205-409-02) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity.