Empagliflozin, Linagliptin, Metformin Hydrochloride

FDA Drug Information • Also known as: Trijardy Xr

Brand Names: Trijardy Xr
Drug Class: Dipeptidyl Peptidase 4 Inhibitor [EPC], Sodium-Glucose Cotransporter 2 Inhibitor [EPC]
Route: ORAL
Dosage Form: TABLET, EXTENDED RELEASE
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1) ] . Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.3) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue TRIJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. ( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected, discontinue TRIJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )

Description

11 DESCRIPTION TRIJARDY XR tablets for oral use contain: empagliflozin, linagliptin, and metformin HCl. Empagliflozin Empagliflozin is an inhibitor of the SGLT2. The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S). The molecular formula is C 23 H 27 ClO 7 and the molecular weight is 450.91. The structural formula is: Empagliflozin is a white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile/water, and practically insoluble in toluene. Chemical Structure Linagliptin Linagliptin is an inhibitor of the 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. The structural formula is: Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water. Linagliptin is soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol, and very slightly soluble in acetone. Chemical Structure Metformin HCl Metformin HCl ( N,N -dimethylimidodicarbonimidic diamide hydrochloride) is a biguanide. Metformin HCl 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. Metformin HCl 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: Chemical Structure TRIJARDY XR Each film-coated tablet of TRIJARDY XR consists of an extended-release metformin HCl core tablet that is coated with the immediate-release drug substances: empagliflozin and linagliptin. TRIJARDY XR...

What Is Empagliflozin, Linagliptin, Metformin Hydrochloride Used For?

1 INDICATIONS AND USAGE TRIJARDY XR is a combination of empagliflozin, linagliptin, and metformin hydrochloride (HCl) indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease [see Clinical Studies (14.2) ] . TRIJARDY XR is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, 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. Empagliflozin is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease. ( 1 ) Limitations of Use Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. ( 1 ) Has not been studied in patients with a history of pancreatitis. ( 1 ) Limitations of Use TRIJARDY XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2) ] . TRIJARDY 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 TRIJARDY XR [see Warnings and Precautions (5.3) ].

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating. ( 2.1 ) Individualize the starting dosage based on the patient's current regimen and renal function. ( 2.2 , 2.3 ) Initiation is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component. ( 2.3 ) The maximum recommended dosage of TRIJARDY XR is 25 mg empagliflozin, 5 mg linagliptin and 2,000 mg metformin HCl. ( 2.2 ) Take once daily with a meal in the morning. ( 2.2 ) Swallow whole; do not split, crush, dissolve, or chew. ( 2.2 ) TRIJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.4 ) Withhold TRIJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.5 ) 2.1 Testing Prior to Initiation of TRIJARDY XR Assess renal function before initiating TRIJARDY XR and as clinically indicated [see Warnings and Precautions (5.1 , 5.4) ] . Assess volume status. In patients with volume depletion, correct this condition before initiating TRIJARDY XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5 , 8.6) ]. 2.2 Recommended Dosage and Administration Individualize the starting dosage of TRIJARDY XR based on the patient's current regimen: In patients on metformin HCl, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl and a total daily dosage of empagliflozin 10 mg and linagliptin 5 mg; In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to TRIJARDY XR containing a similar total daily dosage of metformin HCl, the same total daily dosage of empagliflozin and linagliptin 5 mg. Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dosage of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2,000 mg . Take TRIJARDY XR orally, once daily with a meal in the morning. Take TRIJARDY XR 10 mg/5 mg/1,000 mg or TRIJARDY XR 25 mg/5 mg/1,000 mg as a single tablet once daily. Take TRIJARDY XR 5 mg/2.5 mg/1,000 mg or TRIJARDY XR 12.5 mg/2.5 mg/1,000 mg as two tablets together once daily. Swallow TRIJARDY XR tablets whole. Do not split, crush, dissolve, or chew. 2.3 Dosage Recommendations in Patients with Renal Impairment Initiation of TRIJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component. TRIJARDY XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) , Warnings and Precautions (5.1 , 5.4) , and Use in Specific Populations (8.6) ] . 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue TRIJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 ; in...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) ] Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.3) ] Volume Depletion [see Warnings and Precautions (5.4) ] Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.5) ] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6) ] Lower Limb Amputation [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] Vitamin B 12 Deficiency [see Warnings and Precautions (5.9) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.10) ] Bullous Pemphigoid [see Warnings and Precautions (5.11) ] Heart Failure [see Warnings and Precautions (5.12) ] Most common adverse reactions (5% or greater incidence) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, diarrhea, constipation, headache, and gastroenteritis. ( 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. Empagliflozin, Linagliptin and Metformin HCl The safety of concomitantly administered empagliflozin (daily dosage 10 mg or 25 mg), linagliptin (daily dosage 5 mg) and metformin HCl has been evaluated in a total of 686 patients with type 2 diabetes mellitus treated for up to 52 weeks in an active-controlled clinical trial. The most common adverse reactions are shown in Table 1. Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin, Linagliptin, and Metformin HCl in an Active-Controlled Clinical Trial of 52 Weeks Adverse Reactions Empagliflozin 10 mg + Linagliptin 5 mg + Metformin HCl (%) n=136 Empagliflozin 25 mg + Linagliptin 5 mg + Metformin HCl (%) n=137 a Predefined grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis Upper respiratory tract infection 10.3 8.0 Urinary tract infection a 9.6 10.2 Nasopharyngitis 8.1 5.8 Diarrhea 6.6 2.2 Constipation 5.1 5.8 Headache 5.1 5.1 Gastroenteritis 2.9 5.8 Hypoglycemia The incidence of hypoglycemia (defined as plasma or capillary glucose of less than 54 mg/dL) was 0.7% in patients receiving empagliflozin 10 mg/linagliptin 5 mg/metformin HCl and 0.7% in patients receiving empagliflozin 25 mg/linagliptin 5 mg/metformin HCl. Events of severe hypoglycemia (requiring assistance regardless of blood glucose) did not occur in this trial. Empagliflozin Adverse reactions that occurred in ≥2% of patients receiving empagliflozin and more commonly than in patients given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%), increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and 2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%). Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Events related to volume depletion (hypotension and...

Drug Interactions

7 DRUG INTERACTIONS Table 2 describes clinically relevant interactions with TRIJARDY XR. Table 2 Clinically Relevant Interactions with TRIJARDY XR Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with TRIJARDY XR 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 TRIJARDY XR. Diuretics Clinical Impact Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion. Intervention Before initiating TRIJARDY XR, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating TRIJARDY XR. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when TRIJARDY XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Intervention Coadministration of TRIJARDY XR 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 TRIJARDY XR, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving TRIJARDY XR, the patient should be observed closely for hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during TRIJARDY...

Contraindications

4 CONTRAINDICATIONS TRIJARDY XR is contraindicated in patients with: severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1 , 5.4) and Use in Specific Populations (8.6) ]. acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1) ]. hypersensitivity to empagliflozin, linagliptin, metformin HCl or any of the excipients in TRIJARDY XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.8) and Adverse Reactions (6) ] . Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). ( 4 ) Metabolic acidosis, including diabetic ketoacidosis. ( 4 ) Hypersensitivity to empagliflozin, linagliptin, metformin HCl, or any of the excipients in TRIJARDY XR. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects from empagliflozin, TRIJARDY XR is not recommended during the second and third trimesters of pregnancy. The limited available data with TRIJARDY XR, linagliptin, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk (see Data ) . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations ). In animal studies, empagliflozin, a component of TRIJARDY XR, resulted in adverse renal changes in rats when administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when linagliptin or metformin HCl were administered to pregnant rats or rabbits (see Data ). The estimated background risk of major birth defects is 6% to 10% 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, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related...

Overdosage

10 OVERDOSAGE In the event of an overdose with TRIJARDY XR, consider contacting the Poison Help line (1-800-222-1222) or a 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 empagliflozin by hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING TRIJARDY XR tablets are available as follows: Tablet Strength Color/Shape Tablet Markings Package Size NDC Number 5 mg Empagliflozin 2.5 mg Linagliptin 1,000 mg Metformin HCl Extended-Release grey, oval-shaped, film-coated tablet Printed on one side in white ink with the Boehringer Ingelheim company symbol and "395" on the top line and "5/2.5" on the bottom line. Bottles of 60 Bottles of 180 0597-0395-82 0597-0395-23 10 mg Empagliflozin 5 mg Linagliptin 1,000 mg Metformin HCl Extended-Release tan, oval-shaped, film-coated tablet Printed on one side in white ink with the Boehringer Ingelheim company symbol and "380" on the top line and "10/5" on the bottom line. Bottles of 30 Bottles of 90 0597-0380-13 0597-0380-68 12.5 mg Empagliflozin 2.5 mg Linagliptin 1,000 mg Metformin HCl Extended-Release red, oval-shaped, film-coated tablet Printed on one side in white ink with the Boehringer Ingelheim company symbol and "385" on the top line and "12.5/2.5" on the bottom line. Bottles of 60 Bottles of 180 0597-0385-77 0597-0385-86 25 mg Empagliflozin 5 mg Linagliptin 1,000 mg Metformin HCl Extended-Release brown, oval-shaped, film-coated tablet Printed on one side in white ink with the Boehringer Ingelheim company symbol and "390" on the top line and "25/5" on the bottom line. Bottles of 30 Bottles of 90 0597-0390-71 0597-0390-13 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.