EMPAGLIFLOZIN: 37,059 Adverse Event Reports & Safety Profile

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 tablets for oral administration are available in four strengths containing: 5 mg empagliflozin, 2.5 mg linagliptin, and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 10 mg empagliflozin, 5 mg linagliptin, and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 12.5 mg empagliflozin, 2.5 mg linagliptin, and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 25 mg empagliflozin, 5 mg linagliptin, and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) Each film-coated tablet of TRIJARDY XR contains the following inactive ingredients: Tablet Core: hypromellose, magnesium stearate, and polyethylene oxide.

Film

Coatings and Printing Ink: ammonium hydroxide, arginine, carnauba wax, ferric oxide yellow and ferric oxide red (10 mg/5 mg/1,000 mg), ferrosoferric oxide and ferric oxide red (12.5 mg/2.5 mg/1,000 mg), ferrosoferric oxide and ferric oxide yellow (5 mg/2.5 mg/1,000 mg and 25 mg/5 mg/1,000 mg), hydroxypropyl cellulose, hypromellose, isopropyl alcohol, n-butyl alcohol, polyethylene glycol, propylene glycol, purified water, shellac glaze, talc, and titanium dioxide.

AND USAGE SYNJARDY SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. SYNJARDY XR SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus .

Empagliflozin

Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Cardiovascular (CV) death in adults with established CV disease. ( 1 ) CV death and hospitalization for heart failure in adults with heart failure. ( 1 ) Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. ( 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 ) Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. ( 1 ) Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. ( 1 ) SYNJARDY SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus . SYNJARDY XR SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus .

Empagliflozin

Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:

• Cardiovascular (CV) death in adults with established CV disease.
• CV death and hospitalization for heart failure in adults with heart failure.
• Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. Limitations of Use
• SYNJARDY and SYNJARDY XR are 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) ] .
• Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
• Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease [see Clinical Studies (14.5) ] . Empagliflozin is not expected to be effective in these populations.

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 , 2.4 ) The maximum recommended dosage is 25 mg/day of empagliflozin and 2,000 mg/day of metformin HCl. ( 2.2 , 2.3 ) Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component. ( 2.4 ) SYNJARDY: take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal adverse reactions due to metformin HCl. ( 2.2 , 2.3 ) SYNJARDY XR: take orally once daily with a meal in the morning, with gradual dosage escalation to reduce the gastrointestinal adverse reactions due to metformin HCl. Swallow whole; do not split, crush, dissolve, or chew. ( 2.2 ) SYNJARDY or SYNJARDY XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.5 ) Withhold SYNJARDY or SYNJARDY XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 )

2.1 Testing Prior to Initiation of SYNJARDY or SYNJARDY XR Assess renal function before initiating SYNJARDY or SYNJARDY XR and as clinically indicated <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.3) ]</span> . Assess volume status. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6) ]</span> .

2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults When switching to SYNJARDY or SYNJARDY XR from: Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg. Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg. Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component. Recommended dosage of SYNJARDY or SYNJARDY XR: The recommended total daily dosage of empagliflozin is 10 mg. For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin HCl may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin HCl <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Take SYNJARDY orally twice daily with meals. Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not split, crush, dissolve, or chew.

2.3 Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and Older Individualize the dosage of SYNJARDY based on the patient&apos;s current regimen. Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg . Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal adverse reactions with metformin HCl <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>.

2.4 Dosage Recommendations in Patients with Renal Impairment Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin HCl component. SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 <span class="opacity-50 text-xs">[see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ]</span> .

2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue SYNJARDY or SYNJARDY 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 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 SYNJARDY or SYNJARDY XR if renal function is stable <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> .

2.6 Temporary Interruption for Surgery Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ]</span> .

2.7 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible. Advise patients not to double up the next dose.

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 )

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) ]

Volume

Depletion [see Warnings and Precautions (5.3) ]

Genitourinary

Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections [see Warnings and Precautions (5.4) ] Hypoglycemia [see Warnings and Precautions (5.5) ]

Lower Limb

Amputation [see Warnings and Precautions (5.6) ]

Hypersensitivity

Reactions [see Warnings and Precautions (5.7) ] Vitamin B 12 Deficiency [see Warnings and Precautions (5.8) ] Most common adverse reactions associated with empagliflozin (5% or greater incidence) were urinary tract infections and female genital mycotic infections. ( 6.1 ) Most common adverse reactions associated with metformin HCl (>5%) are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. ( 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. The safety of concomitantly administered empagliflozin (daily dosage 10 mg or 25 mg) and metformin HCl (mean daily dosage of approximately 1,800 mg) has been evaluated in 3,456 adult patients with type 2 diabetes mellitus treated for 16 to 24 weeks, of which 926 patients received placebo, 1,271 patients received a daily dosage of empagliflozin 10 mg, and 1,259 patients received a daily dosage of empagliflozin 25 mg. Discontinuation of therapy due to adverse events across treatment groups was 3.0%, 2.8%, and 2.9% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Adverse

Reactions in a Clinical Trial with Empagliflozin (Add-On Combination Therapy with Metformin HCl and Sulfonylurea) for Glycemic Control in Adults with Type 2 Diabetes Mellitus In a 24-week placebo-controlled trial of empagliflozin 10 mg or 25 mg administered once daily added to metformin HCl and sulfonylurea, adverse reactions reported in ≥5% of empagliflozin-treated patients and more commonly than in placebo-treated patients are presented in Table 1 (see also Table 4 ).

Table

1 Adverse Reactions Reported in ≥5% of Adults with Type 2 Diabetes Mellitus Treated with Empagliflozin added on to Metformin HCl plus Sulfonylurea and Greater than with Placebo in a 24-week Placebo Controlled Clinical Trial Adverse Reactions Placebo (%) n=225 Empagliflozin 10 mg (%) n=224 Empagliflozin 25 mg (%) n=217 Hypoglycemia 9.8 15.6

12.9 Urinary tract infection 6.7 9.4

6.9 Nasopharyngitis 4.9 8.0

6.0 Empagliflozin Clinical Trials in Adults with Type 2 Diabetes Mellitus The data in Table 2 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a placebo-controlled trial with basal insulin in adult patients with type 2 diabetes mellitus. Empagliflozin was used as monotherapy in one trial and as add-on therapy in four trials <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . These data reflect exposure of 1,976 adult patients to empagliflozin with a mean exposure duration of approximately 23 weeks. Patients received placebo (N=995), empagliflozin 10 mg (N=999), or empagliflozin 25 mg (N=977) once daily. The mean age of the population was 56 years and 3% were older than 75 years of age. More than half (55%) of the population was male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes mellitus more than 5 years and had a mean hemoglobin A1c (HbA1c) of 8%. Established microvascular complications of diabetes mellitus at baseline included diabetic nephropathy (7%), retinopathy (8%), or neuropathy (16%). Baseline renal function was normal or mildly impaired in 91% of patients and moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m 2 ).

Table

2 shows adverse reactions (excluding hypoglycemia) that were not present at baseline, occurred more commonly in empagliflozin-treated patients than placebo-treated patients, and occurred in greater than or equal to 2% of empagliflozin-treated patients.

Table

2 Adverse Reactions Reported in ≥2% of Adults with Type 2 Diabetes Mellitus Treated with Empagliflozin and Greater than Placebo in Pooled Placebo-Controlled Clinical Trials of Empagliflozin Monotherapy or Combination Therapy Adverse Reactions Placebo (%) N=995 Empagliflozin 10 mg (%) N=999 Empagliflozin 25 mg (%) N=977 a Predefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis b Female genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), empagliflozin 10 mg (N=443), empagliflozin 25 mg (N=420). c Predefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia d Male genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), empagliflozin 10 mg (N=556), empagliflozin 25 mg (N=557). Urinary tract infection a 7.6 9.3

7.6 Female genital mycotic infections b 1.5 5.4

6.4 Upper respiratory tract infection 3.8 3.1

4.0 Increased urination c 1.0 3.4

3.2 Dyslipidemia 3.4 3.9

2.9 Arthralgia 2.2 2.4

2.3 Male genital mycotic infections d 0.4 3.1

1.6 Nausea 1.4 2.3

1.1 Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Volume Depletion

Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials in adults, adverse reactions related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Empagliflozin may increase the risk of hypotension in patients at risk for volume contraction [see Use in Specific Populations (8.5 , 8.6) ].

Increased

Urination In the pool of five placebo-controlled clinical trials in adults, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on empagliflozin than on placebo (see Table 2 ). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Hypoglycemia in Clinical Trials with Empagliflozin for Glycemic Control in Adults with Type 2 Diabetes Mellitus The incidence of hypoglycemia in adults by trial is shown in Table 3. The incidence of hypoglycemia increased when empagliflozin was administered with insulin or sulfonylurea.

Table

3 Incidence of Overall a and Severe b Hypoglycemic Events in Placebo-Controlled Clinical Trials for Glycemic Control in Adults with Type 2 Diabetes Mellitus c a Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL b Severe hypoglycemic events: requiring assistance regardless of blood glucose c Treated set (patients who had received at least one dosage of trial drug) d Insulin dosage could not be adjusted during the initial 18-week treatment period Monotherapy (24 weeks) Placebo (n=229)

Empagliflozin

10 mg (n=224)

Empagliflozin

25 mg (n=223) Overall (%) 0.4 0.4

0.4 Severe (%) 0 0 0 In Combination with Metformin HCl (24 weeks) Placebo + Metformin HCl (n=206)

Empagliflozin

10 mg + Metformin HCl (n=217)

Empagliflozin

25 mg + Metformin HCl (n=214) Overall (%) 0.5 1.8

1.4 Severe (%) 0 0 0 In Combination with Metformin HCl + Sulfonylurea (24 weeks) Placebo (n=225)

Empagliflozin

10 mg + Metformin HCl + Sulfonylurea (n=224)

Empagliflozin

25 mg + Metformin HCl + Sulfonylurea (n=217) Overall (%) 8.4 16.1

11.5 Severe (%) 0 0 0 In Combination with Pioglitazone +/- Metformin HCl (24 weeks) Placebo (n=165)

Empagliflozin

10 mg + Pioglitazone +/- Metformin HCl (n=165)

Empagliflozin

25 mg + Pioglitazone +/- Metformin HCl (n=168) Overall (%) 1.8 1.2

2.4 Severe (%) 0 0 0 In Combination with Basal Insulin +/- Metformin HCl (18 weeks d ) Placebo (n=170)

Empagliflozin

10 mg (n=169)

Empagliflozin

25 mg (n=155) Overall (%) 20.6 19.5

28.4 Severe (%) 0 0

1.3 In Combination with MDI Insulin +/- Metformin HCl (18 weeks d ) Placebo (n=188)

Empagliflozin

10 mg (n=186)

Empagliflozin

25 mg (n=189) Overall (%) 37.2 39.8

41.3 Severe (%) 0.5 0.5

0.5 Other Adverse Reactions in Clinical Trials with Empagliflozin in Adults Genital Mycotic Infections : In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with empagliflozin compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Discontinuation from trial due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either empagliflozin 10 mg or 25 mg. Genital mycotic infections occurred more frequently in female than male patients (see Table 2 ). Phimosis occurred more frequently in male patients treated with empagliflozin 10 mg (less than 0.1%) and empagliflozin 25 mg (0.1%) than placebo (0%).

Urinary Tract

Infections : In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with empagliflozin compared to placebo (see Table 2 ). Patients with a history of chronic or recurrent urinary tract infections were more likely to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Use in Specific Populations (8.5) ] .

Lower Limb

Amputations : Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95% CI) (0.81, 1.36). In a long-term cardio-renal outcome trial with empagliflozin, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively.

Clinical

Trial of Empagliflozin in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus Empagliflozin was administered to 52 patients in a trial of 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus with a mean exposure to empagliflozin of 23.8 weeks [see Clinical Studies (14.2) ] . Background therapies as adjunct to diet and exercise included metformin HCl (51%), a combination of metformin HCl and insulin (40.1%), insulin (3.2%), or none (5.7%). The mean HbA1c at baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2.1 years. The mean age was 14.5 years (range: 10-17 years) and 51.6% were aged 15 years and older. Approximately, 50% were White, 6% were Asian, 31% were Black or African American, and 38% were of Hispanic or Latino ethnicity. The mean BMI was 36.0 kg/m 2 and mean BMI Z-score was 3.0.

Approximately

25% of the trial population had microalbuminuria or macroalbuminuria. The risk of hypoglycemia was higher in pediatric patients treated with empagliflozin regardless of concomitant insulin use. Hypoglycemia, defined as a blood glucose <54 mg/dL, occurred in 10 (19.2%) patients and in 4 (7.5%) patients treated with empagliflozin and placebo, respectively. No severe hypoglycemic events occurred (severe hypoglycemia was defined as an event requiring the assistance of another person to actively administer carbohydrates, glucagon or take other corrective actions).

Adverse

Reactions with Clinical Trials of Metformin HCl The most common (>5%) established adverse reactions due to initiation of metformin HCl therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. In a 24-week clinical trial in which extended-release metformin HCl 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%).

Pediatric

Patients In clinical trials with metformin HCl immediate-release tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.

Laboratory Test

Abnormalities in Clinical Trials of Empagliflozin or Metformin HCl Empagliflozin Increases in Serum Creatinine and Decreases in eGFR: Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a trial of adults with moderate renal impairment, larger mean changes were observed. In a long-term CV outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m 2 , respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with empagliflozin. Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in adults treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups. Increase in Hematocrit: In a pool of four placebo-controlled trials in adults, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Metformin HCl Decrease in Vitamin B 12 : In metformin HCl 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 Additional 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.

Empagliflozin Gastrointestinal

Disorders: Constipation Infections: Necrotizing fasciitis of the perineum (Fournier's gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis Renal and Urinary Disorders: Acute kidney injury Skin and Subcutaneous Tissue Disorders: Angioedema, skin reactions (e.g., rash, urticaria) Metformin HCl Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk of ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue TRIJARDY XR if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.2 ) Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue TRIJARDY XR. ( 5.3 )

Volume

Depletion: Before initiating TRIJARDY XR, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. ( 5.4 )

Genitourinary

Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier's Gangrene), and Genital Mycotic Infections: Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis and if suspected, discontinue TRIJARDY XR, and promptly institute appropriate medical and/or surgical intervention. ( 5.5 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating TRIJARDY XR. ( 5.6 )

Lower Limb

Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment. ( 5.7 )

Hypersensitivity

Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with empagliflozin and linagliptin. If hypersensitivity reactions occur, discontinue TRIJARDY XR, treat promptly, and monitor until signs and symptoms resolve. ( 5.8 ) 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. ( 5.9 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue TRIJARDY XR if appropriate. ( 5.10 )

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 TRIJARDY XR. ( 5.11 )

Heart

Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of TRIJARDY XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. ( 5.12 )

5.1 Lactic Acidosis 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 (&gt;5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally &gt;5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels, which may increase the 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 TRIJARDY XR. In TRIJARDY XR-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 a clearance of up to 170 mL/minute 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 TRIJARDY XR 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&apos;s renal function include <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]</span> : Before initiating TRIJARDY XR, obtain an estimated glomerular filtration rate (eGFR). TRIJARDY XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>. Obtain an eGFR at least annually in all patients taking TRIJARDY XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug

Interactions: The concomitant use of TRIJARDY XR 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 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 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 TRIJARDY XR 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. TRIJARDY XR 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 TRIJARDY XR.

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 TRIJARDY XR.

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 TRIJARDY XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, empagliflozin, a component of TRIJARDY XR, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin. TRIJARDY XR is not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type

2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including empagliflozin. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing TRIJARDY XR [see Clinical Pharmacology (12.2) ] ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue TRIJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting TRIJARDY XR. Withhold TRIJARDY XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume TRIJARDY XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5) ]. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue TRIJARDY XR and seek medical attention immediately if signs and symptoms occur.

5.3 Pancreatitis Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span> , 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 TRIJARDY XR 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 TRIJARDY XR.

5.4 Volume Depletion Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating TRIJARDY XR in patients with one or more of these characteristics, 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.

5.5 Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier&apos;s Gangrene), and Genital Mycotic Infections Empagliflozin increases urinary glucose excretion <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> and increases the risk of genitourinary infections including urinary tract infections and genital mycotic infections in both male and female patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Serious genitourinary infections, including urosepsis, pyelonephritis, and necrotizing fasciitis of the perineum (Fournier&apos;s gangrene, a rare life-threatening infection requiring urgent surgical intervention), have occurred in patients with and without diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. Cases have required hospitalization. In patients with Fournier&apos;s gangrene, serious outcomes have included multiple surgeries and death. TRIJARDY XR is only indicated for use in patients with type 2 diabetes mellitus. Patients with history of chronic or recurrent genitourinary infections are more likely to develop genitourinary infections when using TRIJARDY XR. Monitor patients for signs and symptoms of genitourinary infections and treat promptly, if indicated. Immediately evaluate patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, for necrotizing fasciitis. If suspected, discontinue TRIJARDY XR and promptly institute appropriate medical and/or surgical intervention.

5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when TRIJARDY XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRIJARDY XR.

5.7 Lower Limb Amputation In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95 % CI) (0.81, 1.36). In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations. TRIJARDY XR is not indicated for the treatment of chronic kidney disease. Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving TRIJARDY XR for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

5.8 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. 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 TRIJARDY XR. There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with empagliflozin. If a hypersensitivity reaction occurs, discontinue TRIJARDY XR, treat promptly per standard of care, and monitor until signs and symptoms resolve. TRIJARDY XR is contraindicated in patients with hypersensitivity to linagliptin, empagliflozin or any of the excipients in TRIJARDY XR <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.9 Vitamin B 12 Deficiency In metformin HCl 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 TRIJARDY XR and manage any abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>.

5.10 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.

5.11 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.3) ]</span> , 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 TRIJARDY XR. If bullous pemphigoid is suspected, TRIJARDY XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

5.12 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 TRIJARDY XR 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 TRIJARDY XR.

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 XR initiation and dosage changes. 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.

Positive Urine Glucose Test Clinical

Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Intervention

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG)

Assay Clinical Impact

Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Intervention

Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

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 ) See full prescribing information for additional drug interactions and information on interference of TRIJARDY XR with laboratory tests. ( 7 )