empagliflozin 12.5 MG / Metformin hydrochloride 500 MG Oral Tablet

Generic Name: EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
Brand Name: Synjardy
  • Substance Name(s):
  • EMPAGLIFLOZIN
  • METFORMIN HYDROCHLORIDE

DRUG INTERACTIONS

7 Carbonic anhydrase inhibitors may increase risk of lactic acidosis.

Consider more frequent monitoring.

( 7.2 ) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin.

Consider the benefits and risks of concomitant use.

( 7.2 ) Alcohol can potentiate the effect of metformin on lactate metabolism.

Warn patients against excessive alcohol intake.

( 7.2 ) 7.1 Drug Interactions with Empagliflozin Diuretics Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion [see Warnings and Precautions (5.2) ] .

Insulin or Insulin Secretagogues Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia [see Warnings and Precautions (5.6) ].

Positive Urine Glucose Test Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Use alternative methods to monitor glycemic control.

7.2 Drug Interactions with Metformin Hydrochloride Drugs that Reduce Metformin Clearance 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) ].

Consider the benefits and risks of concomitant use.

Carbonic Anhydrase Inhibitors 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 SYNJARDY may increase the risk of lactic acidosis.

Consider more frequent monitoring of these patients [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].

Drugs Affecting Glycemic Control 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.

When such drugs are administered to a patient receiving SYNJARDY, the patient should be closely observed to maintain adequate glycemic control [see Clinical Pharmacology (12.3) ] .

When such drugs are withdrawn from a patient receiving SYNJARDY, the patient should be observed closely for hypoglycemia.

Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism.

Warn patients against excessive alcohol intake while receiving SYNJARDY.

OVERDOSAGE

10 In the event of an overdose with SYNJARDY, contact the Poison Control Center.

Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status.

Removal of empagliflozin by hemodialysis has not been studied.

However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.

Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom SYNJARDY overdosage is suspected.

Metformin hydrochloride Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams.

Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established.

Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions (5.1) ].

DESCRIPTION

11 SYNJARDY tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: empagliflozin and metformin hydrochloride.

Empagliflozin Empagliflozin is an orally-active inhibitor of the sodium-glucose co-transporter 2 (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).

Its 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 Metformin hydrochloride 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.

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: Chemical Structure SYNJARDY SYNJARDY tablets for oral administration are available in four dosage strengths containing 5 mg empagliflozin and 500 mg metformin hydrochloride, 5 mg empagliflozin and 1000 mg metformin hydrochloride, 12.5 mg empagliflozin and 500 mg metformin hydrochloride, or 12.5 mg empagliflozin and 1000 mg metformin hydrochloride.

Each film-coated tablet of SYNJARDY contains the following inactive ingredients: copovidone, corn starch, colloidal silicon dioxide, magnesium stearate.

Film-coating: hypromellose, titanium dioxide, talc, polyethylene glycol 400, and yellow ferric oxide (5 mg/500 mg, 5 mg/1000 mg) or red ferric oxide and black ferrosoferric oxide (12.5 mg/500 mg, 12.5 mg/1000 mg).

CLINICAL STUDIES

14 14.1 SYNJARDY Glycemic Control Studies In patients with type 2 diabetes, treatment with empagliflozin and metformin produced clinically and statistically significant improvements in HbA1c compared to placebo.

Reductions in HbA1c were observed across subgroups including age, gender, race, and baseline body mass index (BMI).

Empagliflozin Add-On Combination Therapy with Metformin A total of 637 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin.

Patients with type 2 diabetes inadequately controlled on at least 1500 mg of metformin hydrochloride per day entered an open-label 2-week placebo run-in.

At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

At Week 24, treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 7 ).

Table 7 Results at Week 24 From a Placebo-Controlled Study for Empagliflozin used in Combination with Metformin Empagliflozin 10 mg + Metformin N=217 Empagliflozin 25 mg + Metformin N=213 Placebo + Metformin N=207 a Modified intent to treat population.

Last observation on study (LOCF) was used to impute missing data at Week 24.

At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.

b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region.

Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=216, for empagliflozin 25 mg, n=213, and for placebo, n=207 HbA1c (%) a Baseline (mean) 7.9 7.9 7.9 Change from baseline (adjusted mean) -0.7 -0.8 -0.1 Difference from placebo + metformin (adjusted mean) (95% CI) -0.6 b (-0.7, -0.4) -0.6 b (-0.8, -0.5) — Patients [n (%)] achieving HbA1c <7% 75 (38%) 74 (39%) 23 (13%) FPG (mg/dL) c Baseline (mean) 155 149 156 Change from baseline (adjusted mean) -20 -22 6 Difference from placebo + metformin (adjusted mean) -26 -29 — Body Weight Baseline mean in kg 82 82 80 % change from baseline (adjusted mean) -2.5 -2.9 -0.5 Difference from placebo (adjusted mean) (95% CI) -2.0 b (-2.6, -1.4) -2.5 b (-3.1, -1.9) — At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 25 mg.

Empagliflozin Initial Combination Therapy with Metformin A total of 1364 patients with type 2 diabetes participated in a double-blind, randomized, active-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin as initial therapy compared to the corresponding individual components.

Treatment-naïve patients with inadequately controlled type 2 diabetes entered an open-label placebo run-in for 2 weeks.

At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10.5% were randomized to one of 8 active-treatment arms: empagliflozin 10 mg or 25 mg; metformin hydrochloride 1000 mg, or 2000 mg; empagliflozin 10 mg in combination with 1000 mg or 2000 mg metformin hydrochloride; or empagliflozin 25 mg in combination with 1000 mg or 2000 mg metformin hydrochloride.

At Week 24, initial therapy of empagliflozin in combination with metformin provided statistically significant reductions in HbA1c (p-value <0.01) compared to the individual components (see Table 8 ).

Table 8 Glycemic Parameters at 24 Weeks in a Study Comparing Empagliflozin and Metformin to the Individual Components as Initial Therapy Empagliflozin 10 mg + Metformin 1000 mg a N=161 Empagliflozin 10 mg + Metformin 2000 mg a N=167 Empagliflozin 25 mg + Metformin 1000 mg a N=165 Empagliflozin 25 mg + Metformin 2000 mg a N=169 Empagliflozin 10 mg N=169 Empagliflozin 25 mg N=163 Metformin 1000 mg a N=167 Metformin 2000 mg a N=162 HbA1c (%) a Metformin hydrochloride total daily dose, administered in two equally divided doses per day.

b p-value ≤0.0062 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).

c p-value ≤0.0056 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).

Baseline (mean) 8.7 8.7 8.8 8.7 8.6 8.9 8.7 8.6 Change from baseline (adjusted mean) -2.0 -2.1 -1.9 -2.1 -1.4 -1.4 -1.2 -1.8 Comparison vs empagliflozin (adjusted mean) (95% CI) -0.6 b (-0.9, -0.4) -0.7 b (-1.0, -0.5) -0.6 c (-0.8, -0.3) -0.7 c (-1.0, -0.5) — — — — Comparison vs metformin (adjusted mean) (95% CI) -0.8 b (-1.0, -0.6) -0.3 b (-0.6, -0.1) -0.8 c (-1.0, -0.5) -0.3 c (-0.6, -0.1) — — — — Patients [n (%)] achieving HbA1c <7% 96 (63%) 112 (70%) 91 (57%) 111 (68%) 69 (43%) 51 (32%) 63 (38%) 92 (58%) Empagliflozin Add-On Combination Therapy with Metformin and Sulfonylurea A total of 666 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin plus a sulfonylurea.

Patients with inadequately controlled type 2 diabetes on at least 1500 mg per day of metformin hydrochloride and on a sulfonylurea, entered a 2-week open-label placebo run-in.

At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

Treatment with empagliflozin 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 9 ).

Table 9 Results at Week 24 from a Placebo-Controlled Study for Empagliflozin in Combination with Metformin and Sulfonylurea Empagliflozin 10 mg + Metformin + SU N=225 Empagliflozin 25 mg + Metformin + SU N=216 Placebo + Metformin + SU N=225 a Modified intent to treat population.

Last observation on study (LOCF) was used to impute missing data at Week 24.

At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.

b ANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region.

Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) c FPG (mg/dL); for empagliflozin 10 mg, n=225, for empagliflozin 25 mg, n=215, for placebo, n=224 HbA1c (%) a Baseline (mean) 8.1 8.1 8.2 Change from baseline (adjusted mean) -0.8 -0.8 -0.2 Difference from placebo (adjusted mean) (95% CI) -0.6 b (-0.8, -0.5) -0.6 b (-0.7, -0.4) — Patients [n (%)] achieving HbA1c <7% 55 (26%) 65 (32%) 20 (9%) FPG (mg/dL) c Baseline (mean) 151 156 152 Change from baseline (adjusted mean) -23 -23 6 Difference from placebo (adjusted mean) -29 -29 — Body Weight Baseline mean in kg 77 78 76 % change from baseline (adjusted mean) -2.9 -3.2 -0.5 Difference from placebo (adjusted mean) (95% CI) -2.4 b (-3.0, -1.8) -2.7 b (-3.3, -2.1) — Active-Controlled Study vs Glimepiride in Combination with Metformin The efficacy of empagliflozin was evaluated in a double-blind, glimepiride-controlled, study in 1545 patients with type 2 diabetes with insufficient glycemic control despite metformin therapy.

Patients with inadequate glycemic control and an HbA1c between 7% and 10% after a 2-week run-in period were randomized to glimepiride or empagliflozin 25 mg.

At Week 52, empagliflozin 25 mg and glimepiride lowered HbA1c and FPG (see Table 10 , Figure 3 ).

The difference in observed effect size between empagliflozin 25 mg and glimepiride excluded the pre-specified non-inferiority margin of 0.3%.

The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is 8 mg per day.

Table 10 Results at Week 52 from an Active-Controlled Study Comparing Empagliflozin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin Empagliflozin 25 mg + Metformin N=765 Glimepiride + Metformin N=780 a Modified intent to treat population.

Last observation on study (LOCF) was used to impute data missing at Week 52.

At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to empagliflozin 25 mg and glimepiride, respectively.

b Non-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region) c ANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) d FPG (mg/dL); for empagliflozin 25 mg, n=764, for glimepiride, n=779 HbA1c (%) a Baseline (mean) 7.9 7.9 Change from baseline (adjusted mean) -0.7 -0.7 Difference from glimepiride (adjusted mean) (97.5% CI) -0.07 b (-0.15, 0.01) — FPG (mg/dL) d Baseline (mean) 150 150 Change from baseline (adjusted mean) -19 -9 Difference from glimepiride (adjusted mean) -11 — Body Weight Baseline mean in kg 82.5 83 % change from baseline (adjusted mean) -3.9 2.0 Difference from glimepiride (adjusted mean) (95% CI) -5.9 c (-6.3, -5.5) — Figure 3 Adjusted mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT Population) – LOCF At Week 52, the adjusted mean change from baseline in systolic blood pressure was -3.6 mmHg, compared to 2.2 mmHg for glimepiride.

The differences between treatment groups for systolic blood pressure was statistically significant (p-value <0.0001).

At Week 104, the adjusted mean change from baseline in HbA1c was -0.75% for empagliflozin 25 mg and -0.66% for glimepiride.

The adjusted mean treatment difference was -0.09% with a 97.5% confidence interval of (-0.32%, 0.15%), excluding the pre-specified non-inferiority margin of 0.3%.

The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is 8 mg per day.

The Week 104 analysis included data with and without concomitant glycemic rescue medication, as well as off-treatment data.

Missing data for patients not providing any information at the visit were imputed based on the observed off-treatment data.

In this multiple imputation analysis, 13.9% of the data were imputed for empagliflozin 25 mg and 12.9% for glimepiride.

At Week 104, empagliflozin 25 mg daily resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.1 kg for empagliflozin 25 mg vs.

+1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).

FIGURE 3 14.2 Empagliflozin Cardiovascular Outcome Study in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.

However, the effectiveness of SYNJARDY on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease has not been established.

The effect of empagliflozin on cardiovascular risk in adult patients with type 2 diabetes and established, stable, atherosclerotic cardiovascular disease is presented below.

The EMPA-REG OUTCOME study, a multicenter, multi-national, randomized, double-blind parallel group trial compared the risk of experiencing a major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease.

Coadministered antidiabetic medications were to be kept stable for the first 12 weeks of the trial.

Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 7020 patients were treated (empagliflozin 10 mg = 2345; empagliflozin 25 mg = 2342; placebo = 2333) and followed for a median of 3.1 years.

Approximately 72% of the study population was Caucasian, 22% was Asian, and 5% was Black.

The mean age was 63 years and approximately 72% were male.

All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%).

The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes for more than 10 years.

Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators respectively and the mean eGFR was 74 mL/min/1.73 m 2 .

At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), and sulfonylurea (43%).

All patients had established atherosclerotic cardiovascular disease at baseline including one (82%) or more (18%) of the following; a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%).

At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g.

At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE).

A major adverse cardiac event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal stroke.

The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined.

A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated.

Type-1 error was controlled across multiples tests using a hierarchical testing strategy.

Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI 0.74, 0.99).

The treatment effect was due to a significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin (HR: 0.62; 95% CI 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 11 and Figure 4 and 5 ).

Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.

Table 11 Treatment Effect for the Primary Composite Endpoint, and its Components a Placebo N=2333 Empagliflozin N=4687 Hazard ratio vs placebo (95% CI) a Treated set (patients who had received at least one dose of study drug) b p−value for superiority (2−sided) 0.04 c Total number of events Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) b 282 (12.1%) 490 (10.5%) 0.86 (0.74, 0.99) Non-fatal myocardial infarction c 121 (5.2%) 213 (4.5%) 0.87 (0.70, 1.09) Non-fatal stroke c 60 (2.6%) 150 (3.2%) 1.24 (0.92, 1.67) Cardiovascular death c 137 (5.9%) 172 (3.7%) 0.62 (0.49, 0.77) Figure 4 Estimated Cumulative Incidence of First MACE Figure 5 Estimated Cumulative Incidence of Cardiovascular Death The efficacy of empagliflozin on cardiovascular death was generally consistent across major demographic and disease subgroups.

Vital status was obtained for 99.2% of subjects in the trial.

A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial.

Most of these deaths were categorized as cardiovascular deaths.

The non-cardiovascular deaths were only a small proportion of deaths, and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).

FIGURE 4 FIGURE 5

HOW SUPPLIED

16 /STORAGE AND HANDLING SYNJARDY (empagliflozin and metformin hydrochloride) tablets are available in the following strengths and packages: Tablet Strength Film-Coated Tablet, Color/Shape Tablet Markings Package Size NDC Number 5 mg/500 mg orange yellow, oval, biconvex Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “500” Bottles of 60 Bottles of 180 0597-0159-60 0597-0159-18 5 mg/1000 mg brownish yellow, oval, biconvex Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “1000” Bottles of 60 Bottles of 180 0597-0175-60 0597-0175-18 12.5 mg/500 mg pale brownish purple, oval, biconvex Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “500” Bottles of 60 Bottles of 180 0597-0180-60 0597-0180-18 12.5 mg/1000 mg dark brownish purple, oval, biconvex Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “1000” Bottles of 60 Bottles of 180 0597-0168-60 0597-0168-18 Storage Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Store in a safe place out of reach of children.

RECENT MAJOR CHANGES

Warnings and Precautions, Ketoacidosis ( 5.3 ) 1/2020

GERIATRIC USE

8.5 Geriatric Use Because renal function abnormalities can occur after initiating empagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients [see Dosage and Administration (2.2) and Warnings and Precautions (5.1 , 5.4) ].

Empagliflozin No empagliflozin dosage change is recommended based on age [see Dosage and Administration (2) ] .

In studies assessing the efficacy of empagliflozin in improving glycemic control in patients with type 2 diabetes, a total of 2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older.

Empagliflozin is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6) ] .

The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg.

The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] .

Metformin hydrochloride Controlled clinical studies of metformin hydrochloride did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis.

Assess renal function more frequently in elderly patients [see Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ].

DOSAGE FORMS AND STRENGTHS

3 SYNJARDY is a combination of empagliflozin and metformin hydrochloride.

SYNJARDY is available in the following dosage forms and strengths: 5 mg empagliflozin/500 mg metformin hydrochloride tablets are orange yellow, oval, biconvex, film-coated tablets.

One side is debossed with the Boehringer Ingelheim company symbol and “S5”; the other side is debossed with “500”.

5 mg empagliflozin/1000 mg metformin hydrochloride tablets are brownish yellow, oval, biconvex, film-coated tablets.

One side is debossed with the Boehringer Ingelheim company symbol and “S5”; the other side is debossed with “1000”.

12.5 mg empagliflozin/500 mg metformin hydrochloride tablets are pale brownish purple, oval, biconvex, film-coated tablets.

One side is debossed with the Boehringer Ingelheim company symbol and “S12”; the other side is debossed with “500”.

12.5 mg empagliflozin/1000 mg metformin hydrochloride tablets are dark brownish purple, oval, biconvex, film-coated tablets.

One side is debossed with the Boehringer Ingelheim company symbol and “S12”; the other side is debossed with “1000”.

Tablets: 5 mg empagliflozin/500 mg metformin hydrochloride 5 mg empagliflozin/1000 mg metformin hydrochloride 12.5 mg empagliflozin/500 mg metformin hydrochloride 12.5 mg empagliflozin/1000 mg metformin hydrochloride ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action SYNJARDY SYNJARDY combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a member of the biguanide class.

Empagliflozin Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation.

Empagliflozin is an inhibitor of SGLT2.

By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Metformin Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose.

It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Unlike SUs, metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.6) ] and does not cause hyperinsulinemia.

With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

INDICATIONS AND USAGE

1 SYNJARDY is a combination of empagliflozin and metformin hydrochloride indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin hydrochloride is appropriate .

Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease [see Clinical Studies (14.2) ] .

However, the effectiveness of SYNJARDY on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established.

SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and metformin hydrochloride is appropriate.

Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease.

However, the effectiveness of SYNJARDY on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established.

( 1 ) Limitations of Use : Not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis ( 1 ) Limitations of Use SYNJARDY is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis [see Warnings and Precautions (5.3) ] .

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of SYNJARDY in pediatric patients under 18 years of age have not been established.

PREGNANCY

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, SYNJARDY is not recommended during the second and third trimesters of pregnancy.

Limited available data with SYNJARDY or empagliflozin in pregnant women are not sufficient to determine a drug-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 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, adverse renal changes were observed in rats when empagliflozin was 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.

Empagliflozin was not teratogenic in rats and rabbits up to 300 mg/kg/day, which approximates 48-times and 128-times, respectively, the maximum clinical dose of 25 mg when administered during organogenesis.

No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2000 mg clinical dose, based on body surface area (see Data ) .

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% 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 2-4% and 15-20%, 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, stillbirth, 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 post-marketing 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 Empagliflozin: Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30 and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC.

These findings were not observed after a 13 week drug-free recovery period.

These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.

In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans.

Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects.

In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose.

Empagliflozin crosses the placenta and reaches fetal tissues in rats.

In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.

In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity.

Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).

Metformin hydrochloride: Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at 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 2000 mg, based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

Empagliflozin and Metformin hydrochloride: No adverse developmental effects were observed when empagliflozin and metformin hydrochloride were coadministered to pregnant rats during the period of organogenesis at exposures of approximately 35- and 14-times the clinical AUC exposure of empagliflozin associated with the 10 mg and 25 mg doses, respectively, and 4-times the clinical AUC exposure of metformin associated with the 2000 mg dose.

BOXED WARNING

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 (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7.2) , and Use in Specific Populations (8.6 , 8.7) ].

If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY 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 SYNJARDY and institute general supportive measures in a hospital setting.

Prompt hemodialysis is recommended.

( 5.1 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning ( 5.1 ) Hypotension: Before initiating SYNJARDY assess and correct volume status in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics.

Monitor for signs and symptoms during therapy.

( 5.2 ) Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level.

If suspected, discontinue SYNJARDY, evaluate and treat promptly.

Before initiating SYNJARDY, consider risk factors for ketoacidosis.

Patients on SYNJARDY may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis.

( 5.3 ) Acute Kidney Injury and Impairment in Renal Function: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses.

If acute kidney injury occurs, discontinue and promptly treat.

Monitor renal function during therapy.

( 5.4 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated ( 5.5 ) Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating SYNJARDY ( 5.6 ) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males.

Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise.

If suspected, institute prompt treatment.

( 5.7 ) Genital Mycotic Infections: Monitor and treat as appropriate ( 5.8 ) Hypersensitivity Reactions: Discontinue SYNJARDY, treat promptly, and monitor until signs and symptoms resolve ( 5.9 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels.

Monitor hematologic parameters annually.

( 5.10 ) Increased LDL-C: Monitor and treat as appropriate ( 5.11 ) Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with SYNJARDY.

( 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 (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL.

Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase 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 SYNJARDY.

In SYNJARDY-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride 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 SYNJARDY and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ] .

Before initiating SYNJARDY, obtain an estimated glomerular filtration rate (eGFR).

SYNJARDY is contraindicated in patients with an eGFR below 45 mL/min/1.73 m 2 [see Contraindications (4) ].

Obtain an eGFR at least annually in all patients taking SYNJARDY.

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 SYNJARDY 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 (7.2) ] .

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 SYNJARDY at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.

Re-evaluate eGFR 48 hours after the imaging procedure, and restart SYNJARDY 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.

SYNJARDY 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 SYNJARDY.

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 SYNJARDY.

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 SYNJARDY in patients with clinical or laboratory evidence of hepatic disease.

5.2 Hypotension Empagliflozin causes intravascular volume contraction.

Symptomatic hypotension may occur after initiating empagliflozin [see Adverse Reactions (6.1) ] particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics.

Before initiating SYNJARDY, assess for volume contraction and correct volume status if indicated.

Monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see Use in Specific Populations (8.5) ] .

5.3 Ketoacidosis Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin.

Fatal cases of ketoacidosis have been reported in patients taking empagliflozin.

SYNJARDY is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1) ] .

Patients treated with SYNJARDY who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with SYNJARDY may be present even if blood glucose levels are less than 250 mg/dL.

If ketoacidosis is suspected, SYNJARDY should be discontinued, patient should be evaluated, and prompt treatment should be instituted.

Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL).

Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath.

In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating SYNJARDY, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.

For patients who undergo scheduled surgery, consider temporarily discontinuing SYNJARDY for at least 3 days prior to surgery [see Clinical Pharmacology (12.2 , 12.3) ] .

Consider monitoring for ketoacidosis and temporarily discontinuing SYNJARDY in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery).

Ensure risk factors for ketoacidosis are resolved prior to restarting SYNJARDY.

Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SYNJARDY and seek medical attention immediately if signs and symptoms occur.

5.4 Acute Kidney Injury and Impairment in Renal Function Empagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.2) ] and can cause renal impairment [see Adverse Reactions (6.1) ] .

There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.

Before initiating SYNJARDY, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs).

Consider temporarily discontinuing SYNJARDY in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury.

If acute kidney injury occurs, discontinue SYNJARDY promptly and institute treatment.

Empagliflozin increases serum creatinine and decreases eGFR.

Patients with hypovolemia may be more susceptible to these changes.

Renal function abnormalities can occur after initiating SYNJARDY [see Adverse Reactions (6.1) ] .

Renal function should be evaluated prior to initiation of SYNJARDY and monitored periodically thereafter.

More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m 2 .

Use of SYNJARDY is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m 2 [see Dosage and Administration (2.2) , Contraindications (4) and Use in Specific Populations (8.6) ] .

5.5 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin.

Treatment with SGLT2 inhibitors increases the risk for urinary tract infections.

Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6) ] .

5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Empagliflozin Insulin and insulin secretagogues are known to cause hypoglycemia.

The risk of hypoglycemia is increased when empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1) ] .

Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with SYNJARDY .

Metformin Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol.

Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.

Monitor for a need to lower the dose of SYNJARDY to minimize the risk of hypoglycemia in these patients.

5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin.

Cases have been reported in both females and males.

Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with SYNJARDY presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis.

If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement.

Discontinue SYNJARDY, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.8 Genital Mycotic Infections Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1) ] .

Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections.

Monitor and treat as appropriate.

5.9 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empagliflozin, one of the components of SYNJARDY.

If a hypersensitivity reaction occurs, discontinue SYNJARDY; treat promptly per standard of care, and monitor until signs and symptoms resolve.

SYNJARDY is contraindicated in patients with a previous serious hypersensitivity reaction to empagliflozin or any of the excipients in SYNJARDY [see Contraindications (4) ] .

5.10 Vitamin B 12 Levels In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, 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, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials.

This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing.

The decrease in vitamin B 12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation.

Measurement of hematologic parameters on an annual basis is advised in patients on SYNJARDY and any apparent abnormalities should be appropriately investigated and managed .

Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels.

In these patients, routine serum vitamin B 12 measurement at 2- to 3-year intervals may be useful.

5.11 Increased Low-Density Lipoprotein Cholesterol (LDL-C) Increases in LDL-C can occur with empagliflozin.

Monitor and treat as appropriate.

5.12 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with SYNJARDY.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Medication Guide Instruct patients to read the Medication Guide before starting SYNJARDY therapy and to reread it each time the prescription is renewed.

Instruct patients to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.

Inform patients of the potential risks and benefits of SYNJARDY and of alternative modes of therapy.

Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.

Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.

Lactic Acidosis Inform patients of the risks of lactic acidosis due to the metformin component, its symptoms, and conditions that predispose to its development [see Warnings and Precautions (5.1) ] .

Advise patients to discontinue SYNJARDY immediately and to notify their doctor promptly if unexplained hyperventilation, malaise, myalgia, unusual somnolence, slow or irregular heart beat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur.

GI symptoms are common during initiation of metformin treatment and may occur during initiation of SYNJARDY therapy; however, advise patients to consult their doctor if they develop unexplained symptoms.

Although GI symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to metformin-induced lactic acidosis or other serious disease.

Hypotension Inform patients that hypotension may occur with SYNJARDY and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2) ] .

Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Ketoacidosis Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of empagliflozin, sometimes associated with illness or surgery among other risk factors.

Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated.

If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue SYNJARDY and seek medical attention immediately [see Warnings and Precautions (5.3) ] .

Acute Kidney Injury Inform patients that acute kidney injury has been reported during use of empagliflozin.

Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue SYNJARDY use in those settings [see Warnings and Precautions (5.4) ] .

Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious.

Provide them with information on the symptoms of urinary tract infections.

Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.5) ] .

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with empagliflozin, a component of SYNJARDY.

Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.7) ] .

Genital Mycotic Infections in Females (e.g., Vulvovaginitis) Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections.

Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8) ] .

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections.

Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis).

Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8) ] .

Monitoring of Renal Function Inform patients about the importance of regular testing of renal function when receiving treatment with SYNJARDY.

Instruct patients to inform their doctor that they are taking SYNJARDY prior to any surgical or radiological procedure, as temporary discontinuation of SYNJARDY may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1) ] .

Hypoglycemia Inform patients that the risk of hypoglycemia is increased when SYNJARDY is used in combination with an insulin secretagogue (e.g., sulfonylurea), and that a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.6) ] .

Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with empagliflozin, a component of SYNJARDY.

Advise patients to report immediately any skin reaction or angioedema, and to discontinue the drug until they have consulted prescribing physician [see Warnings and Precautions (5.9) ] .

Laboratory Tests Inform patients that elevated glucose in urinalysis is expected when taking SYNJARDY.

Pregnancy Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with SYNJARDY [see Use in Specific Populations (8.1) ] .

Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.

Lactation Advise women that breastfeeding is not recommended during treatment with SYNJARDY [see Use in Specific Populations (8.2) ] .

Females and Males of Reproductive Potential Inform females that treatment with metformin may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ] .

Missed Dose Instruct patients to take SYNJARDY only as prescribed.

If a dose is missed, it should be taken as soon as the patient remembers.

Advise patients not to double their next dose.

Blood Glucose and A1C Monitoring Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels toward the normal range.

Hemoglobin A1c monitoring is especially useful for evaluating long-term glycemic control.

Inform patients that the most common adverse reactions associated with the use of SYNJARDY are hypoglycemia, urinary tract infection, and nasopharyngitis.

DOSAGE AND ADMINISTRATION

2 Individualize the starting dose of SYNJARDY based on the patient’s current regimen ( 2.1 ) The maximum recommended dose is 12.5 mg empagliflozin/1000 mg metformin hydrochloride twice daily ( 2.1 ) Take twice daily with meals, with gradual dose escalation to reduce the gastrointestinal side effects due to metformin ( 2.1 ) Assess renal function before initiating.

SYNJARDY is contraindicated in patients with an eGFR below 45 mL/min/1.73 m 2 ( 2.2 , 4 ) SYNJARDY may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.3 ) 2.1 Recommended Dosage In patients with volume depletion not previously treated with empagliflozin, correct this condition before initiating SYNJARDY [see Warnings and Precautions (5.2) ] .

Individualize the starting dose of SYNJARDY based on the patient’s current regimen: – In patients on metformin hydrochloride, switch to SYNJARDY containing empagliflozin 5 mg with a similar total daily dose of metformin hydrochloride; – In patients on empagliflozin, switch to SYNJARDY containing metformin hydrochloride 500 mg with a similar total daily dose of empagliflozin; – In patients already treated with empagliflozin and metformin hydrochloride, switch to SYNJARDY containing the same total daily doses of each component.

Take SYNJARDY twice daily with meals; with gradual dose escalation to reduce the gastrointestinal side effects due to metformin [see Dosage Forms and Strengths (3) ].

Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of metformin hydrochloride 2000 mg and empagliflozin 25 mg [see Dosage and Administration (2.2) ].

2.2 Recommended Dosage in Patients with Renal Impairment Assess renal function prior to initiation of SYNJARDY and periodically, thereafter.

SYNJARDY is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m 2 [see Contraindications (4) and Warnings and Precautions (5.1 , 5.4) ] .

2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue SYNJARDY at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 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 SYNJARDY if renal function is stable [see Warnings and Precautions (5.1) ] .