empagliflozin 5 MG / Metformin hydrochloride 1000 MG Oral Tablet [Synjardy]
Generic Name: EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
Brand Name: Synjardy
- Substance Name(s):
- EMPAGLIFLOZIN
- METFORMIN HYDROCHLORIDE
DRUG INTERACTIONS
7 See Table 4 for clinically relevant interactions with SYNJARDY or SYNJARDY XR.
Table 4 Clinically Relevant Interactions with SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR, assess volume status and renal function.
In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention Coadministration of SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR, the patient should be closely observed to maintain adequate glycemic control.
When such drugs are withdrawn from a patient receiving SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR initiation and dosage changes.
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 SYNJARDY or SYNJARDY XR with laboratory tests.
( 7 )
OVERDOSAGE
10 In the event of an overdose with SYNJARDY or SYNJARDY XR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams.
Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1) ].
Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.
Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Removal of empagliflozin by hemodialysis has not been studied.
DESCRIPTION
11 SYNJARDY and SYNJARDY XR tablets for oral use contain: empagliflozin 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).
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 HCl Metformin HCl ( N,N -dimethylimidodicarbonimidic diamide HCl) 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 HCl 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 HCl (equivalent to 389.93 mg of metformin) 5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 12.5 mg empagliflozin and 500 mg metformin HCl (equivalent to 389.93 mg of metformin) 12.5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) Each film-coated tablet of SYNJARDY contains the following inactive ingredients: colloidal silicon dioxide, copovidone, corn starch, and magnesium stearate.
Film-coating: black ferrosoferric oxide and ferric oxide red (12.5 mg/500 mg, 12.5 mg/1,000 mg) or ferric oxide yellow (5 mg/500 mg, 5 mg/1,000 mg), hypromellose, polyethylene glycol 400, talc and titanium dioxide.
SYNJARDY XR Each film-coated tablet of SYNJARDY XR consists of an extended-release metformin HCl core tablet that is coated with the immediate-release drug substance empagliflozin.
SYNJARDY XR tablets for oral administration are available in four dosage strengths containing: 5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 10 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 12.5 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) 25 mg empagliflozin and 1,000 mg metformin HCl (equivalent to 779.86 mg of metformin) Each film-coated tablet of SYNJARDY XR contains the following inactive ingredients: Tablet Core: hypromellose, magnesium stearate, and polyethylene oxide.
Film-coatings and Printing Ink: carnauba wax, FD&C blue#2/indigo carmine aluminum lake (12.5 mg/1,000 mg, 25 mg/1,000 mg), ferric oxide red (10 mg/1,000 mg), ferric oxide yellow (5 mg/1,000 mg, 10 mg/1,000 mg, 25 mg/1,000 mg), ferrosoferric oxide, hypromellose, isopropyl alcohol, polydextrose, polyethylene glycol, propylene glycol, purified water, talc, and titanium dioxide.
CLINICAL STUDIES
14 14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus In adult patients with type 2 diabetes mellitus, treatment with empagliflozin and metformin produced clinically and statistically significant improvements in HbA1c compared to placebo and metformin.
Reductions in HbA1c were observed across subgroups including age, sex, race, and baseline BMI.
Empagliflozin Add-On Combination Therapy with Metformin in Adult Patients with Type 2 Diabetes Mellitus A total of 637 patients with type 2 diabetes mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin.
Patients with type 2 diabetes mellitus inadequately controlled on at least 1,500 mg of metformin HCl 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 Trial for Empagliflozin used in Combination with Metformin Empagliflozin 10 mg N=217 Empagliflozin 25 mg N=213 Placebo N=207 a Modified intent-to-treat population.
Last observation on trial (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 1,364 patients with type 2 diabetes mellitus participated in a double-blind, randomized, active-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin as initial therapy compared to the corresponding individual components.
Treatment-naïve patients with inadequately controlled type 2 diabetes mellitus 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 HCl 1,000 mg, or 2,000 mg; empagliflozin 10 mg in combination with 1,000 mg or 2,000 mg metformin HCl; or empagliflozin 25 mg in combination with 1,000 mg or 2,000 mg metformin HCl.
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 Trial Comparing Empagliflozin and Metformin to the Individual Components as Initial Therapy Empagliflozin 10 mg + Metformin 1,000 mg a N=161 Empagliflozin 10 mg + Metformin 2,000 mg a N=167 Empagliflozin 25 mg + Metformin 1,000 mg a N=165 Empagliflozin 25 mg + Metformin 2,000 mg a N=169 Empagliflozin 10 mg N=169 Empagliflozin 25 mg N=163 Metformin 1,000 mg a N=167 Metformin 2,000 mg a N=162 a Metformin HCl 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).
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 mellitus participated in a double-blind, placebo-controlled trial to evaluate the efficacy of empagliflozin in combination with metformin plus a sulfonylurea.
Patients with inadequately controlled type 2 diabetes mellitus on at least 1,500 mg per day of metformin HCl 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 Trial for Empagliflozin in Combination with Metformin and Sulfonylurea Empagliflozin 10 mg N=225 Empagliflozin 25 mg N=216 Placebo N=225 a Modified intent-to-treat population.
Last observation on trial (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 Trial vs Glimepiride in Combination with Metformin The efficacy of empagliflozin was evaluated in a double-blind, glimepiride-controlled, trial in 1,545 patients with type 2 diabetes mellitus 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 dosage of glimepiride was 2.7 mg and the maximal approved dosage in the United States is 8 mg per day.
Table 10 Results at Week 52 from an Active-Controlled Trial Comparing Empagliflozin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin Empagliflozin 25 mg N=765 Glimepiride N=780 a Modified intent-to-treat population.
Last observation on trial (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 dosage of glimepiride was 2.7 mg and the maximal approved dosage 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 Glycemic Control Trials in Pediatric Patients with Type 2 Diabetes Mellitus Glycemic Control Trial of Empagliflozin in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus DINAMO (NCT03429543) was a 26-week, double-blind, randomized, placebo-controlled, parallel group trial, with a double-blind active treatment safety extension period up to 52 weeks to assess the efficacy of empagliflozin.
The trial enrolled pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1c 6.5 to 10.5%).
Patients treated with metformin (at least 1,000 mg daily or maximally tolerated dose), with or without insulin therapy, and those with a history of intolerance to metformin therapy were enrolled.
Patients were randomized to 3 treatment arms (empagliflozin 10 mg, a dipeptidyl peptidase-4 (DPP-4) inhibitor, or placebo) over 26 weeks.
Patients in the empagliflozin 10 mg group who failed to achieve HbA1c <7.0% at Week 12 underwent a second randomization at Week 14 to remain on the 10 mg dose or increase to 25 mg.
Patients on placebo were re-randomized at Week 26 to one of the empagliflozin doses (10 mg or 25 mg) or a DPP-4 inhibitor.
A total of 157 patients were treated with either empagliflozin (10 mg or 25 mg; N=52), a DPP-4 inhibitor (N=52), or placebo (N=53).
Background therapies as adjunct to diet and exercise included metformin (51%), a combination of metformin 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.
Patients with an eGFR less than 60 mL/min/1.73 m 2 were not enrolled in the trial.
Approximately 25% of the trial population had microalbuminuria or macroalbuminuria.
At Week 26, treatment with empagliflozin was superior in reducing HbA1c from baseline versus placebo (see Table 11 ).
Table 11 Results at Week 26 for a Placebo-Controlled Trial for Empagliflozin in Combination with Metformin and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus a Empagliflozin 10 mg and 25 mg Placebo a Modified intent-to-treat set (All randomized and treated patients with baseline measurement).
b Multiple imputations using placebo wash-out approach with 500 iterations for missing data.
Imputed for HbA1c (empagliflozin N=5 (9.6%), placebo N=3 (5.7%)), for FPG (empagliflozin N=4 (8.3%), placebo N=2 (3.8%)).
c Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value and baseline age stratum (< 15 years vs 15 to < 18 years).
d Not evaluated for statistical significance, not part of sequential testing procedure.
e p-value=0.0116 (two-sided) HbA1c (%) b Number of patients n=52 n=53 Baseline (mean) 8.0 8.1 Change from baseline c -0.2 0.7 Difference from placebo c (95% CI) -0.8 e (-1.5, -0.2) — FPG (mg/dL) b,d Number of patients n=48 n=52 Baseline (mean) 154 159 Change from baseline c -19 17 Difference from placebo c (95% CI) -36 (-60.7, -10.7) — Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus: A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks).
The results are displayed in Table 12.
Table 12 Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl vs.
Placebo in Pediatric Patients a with Type 2 Diabetes Mellitus Metformin HCl Placebo p-value a Pediatric patients mean age 13.8 years (range 10-16 years) FPG (mg/dL) (n=37) (n=36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 <0.001 Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively.
Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively.
14.3 Empagliflozin Cardiovascular Outcome Trial in Adult Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease EMPA-REG OUTCOME was a multicenter, multinational, randomized, double-blind parallel group trial that 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 mellitus and atherosclerotic cardiovascular (CV) disease.
Concomitant antidiabetic medications were 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 7,020 patients were treated (empagliflozin 10 mg = 2,345; empagliflozin 25 mg = 2,342; placebo = 2,333) and followed for a median of 3.1 years.
Approximately 72% of the trial population was White, 22% was Asian, and 5% was Black or African American.
The mean age was 63 years and approximately 72% were male.
All patients in the trial 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 mellitus 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 CV 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 CV death or a non-fatal myocardial infarction (MI) or a non-fatal stroke.
The statistical analysis plan had pre-specified that the 10 and 25 mg dosages 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 CV 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 CV 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 13 and Figures 4 and 5 ).
Results for the 10 mg and 25 mg empagliflozin dosages were consistent with results for the combined dosage groups.
Table 13 Treatment Effect for the Primary Composite Endpoint and its Components a Placebo N=2,333 Empagliflozin N=4,687 Hazard ratio vs placebo (95% CI) a Treated set (patients who had received at least one dose of trial drug) b p-value for superiority (2-sided) 0.04 c Total number of events Composite of CV 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) CV 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 CV Death The efficacy of empagliflozin on CV 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 CV deaths.
The non-CV 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 14.4 Empagliflozin Heart Failure Trials, Including Adult Patients with Type 2 Diabetes Mellitus EMPEROR-Reduced Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction ≤ 40%) EMPEROR-Reduced (NCT03057977) was a double-blind trial conducted in adults with chronic heart failure (New York Heart Association [NYHA] functional class II-IV) with left ventricular ejection fraction (LVEF) ≤40% to evaluate the efficacy of empagliflozin as adjunct to standard of care heart failure therapy.
Of 3,730 patients, 1,863 were randomized to empagliflozin 10 mg once daily and 1,867 to placebo once daily and were followed for a median of 16 months.
Baseline Disease Characteristics and Demographics EMPEROR-Reduced included patients with type 2 diabetes mellitus (n=1,856) and patients without type 2 diabetes mellitus (n=1,874).
The mean age of the trial population was 67 years (range: 25 to 94 years) and 76% were males, 24% were women, and 27% were 75 years of age or older.
Approximately 71% of the trial population were White, 18% Asian and 7% Black or African American.
At randomization, 75% of patients were NYHA class II, 24% were class III and 0.5% were class IV.
The mean LVEF was 28%.
At baseline, the mean eGFR was 62 mL/min/1.73 m 2 and the median urinary albumin to creatinine ratio (UACR) was 22 mg/g.
Approximately half of the patients (52%) had eGFR equal to or above 60 mL/min/1.73 m 2 , 24% had eGFR 45 to less than 60 mL/min/1.73 m 2 , and 19% had eGFR 30 to less than 45 mL/min/1.73 m 2 .
At baseline, 88% of patients were treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), or angiotensin receptor-neprilysin inhibitors (ARNI), 95% with beta-blockers, 71% with mineralocorticoid receptor antagonists (MRA), and 95% with diuretics.
In EMPEROR-Reduced, history of type 2 diabetes mellitus was present in 50% of the patients, and 46% of these patients were treated with metformin (444 patients in the empagliflozin group and 418 in the placebo group) and 25% were treated with insulin.
In the type 2 diabetes mellitus subpopulation, the mean age was 67 years; 77% were males; 69% White, 19% Asian and 7% Black or African American; 32% were Hispanic/Latino.
In the type 2 diabetes mellitus subpopulation, at baseline, 71% of patients were classified as NYHA class II, 28% class III and 0.7% class IV; the mean LVEF was 27%; the mean baseline eGFR was 61 mL/min/1.73 m 2 .
In this subpopulation, at baseline, 88% of patients were treated with ACE inhibitors, ARB, or ARNI, 95% with beta-blockers, 70% with MRA, and 96% with diuretics.
Results In EMPEROR-Reduced, empagliflozin 10 mg, compared with placebo, reduced the risk of the primary composite endpoint of CV death or hospitalization for heart failure (HHF) mostly through a reduction in HHF (HR 0.75 [95% CI 0.65, 0.86]).
Empagliflozin reduced the risk of first and recurrent HHF, a key secondary endpoint.
Because of the metformin component, SYNJARDY and SYNJARDY XR are not indicated for use in patients with heart failure without type 2 diabetes mellitus [see Indications and Usage (1) ] .
The effect of empagliflozin in reducing the risk of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus (HR 0.73 [95% CI 0.60, 0.87]), and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.65 [95% CI 0.49, 0.86]).
EMPEROR-Preserved Trial (Chronic Heart Failure with Left Ventricular Ejection Fraction > 40%) EMPEROR-Preserved (NCT03057951) was a double-blind trial conducted in patients with chronic heart failure NYHA Class II-IV with LVEF >40% to evaluate the efficacy of empagliflozin as adjunct to standard of care therapy.
Of 5,988 patients, 2,997 patients were randomized to empagliflozin 10 mg once daily and 2,991 patients to placebo once daily and were followed for a median of 26 months.
Baseline Disease Characteristics and Demographics EMPEROR-Preserved included patients with type 2 diabetes mellitus (n=2,928) and patients without type 2 diabetes mellitus (n=3,060).
The mean age of the trial population was 72 years (range: 22 to 100 years) and 55% were males, 45% were women, and 43% were 75 years of age or older.
Approximately 76% of the trial population were White, 14% Asian and 4% Black or African American.
At randomization, 82% of patients were NYHA class II, 18% were class III and 0.3% were class IV.
This trial included patients with a LVEF <50% (33.1%), with a LVEF 50 to <60% (34.4%) and a LVEF ≥60% (32.5%).
At baseline, the mean eGFR was 61 mL/min/1.73 m 2 and the median urinary albumin to creatinine ratio (UACR) was 21 mg/g.
Approximately half of the patients (50%) had eGFR equal to or above 60 mL/min/1.73 m 2 , 26% had eGFR 45 to less than 60 mL/min/1.73 m 2 , and 19% had eGFR 30 to less than 45 mL/min/1.73 m 2 .
At baseline, 81% of patients were treated with ACE inhibitors, ARBs, or ARNI, 86% with beta-blockers, 38% with MRAs, and 86% with diuretics.
In EMPEROR-Preserved, history of type 2 diabetes mellitus was present in 49% of the patients, and 54% of these patients were treated with metformin (773 patients in the empagliflozin group and 803 in the placebo group) and 29% were treated with insulin.
In the type 2 diabetes mellitus subpopulation, the mean age was 71 years, 57% were males, 75% White, 13% Asian and 5% Black or African American.
In the type 2 diabetes mellitus subpopulation, at baseline, 79% of patients were classified as NYHA class II, 20% class III and 0.2% class IV; the trial also included type 2 diabetics with LVEF <50% (35%), with a LVEF 50 to <60% (34%) and a LVEF ≥60% (31%).
For this subpopulation, the mean baseline eGFR was 60 mL/min/1.73 m 2 ; and at baseline, 83% of patients were treated with ACE inhibitors, ARB, or ARNI, 88% with beta-blockers, 39% with MRA, and 89% with diuretics.
Results In EMPEROR-Preserved, empagliflozin 10 mg, compared with placebo, reduced the risk of the primary composite endpoint (time to first event of either CV death or HHF) mostly through a reduction in hospitalization for heart failure (HR 0.79 [95% CI 0.69, 0.90]).
Empagliflozin reduced the risk of first and recurrent HHF, a key secondary endpoint.
Because of the metformin component, SYNJARDY and SYNJARDY XR are not indicated for use in patients with heart failure without type 2 diabetes mellitus [see Indications and Usage (1) ] .
The effect of empagliflozin in reducing the risk of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus (HR 0.80 [95% CI 0.67, 0.95]), and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.79 [95% CI 0.61, 1.02]).
HOW SUPPLIED
16 /STORAGE AND HANDLING SYNJARDY tablets are available as follows: Tablet Strength Color/Shape Tablet Markings Package Size NDC Number 5 mg Empagliflozin 500 mg Metformin HCl orange yellow, oval, biconvex, film-coated tablet 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 Empagliflozin 1,000 mg Metformin HCl brownish yellow, oval, biconvex, film-coated tablet 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 Empagliflozin 500 mg Metformin HCl pale brownish purple, oval, biconvex, film-coated tablet 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 Empagliflozin 1,000 mg Metformin HCl dark brownish purple, oval, biconvex, film-coated tablet 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 SYNJARDY XR extended-release tablets are available as follows: Tablet Strength Color/Shape Tablet Markings Package Size NDC Number 5 mg Empagliflozin 1,000 mg Metformin HCl olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S5” on the top line and “1000 M” on the bottom line.
Bottles of 60 Bottles of 180 0597-0290-74 0597-0290-59 10 mg Empagliflozin 1,000 mg Metformin HCl orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S10” on the top line and “1000 M” on the bottom line.
Bottles of 30 Bottles of 90 0597-0280-73 0597-0280-90 12.5 mg Empagliflozin 1,000 mg Metformin HCl blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S12” on the top line and “1000 M” on the bottom line.
Bottles of 60 Bottles of 180 0597-0300-45 0597-0300-93 25 mg Empagliflozin 1,000 mg Metformin HCl light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S25” on the top line and “1000 M” on the bottom line.
Bottles of 30 Bottles of 90 0597-0295-88 0597-0295-78 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Indications and Usage ( 1 ) 6/2023 Dosage and Administration ( 2.2 ) 2/2023 Dosage and Administration ( 2.3 , 2.7 ) 6/2023 Dosage and Administration ( 2.6 ) 10/2023 Warnings and Precautions ( 5.2 , 5.8 ) 10/2023 Warnings and Precautions ( 5.5 ) 6/2023
GERIATRIC USE
8.5 Geriatric Use Assess renal function more frequently in SYNJARDY or SYNJARDY XR-treated geriatric patients because there is a greater risk of empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of metformin-associated lactic acidosis in geriatric patients [see Warnings and Precautions (5.1 , 5.3) ].
The recommended dosage for the metformin component of SYNJARDY or SYNJARDY XR in geriatric patients should usually start at the lower end of the dosage range.
Empagliflozin In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older.
In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.
In heart failure trials, EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older.
EMPEROR-Preserved included 2,402 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older.
No overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients.
Metformin Clinical studies of metformin did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients .
DOSAGE FORMS AND STRENGTHS
3 SYNJARDY Tablets: 5 mg empagliflozin/500 mg metformin HCl ( 3 ) 5 mg empagliflozin/1,000 mg metformin HCl ( 3 ) 12.5 mg empagliflozin/500 mg metformin HCl ( 3 ) 12.5 mg empagliflozin/1,000 mg metformin HCl ( 3 ) SYNJARDY XR Tablets: 5 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 10 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) 25 mg empagliflozin/1,000 mg metformin HCl extended-release ( 3 ) SYNJARDY Tablets: Empagliflozin Strength Metformin HCl Strength Color/Shape Tablet Markings 5 mg 500 mg orange yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “500”.
5 mg 1,000 mg brownish yellow, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S5” debossed on one side; the other side is debossed with “1000”.
12.5 mg 500 mg pale brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “500”.
12.5 mg 1,000 mg dark brownish purple, oval, biconvex, film-coated tablet Boehringer Ingelheim company symbol and “S12” debossed on one side; the other side is debossed with “1000”.
SYNJARDY XR Tablets: Empagliflozin Strength Metformin HCl Extended – Release Strength Color/Shape Tablet Markings 5 mg 1,000 mg olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S5” on the top line and “1000 M” on the bottom line.
10 mg 1,000 mg orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S10” on the top line and “1000 M” on the bottom line.
12.5 mg 1,000 mg blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S12” on the top line and “1000 M” on the bottom line.
25 mg 1,000 mg light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company symbol and “S25” on the top line and “1000 M” on the bottom line.
MECHANISM OF ACTION
12.1 Mechanism of Action SYNJARDY or SYNJARDY XR SYNJARDY and SYNJARDY XR contain: empagliflozin, a SGLT2 inhibitor, and metformin, a biguanide.
Empagliflozin Empagliflozin is an inhibitor of the SGLT2, the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation.
By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule.
This may influence several physiological functions such as lowering both pre- and afterload of the heart and downregulating sympathetic activity.
Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose.
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 (5.5) ] and does not cause hyperinsulinemia.
With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
INDICATIONS AND USAGE
1 SYNJARDY SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl), 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, 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 death in adults with established cardiovascular disease.
( 1 ) Cardiovascular death and hospitalization for heart failure in adults with heart failure.
( 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 component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
( 1 ) SYNJARDY SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) 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 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 death in adults with established cardiovascular disease.
Cardiovascular death and hospitalization for heart failure in adults with heart failure.
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 component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
PEDIATRIC USE
8.4 Pediatric Use SYNJARDY The safety and effectiveness of SYNJARDY as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older.
Use of SYNJARDY for this indication is supported by evidence from a 26-week double-blind, placebo-controlled clinical trial of empagliflozin, with a double-blind active treatment safety extension period of up to 52 weeks in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2) ] .
The safety profile of pediatric patients treated with empagliflozin was similar to that observed in adults with type 2 diabetes mellitus, with the exception of hypoglycemia risk which was higher in pediatric patients treated with empagliflozin regardless of concomitant insulin use [see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ].
Use of SYNJARDY for this indication is also supported by evidence from adequate and well-controlled studies of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical study using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus [see Clinical Studies (14) ] .
In this study, adverse reactions were similar to those described in adults.
The safety and effectiveness of SYNJARDY have not been established in pediatric patients less than 10 years of age.
SYNJARDY XR Safety and effectiveness of SYNJARDY XR have not been established in pediatric patients.
PREGNANCY
8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects from empagliflozin, SYNJARDY and SYNJARDY XR are not recommended during the second and third trimesters of pregnancy.
The limited available data with SYNJARDY, SYNJARDY XR, 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, empagliflozin, a component of SYNJARDY and SYNJARDY XR, resulted in adverse renal changes in rats when administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy.
Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible.
No adverse developmental effects were observed when metformin was administered to pregnant rats or rabbits (see Data ) .
The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10.
The estimated background risk of miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy.
However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data 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 HCl: Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis.
This represents an exposure of approximately 2- and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m 2 ) for rats and rabbits, respectively.
Empagliflozin and Metformin HCl: No adverse developmental effects were observed when empagliflozin and metformin HCl 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 2,000 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 (2.1) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7) ].
If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ].
WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias.
Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain.
Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information.
( 5.1 ) If lactic acidosis is suspected, discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended.
( 5.1 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider monitoring in patients at risk of ketoacidosis, as indicated.
Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue SYNJARDY or SYNJARDY XR if ketoacidosis is suspected.
Monitor patients for resolution of ketoacidosis before restarting.
( 5.2 ) Volume Depletion: Before initiating SYNJARDY or SYNJARDY 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.
( 5.3 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.
( 5.4 ) Hypoglycemia: Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia.
In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher regardless of insulin use.
Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating SYNJARDY or SYNJARDY XR.
( 5.5 ) 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.
( 5.6 ) Genital Mycotic Infections: Monitor and treat as appropriate.
( 5.7 ) Lower Limb Amputation: Monitor patients for infections or ulcers of lower limbs, and institute appropriate treatment.
( 5.8 ) Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have occurred with empagliflozin.
If hypersensitivity reactions occur, discontinue SYNJARDY or SYNJARDY XR, treat promptly, and monitor until signs and symptoms resolve.
( 5.9 ) 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.
( 5.10 ) 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 or SYNJARDY XR.
In SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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’s renal function include [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] : Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate (eGFR).
SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 [see Contraindications (4) ].
Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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 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 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 or SYNJARDY 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.
SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY 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.
SYNJARDY and SYNJARDY XR are 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 SYNJARDY or SYNJARDY XR.
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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed.
Monitor patients for resolution of ketoacidosis before restarting SYNJARDY or SYNJARDY XR.
Withhold SYNJARDY or SYNJARDY XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis.
Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.6) ] .
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SYNJARDY or SYNJARDY XR and seek medical attention immediately if signs and symptoms occur.
5.3 Volume Depletion Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1) ] .
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 SYNJARDY or SYNJARDY 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 SYNJARDY or SYNJARDY XR.
Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
5.4 Urosepsis and Pyelonephritis There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving empagliflozin.
Treatment with empagliflozin 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) ] .
5.5 Hypoglycemia Insulin and insulin secretagogues are known to cause hypoglycemia.
In adult patients, the risk of hypoglycemia may be increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with empagliflozin regardless of insulin use [see Adverse Reactions (6.1) ] .
The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin.
Inform patients using these concomitant medications and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
5.6 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 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 or SYNJARDY XR 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 or SYNJARDY XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
5.7 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.
5.8 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.
SYNJARDY and SYNJARDY XR are 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 SYNJARDY or SYNJARDY 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.
5.9 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with empagliflozin.
If a hypersensitivity reaction occurs, discontinue SYNJARDY or SYNJARDY XR; treat promptly per standard of care, and monitor until signs and symptoms resolve.
SYNJARDY and SYNJARDY XR are contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in SYNJARDY or SYNJARDY XR [see Contraindications (4) ] .
5.10 Vitamin B 12 Deficiency In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of 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 SYNJARDY or SYNJARDY XR and manage any abnormalities [see Adverse Reactions (6.1) ].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Lactic Acidosis Inform patients of the risks of lactic acidosis due to metformin, its symptoms, and conditions that predispose to its development.
Advise patients to discontinue SYNJARDY or SYNJARDY XR immediately and to notify their healthcare provider promptly if unexplained hyperventilation, malaise, myalgia, unusual somnolence, or other nonspecific symptoms occur.
Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving SYNJARDY or SYNJARDY XR.
Instruct patients to inform their healthcare provider that they are taking SYNJARDY or SYNJARDY XR prior to any surgical or radiological procedure, as temporary discontinuation may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1) ] .
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis Inform patients that SYNJARDY or SYNJARDY XR can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.
Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing).
Inform patients that blood glucose may be normal even in the presence of ketoacidosis.
Advise patients that they may be asked to monitor ketones.
If symptoms of ketoacidosis occur, instruct patients to discontinue SYNJARDY or SYNJARDY XR and seek medical attention immediately [see Warnings and Precautions (5.2) ] .
Volume Depletion Inform patients that symptomatic hypotension may occur with SYNJARDY or SYNJARDY XR and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.3) ] .
Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.
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 (5.4) ] .
Hypoglycemia Inform patients that hypoglycemia has been reported when SYNJARDY or SYNJARDY XR is used with insulin secretagogues or insulin.
Hypoglycemia may occur in pediatric patients regardless of concomitant antidiabetic treatment.
Educate patients or caregivers on the signs and symptoms of hypoglycemia [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 and SYNJARDY XR.
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 (5.6) ] .
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 (5.7) ] .
Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infection of the 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 (5.7) ] .
Lower Limb Amputation Counsel patients about the importance of routine preventative foot care.
Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.8) ].
Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with empagliflozin, a component of SYNJARDY and SYNJARDY XR.
Advise patients to report immediately any skin reaction or angioedema, and to discontinue the drug until they have consulted prescribing healthcare provider [see Warnings and Precautions (5.9) ] .
Vitamin B 12 Deficiency Inform patients about the importance of regular hematological parameters while receiving SYNJARDY or SYNJARDY XR [see Warnings and Precautions (5.10) ] .
Laboratory Tests Inform patients that elevated glucose in urinalysis is expected when taking SYNJARDY or SYNJARDY XR [see Drug Interactions (7) ] .
Pregnancy Advise pregnant patients, and patients of reproductive potential, of the potential risk to a fetus with treatment with SYNJARDY or SYNJARDY XR [see Use in Specific Populations (8.1) ] .
Instruct patients to report pregnancies to their healthcare provider as soon as possible.
Lactation Advise patients that breastfeeding is not recommended during treatment with SYNJARDY or SYNJARDY XR [see Use in Specific Populations (8.2) ] .
Patients of Reproductive Potential Inform patients that treatment with metformin may result in ovulation in some premenopausal anovulatory patients, which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ] .
Administration Instructions Inform patients that SYNJARDY XR tablets must be swallowed whole and never split, crushed, dissolved, or chewed and that incompletely dissolved SYNJARDY XR tablets may be eliminated in the feces.
Missed Dose Instruct patients to take SYNJARDY or SYNJARDY XR 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 [see Dosage and Administration (2.7) ] .
DOSAGE AND ADMINISTRATION
2 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 component.
( 2.4 ) SYNJARDY: take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal side effects due to metformin.
( 2.2 , 2.3 ) SYNJARDY XR: take orally once daily with a meal in the morning, with gradual dosage escalation to reduce the gastrointestinal side effects due to metformin.
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 major 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 [see Warnings and Precautions (5.1 , 5.3) ] .
Assess volume status.
In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6) ] .
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 may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1) ].
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’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 [see Adverse Reactions (6.1) ].
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 component.
SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 or in patients on dialysis [see Contraindications (4) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.6) ] .
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 [see Warnings and Precautions (5.1) ] .
2.6 Temporary Interruption for Surgery Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.
Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] .
2.7 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible.
Do not double up the next dose.