Data from FDA (Food and Drug Administration, USA) - Curated by Marshall Pearce - Last updated 12 September 2017

Indication(s)

1 INDICATIONS AND USAGE 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 when treatment with both empagliflozin and metformin is appropriate [see Clinical Studies (14)]. Limitations of Use SYNJARDY XR is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. SYNJARDY XR is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin, 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 is appropriate. (1) Limitations of Use: Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS SYNJARDY XR is contraindicated in patients with: Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end stage renal disease, or dialysis [see Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.6)]. Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1)]. History of serious hypersensitivity reaction to empagliflozin or metformin hydrochloride. Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), end stage renal disease, or dialysis (4, 5.1, 5.4) Metabolic acidosis, including diabetic ketoacidosis (1, 4, 5.1) History of serious hypersensitivity reaction to empagliflozin or metformin (4)
Adverse reactions
6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)] Hypotension [see Warnings and Precautions (5.2)] Ketoacidosis [see Warnings and Precautions (5.3)] Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.4)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6)] Genital Mycotic Infections [see Warnings and Precautions (5.7)] Vitamin B12 Deficiency [see Warnings and Precautions (5.8)] Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.9)] Most common adverse reactions associated with empagliflozin (5% or greater incidence) were urinary tract infection and female genital mycotic infections. (6.1) Most common adverse reactions associated with metformin (>5%) are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of concomitantly administered empagliflozin (daily dose 10 mg and 25 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 3456 patients with type 2 diabetes mellitus treated for 16 to 24 weeks, of which 926 patients received placebo, 1271 patients received a daily dose of empagliflozin 10 mg, and 1259 patients received a daily dose of empagliflozin 25 mg. Discontinuation of therapy due to adverse events across treatment groups was 3.0%, 2.8%, and 2.9% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Empagliflozin Add-On Combination Therapy with Metformin In a 24-week placebo-controlled trial of empagliflozin 10 mg and 25 mg administered once daily added to metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Empagliflozin Add-On Combination Therapy with Metformin and Sulfonylurea In a 24-week placebo-controlled trial of empagliflozin 10 mg and 25 mg administered once daily added to metformin and sulfonylurea, adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo are presented in Table 1 (see also Table 4). Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin added on to Metformin plus Sulfonylurea and Greater than with Placebo in a 24-week Placebo Controlled Clinical Study Number (%) of Patients Placebo n=225 Empagliflozin 10 mg n=224 Empagliflozin 25 mg n=217 Hypoglycemia 22 (9.8) 35 (15.6) 28 (12.9) Urinary tract infection 15 (6.7) 21 (9.4) 15 (6.9) Nasopharyngitis 11 (4.9) 18 (8.0) 13 (6.0) Empagliflozin The data in Table 2 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a placebo-controlled trial with basal insulin. Empagliflozin was used as monotherapy in one trial and as add-on therapy in four trials [see Clinical Studies (14)]. These data reflect exposure of 1976 patients to empagliflozin with a mean exposure duration of approximately 23 weeks. Patients received placebo (N=995), empagliflozin 10 mg (N=999), or empagliflozin 25 mg (N=977) once daily. The mean age of the population was 56 years and 3% were older than 75 years of age. More than half (55%) of the population was male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes more than 5 years and had a mean hemoglobin A1c (HbA1c) of 8%. Established microvascular complications of diabetes at baseline included diabetic nephropathy (7%), retinopathy (8%), or neuropathy (16%). Baseline renal function was normal or mildly impaired in 91% of patients and moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m2). Table 2 shows common adverse reactions (excluding hypoglycemia) associated with the use of empagliflozin. The adverse reactions were not present at baseline, occurred more commonly on empagliflozin than on placebo and occurred in greater than or equal to 2% of patients treated with empagliflozin 10 mg or empagliflozin 25 mg. Table 2 Adverse Reactions Reported in ≥2% of Patients Treated with Empagliflozin and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of Empagliflozin Monotherapy or Combination Therapy aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis bFemale genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), empagliflozin 10 mg (N=443), empagliflozin 25 mg (N=420). cPredefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia dMale genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), empagliflozin 10 mg (N=556), empagliflozin 25 mg (N=557). Number (%) of Patients Placebo N=995 Empagliflozin 10 mg N=999 Empagliflozin 25 mg N=977 Urinary tract infectiona 7.6% 9.3% 7.6% Female genital mycotic infectionsb 1.5% 5.4% 6.4% Upper respiratory tract infection 3.8% 3.1% 4.0% Increased urinationc 1.0% 3.4% 3.2% Dyslipidemia 3.4% 3.9% 2.9% Arthralgia 2.2% 2.4% 2.3% Male genital mycotic infectionsd 0.4% 3.1% 1.6% Nausea 1.4% 2.3% 1.1% Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Volume Depletion Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactions related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Empagliflozin may increase the risk of hypotension in patients at risk for volume contraction [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)]. Increased Urination In the pool of five placebo-controlled clinical trials, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on empagliflozin than on placebo (see Table 3). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Acute Impairment in Renal Function Treatment with empagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 3). Patients with moderate renal impairment at baseline had larger mean changes [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5, 8.6)]. In a long-term cardiovascular outcome trial, the acute impairment in renal function was observed to reverse after treatment discontinuation suggesting acute hemodynamic changes play a role in the renal function changes observed with empagliflozin. Table 3 Changes from Baseline in Serum Creatinine and eGFRa in the Pool of Four 24-week Placebo-Controlled Studies and Renal Impairment Study aObserved cases on treatment. bSubset of patients from renal impairment study with eGFR 30 to less than 60 mL/min/1.73 m2. cApproximately 3 weeks after end of treatment. Pool of 24-Week Placebo-Controlled Studies Placebo Empagliflozin 10 mg Empagliflozin 25 mg Baseline Mean N 825 830 822 Creatinine (mg/dL) 0.84 0.85 0.85 eGFR (mL/min/1.73 m2) 87.3 87.1 87.8 Week 12 Change N 771 797 783 Creatinine (mg/dL) 0.00 0.02 0.01 eGFR (mL/min/1.73 m2) -0.3 -1.3 -1.4 Week 24 Change N 708 769 754 Creatinine (mg/dL) 0.00 0.01 0.01 eGFR (mL/min/1.73 m2) -0.3 -0.6 -1.4 Moderate Renal Impairmentb Placebo Empagliflozin 25 mg Baseline Mean N 187 -- 187 Creatinine (mg/dL) 1.49 -- 1.46 eGFR (mL/min/1.73 m2) 44.3 -- 45.4 Week 12 Change N 176 -- 179 Creatinine (mg/dL) 0.01 -- 0.12 eGFR (mL/min/1.73 m2) 0.1 -- -3.8 Week 24 Change N 170 -- 171 Creatinine (mg/dL) 0.01 -- 0.10 eGFR (mL/min/1.73 m2) 0.2 -- -3.2 Week 52 Change N 164 -- 162 Creatinine (mg/dL) 0.02 -- 0.11 eGFR (mL/min/1.73 m2) -0.3 -- -2.8 Post-treatment Changec N 98 -- 103 Creatinine (mg/dL) 0.03 -- 0.02 eGFR (mL/min/1.73 m2) 0.16 -- 1.48 Hypoglycemia The incidence of hypoglycemia by study is shown in Table 4. The incidence of hypoglycemia increased when empagliflozin was administered with insulin or sulfonylurea [see Warnings and Precautions (5.6)]. Table 4 Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL bSevere hypoglycemic events: requiring assistance regardless of blood glucose cTreated set (patients who had received at least one dose of study drug) dInsulin dose could not be adjusted during the initial 18 week treatment period Monotherapy (24 weeks) Placebo (n=229) Empagliflozin 10 mg (n=224) Empagliflozin 25 mg (n=223) Overall (%) 0.4% 0.4% 0.4% Severe (%) 0% 0% 0% In Combination with Metformin (24 weeks) Placebo + Metformin (n=206) Empagliflozin 10 mg + Metformin (n=217) Empagliflozin 25 mg + Metformin (n=214) Overall (%) 0.5% 1.8% 1.4% Severe (%) 0% 0% 0% In Combination with Metformin + Sulfonylurea (24 weeks) Placebo (n=225) Empagliflozin 10 mg + Metformin + Sulfonylurea (n=224) Empagliflozin 25 mg + Metformin + Sulfonylurea (n=217) Overall (%) 8.4% 16.1% 11.5% Severe (%) 0% 0% 0% In Combination with Pioglitazone +/- Metformin (24 weeks) Placebo (n=165) Empagliflozin 10 mg + Pioglitazone +/- Metformin (n=165) Empagliflozin 25 mg + Pioglitazone +/- Metformin (n=168) Overall (%) 1.8% 1.2% 2.4% Severe (%) 0% 0% 0% In Combination with Basal Insulin +/- Metformin (18 weeksd) Placebo (n=170) Empagliflozin 10 mg (n=169) Empagliflozin 25 mg (n=155) Overall (%) 20.6% 19.5% 28.4% Severe (%) 0% 0% 1.3% In Combination with MDI Insulin +/- Metformin (18 weeksd) Placebo (n=188) Empagliflozin 10 mg (n=186) Empagliflozin 25 mg (n=189) Overall (%) 37.2% 39.8% 41.3% Severe (%) 0.5% 0.5% 0.5% Genital Mycotic Infections In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with empagliflozin compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either empagliflozin 10 or 25 mg. Genital mycotic infections occurred more frequently in female than male patients (see Table 2). Phimosis occurred more frequently in male patients treated with empagliflozin 10 mg (less than 0.1%) and empagliflozin 25 mg (0.1%) than placebo (0%). Urinary Tract Infections In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with empagliflozin compared to placebo (see Table 2). Patients with a history of chronic or recurrent urinary tract infections were more likely to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Warnings and Precautions (5.5) and Use in Specific Populations (8.5)]. Metformin hydrochloride The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs 4.9%), diarrhea (12.5% vs 5.6%), and nausea (6.7% vs 4.2%). Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions (5.8)]. Laboratory Tests Empagliflozin Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions (5.9)]. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups. Increase in Hematocrit: In a pool of four placebo-controlled studies, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Metformin hydrochloride In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation [see Warnings and Precautions (5.8)]. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of empagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Ketoacidosis [see Warnings and Precautions (5.3)] Urosepsis and pyelonephritis [see Warnings and Precautions (5.5)]

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Individualize the starting dose of SYNJARDY XR based on the patient’s current regimen (2.1) The maximum recommended total daily dose is 25 mg empagliflozin and 2000 mg metformin (2.1) Take once daily with a meal in the morning, with gradual dose escalation to reduce the gastrointestinal side effects due to metformin (2.1) Swallow whole; do not split, crush, dissolve, or chew (2.1) Assess renal function before initiating. SYNJARDY XR is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 (2.2, 4) SYNJARDY XR 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 XR [see Warnings and Precautions (5.2)]. Individualize the starting dose of SYNJARDY XR based on the patient’s current regimen: -In patients on metformin, switch to SYNJARDY XR containing a similar total daily dose of metformin and a total daily dose of empagliflozin 10 mg; -In patients on empagliflozin, switch to SYNJARDY XR containing the same total daily dose of empagliflozin and a total daily dose of metformin extended-release 1000 mg; -In patients already treated with empagliflozin and metformin, switch to SYNJARDY XR containing the same total daily doses of empagliflozin and a similar total daily dose of metformin. Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of metformin 2000 mg and empagliflozin 25 mg [see Dosage and Administration (2.2)] . The dose of metformin should be gradually escalated to reduce the gastrointestinal side effects due to metformin [see Dosage Forms and Strengths (3)]. Take SYNJARDY XR orally once daily with a meal in the morning Swallow SYNJARDY XR tablets whole. Do not split, crush, dissolve, or chew before swallowing. There have been reports of incompletely dissolved tablets being eliminated in the feces for other tablets containing metformin extended-release. If a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control. SYNJARDY XR 10 mg/1000 mg and 25 mg/1000 mg tablets should be taken as a single tablet once daily. SYNJARDY XR 5 mg/1000 mg and 12.5 mg/1000 mg tablets should be taken as two tablets together once daily. 2.2 Recommended Dosage in Patients with Renal Impairment Assess renal function prior to initiation of SYNJARDY XR and periodically, thereafter. SYNJARDY XR is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.4)]. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue SYNJARDY XR 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 m2; 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 XR if renal function is stable [see Warnings and Precautions (5.1)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters. (8.1) Lactation: SYNJARDY XR is not recommended when breastfeeding. (8.2) Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3). Geriatric patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function. Assess renal function more frequently (5.2, 5.4, 8.5) Patients with renal impairment: Higher incidence of adverse reactions related to reduced renal function (2.2, 5.4, 8.6) Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) 8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, SYNJARDY XR is not recommended during the second and third trimesters of pregnancy. Limited available data with 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, 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, still birth, 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. 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/m2) for rats and rabbits, respectively. Empagliflozin and Metformin: No adverse developmental effects were observed when empagliflozin and metformin 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. 8.2 Lactation Risk Summary There is no information regarding the presence of SYNJARDY XR or empagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Empagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of SYNJARDY XR is not recommended while breastfeeding. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 -5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of SYNJARDY XR in pediatric patients under 18 years of age have not been established. 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 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)]. 8.6 Renal Impairment SYNJARDY XR is contraindicated in patients with moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2). Empagliflozin The efficacy and safety of empagliflozin have not been established in patients with severe renal impairment, with ESRD, or receiving dialysis. Empagliflozin is not expected to be effective in these patient populations [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2)]. The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment [see Warnings and Precautions (5.4)], volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function. Empagliflozin may be used in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2 [see Clinical Pharmacology (12.3)]. Empagliflozin is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2. Metformin hydrochloride Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. SYNJARDY XR is contraindicated in moderate to severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)]. 8.7 Hepatic Impairment SYNJARDY XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions (5.1)]. Empagliflozin Empagliflozin may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Metformin hydrochloride Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].
Pregnancy and lactation
8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

Interactions

7 DRUG INTERACTIONS 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 XR 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 XR, 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 XR, 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 XR.

More information

Category Value
Authorisation number NDA208658
Agency product number HDC1R2M35U
Orphan designation No
Product NDC 0597-0300,0597-0280,0597-0290,0597-0295
Date Last Revised 06-12-2016
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Boehringer Ingelheim Pharmaceuticals, Inc.
Warnings 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 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 XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)