^ 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:
^ 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.
^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)].
^ Empagliflozin Chronic Kidney Disease Trial, Including Adult Patients With Type 2 Diabetes Mellitus
The effectiveness of empagliflozin, a component of SYNJARDY and SYNJARDY XR, to reduce the risk of sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization has been established in adults with chronic kidney disease at risk of progression based on an adequate and well-controlled study of empagliflozin [EMPA-KIDNEY (NCT03594110)]. This trial was designed to determine the treatment effect of empagliflozin compared to placebo in adults with CKD (with and without type 2 diabetes). The trial, which studied empagliflozin rather than SYNJARDY or SYNJARDY XR, included adults taking metformin HCl as a concomitant medication. The efficacy results of EMPA-KIDNEY are reported below.
EMPA-KIDNEY was a randomized, double-blind, placebo-controlled trial conducted in adults with chronic kidney disease [eGFR ≥20 to <45 mL/min/1.73 m2; or eGFR ≥45 to <90 mL/min/1.73 m2 with urine albumin to creatinine ratio (UACR) ≥200 mg/g]. The trial excluded patients with polycystic kidney disease or patients requiring intravenous immunosuppressive therapy in the preceding three months or >45 mg of prednisone (or equivalent) at the time of screening. The primary objective of the trial was to assess the effects of empagliflozin as an adjunct to standard of care therapy, including RAS-inhibitor therapy when appropriate, on time to kidney disease progression or CV death. A total of 6,609 patients, were equally randomized to empagliflozin 10 mg orally once-daily or placebo and were followed for a median of 24 months.
^ 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 with empagliflozin, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. 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.
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.
^ 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.
^ Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
^ Description
SYNJARDY and SYNJARDY XR tablets for oral use contain: empagliflozin and metformin HCl.
^ Empagliflozin Cv Outcome Trial In Adult Patients With Type 2 Diabetes Mellitus And Atherosclerotic Cv Disease
EMPA-REG OUTCOME was a multicenter, multinational, randomized, double-blind parallel group trial that compared the risk of experiencing a major adverse CV event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes mellitus and atherosclerotic 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 m2. At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin HCl (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.
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).
^ 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 m2), 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.
^ 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.
^ Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of concomitantly administered empagliflozin (daily dosage 10 mg or 25 mg) and metformin HCl (mean daily dosage of approximately 1,800 mg) has been evaluated in 3,456 adult patients with type 2 diabetes mellitus treated for 16 to 24 weeks, of which 926 patients received placebo, 1,271 patients received a daily dosage of empagliflozin 10 mg, and 1,259 patients received a daily dosage of empagliflozin 25 mg. Discontinuation of therapy due to adverse events across treatment groups was 3.0%, 2.8%, and 2.9% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.
^ Hepatic Impairment
Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY and SYNJARDY XR are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].
^ Overdosage
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.
^ 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)].
^ Recommended Dosage And Administration Of Synjardy Or Synjardy Xr In Adults
^ Renal Impairment
SYNJARDY or SYNJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2 due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).
^ Recommended Dosage And Administration Of Synjardy In Pediatric Patients Aged Years And Older
^4 Contraindications
SYNJARDY and SYNJARDY XR are contraindicated in patients with:
^ Postmarketing Experience
Additional adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
^ How Supplied/storage And Handling
SYNJARDY tablets are available as follows:
SYNJARDY XR extended-release tablets are available as follows:
^ Dosage Recommendations In Patients With Renal Impairment
^ 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 Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.3)].
The recommended dosage for the metformin HCl component of SYNJARDY or SYNJARDY XR in geriatric patients should usually start at the lower end of the dosage range.
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
NDC 0597-0180-60
DISPENSE WITH ACCOMPANYINGMEDICATION GUIDE
Synjardy® (empagliflozin and metformin hydrochloride tablets)
12.5 mg/500 mg*
Rx only
60 tablets
Boehringer Ingelheim
Lilly
^ Testing Prior To Initiation Of Synjardy Or Synjardy Xr
^ Vitamin B Deficiency
In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on SYNJARDY or SYNJARDY XR and manage any abnormalities [see Adverse Reactions (6.1)].
^Principal Display Panel - Mg/1, Mg Tablet Bottle Label
NDC 0597-0168-60
DISPENSE WITH ACCOMPANYING MEDICATION GUIDE
Synjardy® (empagliflozin and metformin hydrochloride tablets)
12.5 mg/1,000 mg*
Rx only
60 tablets
Boehringer Ingelheim
Lilly
^ 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)].
^ 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.
^Principal Display Panel - 5 Mg/1, Mg Tablet Bottle Label
NDC 0597-0175-60
DISPENSE WITH ACCOMPANYING MEDICATION GUIDE
Synjardy® (empagliflozin and metformin hydrochloride tablets)
5 mg/1,000 mg*
Rx only
60 tablets
Boehringer Ingelheim
Lilly
^ Glycemic Control Trials In Adults With Type 2 Diabetes Mellitus
In adult patients with type 2 diabetes mellitus, treatment with empagliflozin and metformin HCl produced clinically and statistically significant improvements in HbA1c compared to placebo and metformin HCl. Reductions in HbA1c were observed across subgroups including age, sex, race, and baseline BMI.
^Principal Display Panel - 5 Mg/ Mg Tablet Bottle Label
NDC 0597-0159-60
DISPENSE WITH ACCOMPANYING MEDICATION GUIDE
Synjardy® (empagliflozin and metformin hydrochloride tablets)
5 mg/500 mg*
Rx only
60 tablets
Boehringer Ingelheim
Lilly
^ Females And Males Of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
^ Temporary Interruption For Surgery
Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
^6 Adverse Reactions
The following important adverse reactions are described below and elsewhere in the labeling:
^7 Drug Interactions
See Table 4 for clinically relevant interactions with SYNJARDY or SYNJARDY XR.
^ 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 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 or SYNJARDY XR if renal function is stable [see Warnings and Precautions (5.1)].
^ Recommendations Regarding Missed Dose