SYNJARDY®

SYNJARDY tablets for oral use contain: empagliflozin and metformin hydrochloride.

Empagliflozin

Empagliflozin is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2).

The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3furanyl]oxy]phenyl]methyl]phenyl]-, (1S).

Its molecular formula is C₂₃H₂₇ClO₇ and the molecular weight is 450.91.

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.

Metformin hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a biguanide. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

SYNJARDY

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

Each film-coated tablet of SYNJARDY contains the following inactive ingredients: copovidone, corn starch, colloidal silicon dioxide, magnesium stearate. Film-coating: hypromellose, titanium dioxide, talc, polyethylene glycol 400, and yellow ferric oxide (5 mg/500 mg, 5 mg/1000 mg) or red ferric oxide and black ferrosoferric oxide (12.5 mg/500 mg, 12.5 mg/1000 mg).

SYNJARDY® (empagliflozin and metformin hydrochloride tablets)

INDICATIONS AND USAGE

SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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

Limitation of Use

SYNJARDY is not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.

Mechanism of Action

SYNJARDY

SYNJARDY contains: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a biguanide.

Empagliflozin

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

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) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

DOSAGE AND ADMINISTRATION

Prior to Initiation of SYNJARDY

Assess renal function before initiating SYNJARDY and as clinically indicated.
In patients with volume depletion, correct this condition before initiating SYNJARDY.

Recommended Dosage and Administration

Individualize the starting dose of SYNJARDY based on the patient’s current regimen:

In patients on metformin HCl, switch to SYNJARDY containing empagliflozin 5 mg with a similar total daily dose of metformin HCl;
- In patients on empagliflozin, switch to SYNJARDY containing metformin HCl 500 mg with a similar total daily dose of empagliflozin;
- In patients already treated with empagliflozin and metformin HCl, switch to SYNJARDY containing the same total daily doses of each component.

Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dose of empagliflozin 25 mg and metformin HCl 2000 mg.

Take SYNJARDY twice daily with meals; with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.

Dosage Recommendations in Patients with Renal Impairment

Initiation of SYNJARDY is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin component.
SYNJARDY is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²or in patients on dialysis.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue SYNJARDY at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR 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 if renal function is stable.

CONTRAINDICATIONS

SYNJARDY is contraindicated in patients with:

Severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage renal disease, or dialysis.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
Hypersensitivity to empagliflozin, metformin or any of the excipients in SYNJARDY, reactions such as angioedema have occurred.

WARNINGS AND PRECAUTIONS

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.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue SYNJARDY and report these symptoms to their healthcare provider.

Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. SYNJARDY is not indicated for the treatment of patients with type 1 diabetes mellitus.

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

For patients who undergo scheduled surgery, consider temporarily discontinuing SYNJARDY for at least 3 days prior to surgery.

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

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

Volume Depletion: Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. 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 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. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

Urosepsis and Pyelonephritis: There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

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

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 presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue SYNJARDY, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Genital Mycotic Infections: Empagliflozin increases the risk for genital mycotic infections. Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate.

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; treat promptly per standard of care, and monitor until signs and symptoms resolve. SYNJARDY is contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in SYNJARDY.

Vitamin B12 Deficiency: In metformin 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 and manage any abnormalities

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with SYNJARDY may increase the risk of lactic acidosis.

Consider more frequent monitoring of these patients.

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.

Consider the benefits and risks of concomitant use.

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

Warn patients against excessive alcohol intake while receiving SYNJARDY.

Diuretics: Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.

Before initiating SYNJARDY, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SYNJARDY. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.

Insulin or Insulin Secretagogues: The risk of hypoglycemia is increased when SYNJARDY is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.

Coadministration of SYNJARDY with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

When such drugs are administered to a patient receiving SYNJARDY, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving SYNJARDY, the patient should be observed closely for hypoglycemia.

Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Monitor serum lithium concentration more frequently during SYNJARDY initiation and dosage changes.

Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

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

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

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data showing adverse renal effects from empagliflozin, SYNJARDY is not recommended during the second and third trimesters of pregnancy.

The limited available data with SYNJARDY or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

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.

Lactation: There is limited information regarding the presence of SYNJARDY or its components (empagliflozin or metformin) 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. Empagliflozin is present in the milk of lactating rats. 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, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of SYNJARDY is not recommended while breastfeeding.

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.

Pediatric Use: Safety and effectiveness of SYNJARDY have not been established in pediatric patients.

Geriatric Use: Assess renal function more frequently in SYNJARDY-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.

The recommended dosage for the metformin component of SYNJARDY in geriatric patients should usually start at the lower end of the dosage range.

Hepatic Impairment: Use of metformin hydrochloride in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY is not recommended in patients with hepatic impairment.

OVERDOSAGE

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

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 case. 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.

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SYNJARDY® (empagliflozin and metformin hydrochloride tablets)

SYNJARDY®