Synjardy XR

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 5/18/2022
Drug Description

What is Synjardy XR and how is it used?

Synjardy XR is a prescription medicine used to treat the symptoms of Type 2 Diabetes Mellitus. Synjardy XR may be used alone or with other medications.

Synjardy XR belongs to a class of drugs called Antidiabetics, Biguanides; Antidiabetics, SGLT2 Inhibitors.

It is not known if Synjardy XR is safe and effective in children younger than 18 years of age.

What are the possible side effects of Synjardy XR?

Synjardy XR may cause serious side effects including:

  • hives,
  • difficulty breathing,
  • swelling of your face, lips, tongue, or throat,
  • burning, itching, odor, discharge, pain, tenderness, redness or swelling of the genital or rectal area,
  • fever,
  • feeling unwell,
  • little or no urination,
  • dizziness,
  • weakness,
  • lightheadedness,
  • nausea,
  • vomiting,
  • stomach pain,
  • confusion,
  • unusual drowsiness,
  • unusual muscle pain,
  • trouble breathing,
  • stomach pain,
  • irregular heart rate,
  • feeling cold,
  • tiredness,
  • pain or burning when you urination,
  • increased urination,
  • blood in your urine, and
  • pain in your pelvis or back

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Synjardy XR include:

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Synjardy XR. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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].

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, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and Use In Specific Populations].

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].

DESCRIPTION

SYNJARDY XR (empagliflozin and metformin hydrochloride extended-release) tablets, for oral use, contain two antihyperglycemic drugs used in the management of type 2 diabetes: empagliflozin and metformin hydrochloride.

Empagliflozin

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

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

Its molecular formula is C23H27ClO7 and the molecular weight is 450.91. The structural formula is:

Empagliflozin - Structural Formula Illustration

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 not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. 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. The structural formula is:

Metformin hydrochloride  - Structural Formula Illustration

Each film-coated tablet of SYNJARDY XR consists of an extended-release metformin hydrochloride 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 1000 mg metformin hydrochloride extended-release
  • 10 mg empagliflozin and 1000 mg metformin hydrochloride extended-release
  • 12.5 mg empagliflozin and 1000 mg metformin hydrochloride extended-release
  • 25 mg empagliflozin and 1000 mg metformin hydrochloride extended-release

Each film-coated tablet of SYNJARDY XR contains the following inactive ingredients: Tablet Core: polyethylene oxide, hypromellose, and magnesium stearate. Film Coatings and Printing Ink: hypromellose, titanium dioxide, polydextrose, polyethylene glycol, talc, carnauba wax, purified water, ferrosoferric oxide, propylene glycol, isopropyl alcohol, ferric oxide yellow (5 mg/1000 mg, 10 mg/1000 mg, 25 mg/1000 mg), ferric oxide red (10 mg/1000 mg), FD&C blue#2/indigo carmine aluminum lake (12.5 mg/1000 mg, 25 mg/1000 mg).

Indications & Dosage

INDICATIONS

SYNJARDY XR 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 [see Clinical Studies].

Limitation Of Use

SYNJARDY XR is not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see WARNINGS AND PRECAUTIONS].

DOSAGE AND ADMINISTRATION

Prior To Initiation Of SYNJARDY XR

  • Assess renal function before initiating SYNJARDY XR and as clinically indicated [see WARNINGS AND PRECAUTIONS].
  • In patients with volume depletion, correct this condition before initiating SYNJARDY XR [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Recommended Dosage And Administration

  • Individualize the starting dose of SYNJARDY XR based on the patient’s current regimen:
    • In patients on metformin HCl, switch to SYNJARDY XR containing a similar total daily dose of metformin HCl 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 HCl extended-release 1000 mg;
    • In patients already treated with empagliflozin and metformin HCl, switch to SYNJARDY XR containing the same total daily doses of empagliflozin and a similar total daily dose of metformin HCl.
  • 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.
  • The dose of metformin HCl should be gradually escalated to reduce the gastrointestinal side effects due to metformin.
  • Take SYNJARDY XR orally once daily with a meal in the morning
  • Swallow SYNJARDY XR tablets whole. Do not split, crush, dissolve, or chew.
  • 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.

Dosage Recommendations In Patients With Renal Impairment

  • Initiation of SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m², due to the metformin component.
  • SYNJARDY XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² or in patients on dialysis [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and Use In Specific Populations].

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 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 XR if renal function is stable [see WARNINGS AND PRECAUTIONS].

HOW SUPPLIED

Dosage Forms And Strengths

SYNJARDY XR Tablets:

Empagliflozin Strength Metformin HCl Strength Color/Shape Tablet Markings
5 mg 1000 mg olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo and “S5” on the top line and “1000 M” on the bottom line.
10 mg 1000 mg orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo and “S10” on the top line and “1000 M” on the bottom line.
12.5 mg 1000 mg blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo and “S12” on the top line and “1000 M” on the bottom line.
25 mg 1000 mg light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo and “S25” on the top line and “1000 M” on the bottom line.

Storage And Handling

SYNJARDY XR tablets are available as follows:

Tablet Strength Color/Shape Tablet Markings Package Size NDC Number
5 mg Empagliflozin 1000 mg Metformin HCl olive green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo 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 1000 mg Metformin HCl orange, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo 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 1000 mg Metformin HCl blue, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo 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 1000 mg Metformin HCl light green, oval, biconvex, film-coated tablet Printed on one side in black ink with the Boehringer Ingelheim company logo 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].

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USA. Revised: Jun 2021

QUESTION

______________ is another term for type 2 diabetes. See Answer
Side Effects

SIDE EFFECTS

The following important adverse reactions are described below and elsewhere in the labeling:

  • Lactic Acidosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
  • Ketoacidosis [see WARNINGS AND PRECAUTIONS]
  • Volume Depletion [see WARNINGS AND PRECAUTIONS]
  • Urosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS]
  • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see WARNINGS AND PRECAUTIONS]
  • Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see WARNINGS AND PRECAUTIONS]
  • Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Vitamin B12 Deficiency [see WARNINGS AND PRECAUTIONS]

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 hydrochloride (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

Adverse Reactions Placebo (%)
n=225
Empagliflozin 10 mg (%)
n=224
Empagliflozin 25 mg (%)
n=217
Hypoglycemia 9.8 15.6 12.9
Urinary tract infection 6.7 9.4 6.9
Nasopharyngitis 4.9 8.0 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].

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

Adverse Reactions 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
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).

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 Use In Specific Populations].

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 2). 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.

Hypoglycemia

The incidence of hypoglycemia by study is shown in Table 3. The incidence of hypoglycemia increased when empagliflozin was administered with insulin or sulfonylurea.

Table 3 : Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc

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
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

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 Use In Specific Populations].

Metformin

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%).

Laboratory Tests

Empagliflozin

Increases In Serum Creatinine And Decreases In eGFR

Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m², respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with 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. 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

Decrease In Vitamin B12

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 patients.

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.

Empagliflozin
  • Ketoacidosis
  • Urosepsis and Pyelonephritis
  • Necrotizing Fasciitis of the Perineum (Fournier's gangrene)
  • Angioedema
  • Acute Kidney Injury
  • Skin Reactions (e.g., rash, urticaria)
Metformin Hydrochloride
  • Cholestatic, hepatocellular, and mixed hepatocellular liver injury
Drug Interactions

DRUG INTERACTIONS

Table 4 : Clinically Relevant Interactions with 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.
Intervention Concomitant use of these drugs with SYNJARDY XR may increase the risk of lactic acidosis. 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].
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 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 XR, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating 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 empagliflozin is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin. Metformin may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue.
Intervention Coadministration of SYNJARDY XR 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
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 XR, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving SYNJARDY XR, the patient should be observed closely for hypoglycemia.
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.

Overdosage & Contraindications

OVERDOSE

In the event of an overdose with SYNJARDY XR, 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 cases [see WARNINGS AND PRECAUTIONS]. 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.

CONTRAINDICATIONS

SYNJARDY XR is contraindicated in patients with:

  • Severe renal impairment (eGFR less than 30 mL/min/1.73 m²), end stage renal disease, or dialysis [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see WARNINGS AND PRECAUTIONS].
  • Hypersensitivity to empagliflozin, metformin or any of the excipients in SYNJARDY XR, reactions such as angioedema have occurred [see WARNINGS AND PRECAUTIONS].
Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

SYNJARDY XR

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

Empagliflozin

Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Metformin 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] 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.

Pharmacodynamics

Empagliflozin

Urinary Glucose Excretion

In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily [see Clinical Studies]. Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg and 25 mg doses.

Urinary Volume

In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment.

Cardiac Electrophysiology

In a randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered a single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

Pharmacokinetics

SYNJARDY XR

Administration of SYNJARDY XR with food resulted in no change in overall exposure of empagliflozin. For metformin hydrochloride extended-release high-fat meals increased systemic exposure to metformin (as measured by area-under-the-curve [AUC]) by approximately 70% relative to fasting, while Cmax is not affected. Meals prolonged Tmax by approximately 3 hours.

Empagliflozin

Absorption

The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady-state mean plasma AUC and Cmax were 1870 nmol•h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmol•h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.

Distribution

The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.

Elimination

The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life.

Metabolism

No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.

Excretion

Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.

Metformin Hydrochloride

Absorption

Following a single oral dose of 1000 mg (2 x 500 mg tablets) metformin hydrochloride extended-release after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7 to 8 hours. In both single-and multiple-dose studies in healthy subjects, once daily 1000 mg (2 x 500 mg tablets) dosing provides equivalent systemic exposure, as measured by AUC, and up to 35% higher Cmax of metformin relative to the immediate-release given as 500 mg twice daily.

Single oral doses of metformin hydrochloride extended-release from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and Cmax. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not affected.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Elimination

Metformin has a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Metabolism

Intravenous single-dose studies in normal subjects demonstrate that metformin does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion

Following oral administration, approximately 90% of the absorbed drug is excreted via the renal route within the first 24 hours. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination.

Specific Populations

Renal Impairment

SYNJARDY XR

Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of SYNJARDY XR in renally impaired patients have not been performed.

Empagliflozin

In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m²), moderate (eGFR: 30 to less than 60 mL/min/1.73 m²), and severe (eGFR: less than 30 mL/min/1.73 m²) renal impairment and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and kidney failure/ESRD compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.

Metformin hydrochloride

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Hepatic Impairment

SYNJARDY XR

Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of SYNJARDY XR in hepatically impaired patients have not been performed [see WARNINGS AND PRECAUTIONS].

Empagliflozin

In patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Effects Of Age, Body Mass Index, Gender, And Race

Empagliflozin

Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin [see Use In Specific Populations].

Metformin Hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin HCl in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Caucasians (n=249), Blacks (n=51), and Hispanics (n=24).

Geriatric

SYNJARDY XR

Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of SYNJARDY XR in geriatric patients have not been performed [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Empagliflozin

Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on a population pharmacokinetic analysis [see Use In Specific Populations].

Metformin Hydrochloride

Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Drug Interactions

Pharmacokinetic drug interaction studies with SYNJARDY XR have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin HCl.

Empagliflozin

In vitro Assessment Of Drug Interactions

Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated.

Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.

In vivo Assessment Of Drug Interactions

Empagliflozin pharmacokinetics were similar with and without coadministration of metformin hydrochloride, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes (see Figure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown.

Figure 1 : Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% -125%)]

Effect of Various Medications on the
Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of
Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% -125%)] - Illustration

aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin, 10 mg, single dose

Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered with empagliflozin (see Figure 2).

Figure 2 : Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% -125%)]

Effect of Empagliflozin on the
Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval
of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80%
-125%)] - Illustration

aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon®; gadministered as ramipril

Metformin Hydrochloride

Table 5 : Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug Dosing of Coadministered Drug* Dose of Metformin hydrochloride* Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.0
AUC† Cmax
Glyburide mg 5 500 mg≠ metformin 0.98‡ 0.99‡
Furosemide 40 mg 850 mg metformin 1.09‡ 1.22‡
Nifedipine 10 mg 850 mg metformin 1.16 1.21
Propranolol 40 mg 850 mg metformin 0.90 0.94
Ibuprofen 400 mg 850 mg metformin 1.05‡ 1.07‡
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [see DRUG INTERACTIONS].
Cimetidine 400 mg 850 mg metformin 1.40 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [see DRUG INTERACTIONS].
Topiramate** 100 mg 500 mg metformin 1.25 1.17
* All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF) ≠ Metformin hydrochloride extended-release tablets 500 mg
‡ Ratio of arithmetic means
**At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC(0-12hours)

Table 6 : Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered Drug Dosing of Coadministered Drug* Dose of Metformin hydrochloride* Geometric Mean Ratio (ratio with/without metformin) No effect=1.0
AUC† Cmax
Glyburide 5 mg 500 mg§ glyburide 0.78‡ 0.63‡
Furosemide 40 mg 850 mg furosemide 0.87‡ 0.69‡
Nifedipine 10 mg 850 mg nifedipine 1.10§ 1.08
Propranolol 40 mg 850 mg propranolol 1.01§ 0.94
Ibuprofen 400 mg 850 mg ibuprofen 0.97¶ 1.01¶
Cimetidine 400 mg 850 mg cimetidine 0.95§ 1.01
* All metformin and coadministered drugs were given as single doses
† AUC = AUC(INF) unless otherwise noted
§ AUC(0-24 hours) reported
‡ Ratio of arithmetic means, p-value of difference <0.05
¶ Ratio of arithmetic means

Clinical Studies

SYNJARDY XR Glycemic Control Studies

In patients with type 2 diabetes, treatment with empagliflozin and metformin produced clinically and statistically significant improvements in HbA1c compared to placebo. Reductions in HbA1c were observed across subgroups including age, gender, race, and baseline body mass index (BMI).

Empagliflozin Add-On Combination Therapy With Metformin

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

Patients with type 2 diabetes inadequately controlled on at least 1500 mg of metformin hydrochloride per day entered an open-label 2-week placebo run-in. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

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

Table 7 : Results at Week 24 From a Placebo-Controlled Study for Empagliflozin used in Combination with Metformin

Empagliflozin 10 mg + Metformin
N=217
Empagliflozin 25 mg + Metformin
N=213
Placebo + Metformin
N=207
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) -0.6b
(-0.7, -0.4)
-0.6b
(-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) -2.0b
(-2.6, -1.4)
-2.5b
(-3.1, -1.9)
-
aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
bANCOVA 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.)
cFPG (mg/dL); for empagliflozin 10 mg, n=216, for empagliflozin 25 mg, n=213, and for placebo, n=207

At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for empagliflozin 25 mg.

Empagliflozin Initial Combination Therapy With Metformin

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

Treatment-naïve patients with inadequately controlled type 2 diabetes entered an open-label placebo run-in for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10.5% were randomized to one of 8 active-treatment arms: empagliflozin 10 mg or 25 mg; metformin hydrochloride 1000 mg, or 2000 mg; empagliflozin 10 mg in combination with 1000 mg or 2000 mg metformin; or empagliflozin 25 mg in combination with 1000 mg or 2000 mg metformin hydrochloride.

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

Table 8 : Glycemic Parameters at 24 Weeks in a Study Comparing Empagliflozin and Metformin to the Individual Components as Initial Therapy

Empagliflozin 10 mg + Metformin 1000 mga
N=161
Empagliflozin 10 mg + Metformin 2000 mga
N=167
Empagliflozin 25 mg + Metformin 1000 mga
N=165
Empagliflozin 25 mg + Metformin 2000 mga
N=169
Empagliflozin 10 mg
N=169
Empagliflozin 25 mg
N=163
Metformin 1000 mga
N=167
Metformin 2000 mga
N=162
HbAlc (%)
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) -0.6b
(-0.9, -0.4)
-0.7b
(-1.0, -0.5)
-0.6c
(-0.8, -0.3)
-0.7c
(-1.0, -0.5)
-- -- -- --
Comparison vs metformin (adjusted mean) (95% CI) -0.8b
(-1.0, -0.6)
-0.3b
(-0.6, -0.1)
-0.8c
(-1.0, -0.5)
-0.3c
(-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%)
aMetformin hydrochloride total daily dose, administered in two equally divided doses per day.
bp-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).
cp-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).

Empagliflozin Add-On Combination Therapy With Metformin And Sulfonylurea

A total of 666 patients with type 2 diabetes participated in a double-blind, placebo-controlled study to evaluate the efficacy and safety of empagliflozin in combination with metformin plus a sulfonylurea.

Patients with inadequately controlled type 2 diabetes on at least 1500 mg per day of metformin hydrochloride and on a sulfonylurea, entered a 2-week open-label placebo run-in. At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, empagliflozin 10 mg, or empagliflozin 25 mg.

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

Table 9 : Results at Week 24 from a Placebo-Controlled Study for Empagliflozin in Combination with Metformin and Sulfonylurea

Empagliflozin 10 mg + Metformin + SU
N=225
Empagliflozin 25 mg + Metformin + SU
N=216
Placebo + Metformin + SU
N=225
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) -0.6b
(-0.8, -0.5)
-0.6b
(-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) -2.4b
(-3.0, -1.8)
-2.7b
(-3.3, -2.1)
--
aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.
bANCOVA 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.)
cFPG (mg/dL); for empagliflozin 10 mg, n=225, for empagliflozin 25 mg, n=215, for placebo, n=224

Active-Controlled Study vs Glimepiride In Combination With Metformin

The efficacy of empagliflozin was evaluated in a double-blind, glimepiride-controlled, study in 1545 patients with type 2 diabetes with insufficient glycemic control despite metformin therapy.

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

At Week 52, empagliflozin 25 mg and glimepiride lowered HbA1c and FPG (see Table 10, Figure 3). The difference in observed effect size between empagliflozin 25 mg and glimepiride excluded the pre-specified non-inferiority margin of 0.3%. The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is 8 mg per day.

Table 10 : Results at Week 52 from an Active-Controlled Study Comparing Empagliflozin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin

Empagliflozin 25 mg + Metformin
N=765
Glimepiride + Metformin
N=780
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) -0.07b
(-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) -5.9c (-6.3, -5.5) --
aModified intent to treat population. Last observation on study (LOCF) was used to impute data missing at Week 52. At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to empagliflozin 25 mg and glimepiride, respectively.
bNon-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region)
cANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.)
dFPG (mg/dL); for empagliflozin 25 mg, n=764, for glimepiride, n=779

Figure 3 : Adjusted mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT Population) –LOCF

Adjusted mean HbA1c Change at Each Time
Point (Completers) and at Week 52 (mITT Population) –LOCF - Illustration

At Week 52, the adjusted mean change from baseline in systolic blood pressure was -3.6 mmHg, compared to  2.2 mmHg for glimepiride. The differences between treatment groups for systolic blood pressure was statistically significant (p-value <0.0001).

At Week 104, the adjusted mean change from baseline in HbA1c was -0.75% for empagliflozin 25 mg and -0.66% for glimepiride. The adjusted mean treatment difference was -0.09% with a 97.5% confidence interval of (-0.32%, 0.15%), excluding the pre-specified non-inferiority margin of 0.3%. The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is 8 mg per day. The Week 104 analysis included data with and without concomitant glycemic rescue medication, as well as off-treatment data. Missing data for patients not providing any information at the visit were imputed based on the observed off-treatment data. In this multiple imputation analysis, 13.9% of the data were imputed for empagliflozin 25 mg and 12.9% for glimepiride.

At Week 104, empagliflozin 25 mg daily resulted in a statistically significant difference in change from baseline for body weight compared to glimepiride (-3.1 kg for empagliflozin 25 mg vs. +1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).

Empagliflozin Cardiovascular Outcome Study In Patients With Type 2 Diabetes Mellitus And Atherosclerotic Cardiovascular Disease

Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. The effect of empagliflozin on cardiovascular risk in adult patients with type 2 diabetes and established, stable, atherosclerotic cardiovascular disease is presented below.

The EMPA-REG OUTCOME study, a multicenter, multi-national, randomized, double-blind parallel group trial compared the risk of experiencing a major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. Coadministered antidiabetic medications were to be kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 7020 patients were treated (empagliflozin 10 mg = 2345; empagliflozin 25 mg = 2342; placebo = 2333) and followed for a median of 3.1 years. Approximately 72% of the study population was Caucasian, 22% was Asian, and 5% was Black. The mean age was 63 years and approximately 72% were male.

All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes for more than 10 years. Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators respectively and the mean eGFR was 74 mL/min/1.73 m². At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), and sulfonylurea (43%).

All patients had established atherosclerotic cardiovascular disease at baseline including one (82%) or more (18%) of the following: a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).

The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a cardiovascular death or a non-fatal myocardial infarction (MI) or a non-fatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.

Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI: 0.74, 0.99). The treatment effect was due to a significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin (HR: 0.62; 95% CI: 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 11 and Figures 4 and 5). Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.

Table 11 : Treatment Effect for the Primary Composite Endpoint, and its Componentsa

Placebo
N=2333
Empagliflozin
N=4687
Hazard ratio vs placebo (95% CI)
Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b 282 (12.1%) 490 (10.5%) 0.86
(0.74, 0.99)
Non-fatal myocardial infarctionc 121 (5.2%) 213 (4.5%) 0.87
(0.70, 1.09)
Non-fatal strokec 60 (2.6%) 150 (3.2%) 1.24
(0.92, 1.67)
Cardiovascular deathc 137 (5.9%) 172 (3.7%) 0.62
(0.49, 0.77)
aTreated set (patients who had received at least one dose of study drug)
bp-value for superiority (2-sided) 0.04
cTotal number of events

Figure 4 : Estimated Cumulative Incidence of First MACE

Estimated Cumulative Incidence of First MACE - Illustration

Figure 5 : Estimated Cumulative Incidence of Cardiovascular Death

Estimated
Cumulative Incidence of Cardiovascular Death - Illustration

The efficacy of empagliflozin on cardiovascular death was generally consistent across major demographic and disease subgroups.

Vital status was obtained for 99.2% of subjects in the trial. A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as cardiovascular deaths. The non-cardiovascular deaths were only a small proportion of deaths, and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).

Medication Guide

PATIENT INFORMATION

SYNJARDY® XR
(sin-JAR-dee XR)
(empagliflozin and metformin hydrochloride extended-release) Tablets

What is the most important information I should know about SYNJARDY XR?

Serious side effects can happen in people taking SYNJARDY XR, including:

Lactic Acidosis. Metformin, one of the medicines in SYNJARDY XR can cause a rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

  • you feel cold in your hands or feet
  • you feel dizzy or lightheaded
  • you have a slow or irregular heartbeat
  • you feel very weak or tired
  • you have unusual (not normal) muscle pain
  • you have trouble breathing
  • you feel sleepy or drowsy
  • you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with SYNJARDY XR if you:

  • have moderate to severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.
  • have liver problems
  • drink alcohol very often, or drink a lot of alcohol in the short-term (“binge” drinking)
  • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids.
  • have surgery
  • have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your SYNJARDY XR for a while if you have any of these things. SYNJARDY XR can have other serious side effects. See “What are the possible side effects of SYNJARDY XR?”

What is SYNJARDY XR?

  • SYNJARDY XR is a prescription medicine that contains 2 prescription diabetes medicines, empagliflozin and metformin. SYNJARDY XR can be used:
    • along with diet and exercise to improve blood sugar in adults with type 2 diabetes,
    • in adults with type 2 diabetes who have known cardiovascular disease when both empagliflozin and metformin is appropriate and empagliflozin is needed to reduce the risk of cardiovascular death.
  • SYNJARDY XR is not for people with type 1 diabetes.
  • SYNJARDY XR is not for people with diabetic ketoacidosis (increased ketones in the blood or urine).
  • It is not known if SYNJARDY XR is safe and effective in children under 18 years of age.

Who should not take SYNJARDY XR?

Do not take SYNJARDY XR if you:

  • have moderate to severe kidney problems or are on dialysis
  • have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine)
  • are allergic to empagliflozin, metformin, or any of the ingredients in SYNJARDY XR. See the end of this Medication Guide for a list of ingredients in SYNJARDY XR.

What should I tell my doctor before using SYNJARDY XR?

Before taking SYNJARDY XR, tell your healthcare provider about all of your medical conditions, including if you:

  • have moderate to severe kidney problems
  • have liver problems
  • have a history of urinary tract infection or problems with urination
  • have heart problems, including congestive heart failure
  • are going to have surgery
  • are eating less due to illness, surgery, or a change in your diet
  • have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas
  • drink alcohol very often, or drink a lot of alcohol in the short term (“binge” drinking)
  • are going to get an injection of dye or contrast agents for an x-ray procedure. SYNJARDY XR may need to be stopped for
  • a short time. Talk to your doctor about when you should stop SYNJARDY XR and when you should start SYNJARDY XR again. See “What is the most important information I should know about SYNJARDY XR?”
  • have type 1 diabetes. SYNJARDY XR should not be used to treat people with type 1 diabetes.
  • have any other medical conditions
  • are pregnant or plan to become pregnant. SYNJARDY XR may harm your unborn baby. If you become pregnant while taking SYNJARDY
  • XR, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.
  • are a premenopausal woman (before the “change of life”), who does not have periods regularly or at all. Talk to your doctor about birth control choices while taking SYNJARDY XR if you are not planning to become pregnant since SYNJARDY XR may increase your chance of becoming pregnant. Tell your doctor right away if you become pregnant while taking SYNJARDY XR.
  • are breastfeeding or plan to breastfeed. SYNJARDY XR may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking SYNJARDY XR. Do not breastfeed while taking SYNJARDY XR.

Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, or herbal supplements.

How should I take SYNJARDY XR?

  • Take SYNJARDY XR exactly as your doctor tells you to take it.
  • Take SYNJARDY XR by mouth 1 time each day with a meal in the morning. Taking SYNJARDY XR with a meal may lower your chance of having an upset stomach.
  • Take SYNJARDY XR tablets whole. Do not break, cut, crush, dissolve, or chew SYNJARDY XR tablets before swallowing. If you cannot swallow SYNJARDY XR tablets whole, tell your doctor.
  • You may see something that looks like the SYNJARDY XR tablet in your stool (bowel movement). If you see tablets in your stool talk to your doctor. Do not stop taking SYNJARDY XR without talking to your doctor.
  • Your doctor will tell you how much SYNJARDY XR to take and when to take it.
  • Your doctor may change your dose if needed.
  • If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of SYNJARDY XR at the same time. Talk with your doctor if you have questions about a missed dose.
  • Your doctor may tell you to take SYNJARDY XR along with other diabetes medicines. Low blood sugar can happen more often when SYNJARDY XR is taken with certain other diabetes medicines. See “What are the possible side effects of SYNJARDY XR?”
  • If you take too much SYNJARDY XR, call your doctor or go to the nearest hospital emergency room right away.
  • When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these conditions and follow your doctor's instructions.
  • Check your blood sugar as your doctor tells you to.
  • When taking SYNJARDY XR, you may have sugar in your urine, which will show up on a urine test.
  • Stay on your prescribed diet and exercise program while taking SYNJARDY XR.
  • Talk to your doctor about how to prevent, recognize and manage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and complications of diabetes.
  • Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.
  • Your doctor will do blood tests to check how well your kidneys are working before and during your treatment with SYNJARDY XR.
  • Your doctor may do certain blood tests before you start SYNJARDY XR and during treatment.

What should I avoid while taking SYNJARDY XR?

Avoid drinking alcohol very often, or drinking a lot of alcohol in a short period of time (“binge” drinking). It can increase your chances of getting serious side effects.

What are the possible side effects of SYNJARDY XR?

SYNJARDY XR may cause serious side effects, including:

  • See “What is the most important information I should know about SYNJARDY XR?”
  • Dehydration. SYNJARDY XR can cause some people to have dehydration (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension). You may be at higher risk of dehydration if you:
    • have low blood pressure
    • are on low sodium (salt) diet
    • have kidney problems
    • are 65 years of age or older
    • take medicines to lower your blood pressure, including diuretics (water pills)
  • Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with empagliflozin, one of the medicines in SYNJARDY XR.

Ketoacidosis is a serious condition, which may need to be treated in a hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with SYNJARDY XR even if your blood sugar is less than 250 mg/dL. Stop taking SYNJARDY XR and call your doctor right away if you get any of the following symptoms:

  • nausea
  • tiredness
  • vomiting
  • trouble breathing
  • stomach-area (abdominal) pain

If you get any of these symptoms during treatment with SYNJARDY XR, if possible, check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.

  • Kidney problems. Sudden kidney injury has happened to people taking SYNJARDY XR. Talk to your doctor right away if you:
    • reduce the amount of food or liquid you drink for example, if you are sick or cannot eat or
    • start to lose liquids from your body for example, from vomiting, diarrhea or being in the sun too long
  • Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking empagliflozin, one of the medicines in SYNJARDY XR. Tell your doctor if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting.
  • Low blood sugar (hypoglycemia). If you take SYNJARDY XR with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take SYNJARDY XR. Signs and symptoms of low blood sugar may include:
    • headache
    • irritability
    • confusion
    • dizziness
    • drowsiness
    • hunger
    • shaking or feeling jittery
    • sweating
    • weakness
    • fast heartbeat
  • Vaginal yeast infection. Women who take SYNJARDY XR may get vaginal yeast infections. Symptoms of a vaginal yeast infection include vaginal odor, white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese), or vaginal itching.
  • Yeast infection of the penis (balanitis). Men who take SYNJARDY XR may get a yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include redness, itching, or swelling of the penis, rash of the penis, foul smelling discharge from the penis, or pain in the skin around the penis.
    Talk to your doctor about what to do if you get symptoms of a yeast infection of the vagina or penis. Your doctor may suggest you use an over-the-counter antifungal medicine. Talk to your doctor right away if you use an over-thecounter antifungal medication and your symptoms do not go away.
  • Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking empagliflozin, one of the medicines in SYNJARDY XR. Symptoms may include
    • swelling of your face, lips, throat and other areas of your skin
    • difficulty with swallowing or breathing.
    • raised, red areas on your skin (hives)

If you have any of these symptoms, stop taking SYNJARDY XR and call your doctor right away or go to the nearest hospital emergency room.

  • Low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause a decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 blood levels before. Your doctor may do blood tests to check your vitamin B12 levels.
  • Increased fats in your blood (cholesterol)

Other common side effects of SYNJARDY XR include diarrhea, nausea, vomiting, gas, stomach pain, indigestion, weakness, and headache.

These are not all the possible side effects of SYNJARDY XR. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SYNJARDY XR?

Store SYNJARDY XR at room temperature between 68°F to 77°F (20°C to 25°C).

General information about the safe and effective use of SYNJARDY XR.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SYNJARDY XR for a condition for which it was not prescribed. Do not give SYNJARDY XR to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about SYNJARDY XR. If you would like more information, talk with your doctor. You can ask your pharmacist or healthcare provider for information about SYNJARDY XR that is written for health professionals.

What are the ingredients in SYNJARDY XR?

Active Ingredients: empagliflozin and metformin hydrochloride

Inactive Ingredients: Tablet core contains: polyethylene oxide, hypromellose, and magnesium stearate. The Film Coatings and Printing Ink contain: hypromellose, titanium dioxide, polydextrose, polyethylene glycol, talc, carnauba wax, purified water, ferrosoferric oxide, propylene glycol, isopropyl alcohol, ferric oxide yellow (5 mg /1000 mg, 10 mg /1000 mg, 25 mg /1000 mg), ferric oxide red (10 mg /1000 mg), FD&C blue#2/indigo carmine aluminum lake (12.5mg/1000mg, 25mg/1000mg).

This Medication Guide has been approved by the U.S. Food and Drug Administration.

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Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

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