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Synjardy

Last reviewed on RxList: 7/14/2017
Synjardy Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Last reviewed on RxList 7/14/2017

Synjardy (empagliflozin and metformin hydrochloride) is a combination of a sodium-glucose co-transporter 2 (SGLT2) inhibitor and a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing empagliflozin or metformin, or in patients already being treated with both empagliflozin and metformin. Synjardy is not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Common side effects of Synjardy include low blood sugar (hypoglycemia), urinary tract infection, increased urination, genital yeast infections, diarrhea, nausea, vomiting, gas, abdominal discomfort, indigestion, weakness or lack of energy, high cholesterol, joint pain, and headache.

The starting dose of Synjardy is individualized, based on the patient's current regimen. The maximum recommended dose of Synjardy is 12.5 mg empagliflozin/1000 mg metformin twice daily. Synjardy may interact with diuretics, insulin or insulin secretagogues, cationic drugs, topiramate or other carbonic anhydrase inhibitors, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Tell your doctor all medications and supplements you use. Tell your doctor if you are pregnant or plan to become pregnant before using Synjardy. Synjardy is not recommended for use while breastfeeding.

Our Synjardy (empagliflozin and metformin hydrochloride) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

QUESTION

______________ is another term for type 2 diabetes. See Answer
Synjardy Professional Information

SIDE EFFECTS

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

  • Lactic Acidosis [see BOX WARNING and WARNINGS AND PRECAUTIONS]
  • Hypotension [see WARNINGS AND PRECAUTIONS]
  • Ketoacidosis [see WARNINGS AND PRECAUTIONS]
  • Acute Kidney Injury and Impairment in Renal Function [see WARNINGS AND PRECAUTIONS]
  • Urosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS]
  • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see WARNINGS AND PRECAUTIONS]
  • Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS]
  • Vitamin B12 Deficiency [see WARNINGS AND PRECAUTIONS]
  • Increased Low-Density Lipoprotein Cholesterol (LDL-C) [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

  Number (%) of Patients
Placebo
n=225
Empagliflozin 10 mg
n=224
Empagliflozin 25 mg
n=217
Hypoglycemia 22 (9.8) 35 (15.6) 28 (12.9)
Urinary tract infection 15 (6.7) 21 (9.4) 15 (6.9)
Nasopharyngitis 11 (4.9) 18 (8.0) 13 (6.0)

Empagliflozin

The data in Table 2 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a placebo-controlled trial with basal insulin. Empagliflozin was used as monotherapy in one trial and as add-on therapy in four trials [see Clinical Studies].

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

  Number (%) of Patients
Placebo
N=995
Empagliflozin 10 mg
N=999
Empagliflozin 25 mg
N=977
Urinary tract infectiona 7.6% 9.3% 7.6%
Female genital mycotic infectionsb 1.5% 5.4% 6.4%
Upper respiratory tract infection 3.8% 3.1% 4.0%
Increased urinationc 1.0% 3.4% 3.2%
Dyslipidemia 3.4% 3.9% 2.9%
Arthralgia 2.2% 2.4% 2.3%
Male genital mycotic infectionsd 0.4% 3.1% 1.6%
Nausea 1.4% 2.3% 1.1%
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 WARNINGS AND PRECAUTIONS and 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 3).

Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.

Acute Impairment in Renal Function

Treatment with empagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 3). Patients with moderate renal impairment at baseline had larger mean changes [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

In a long-term cardiovascular outcome trial, the acute impairment in renal function was observed to reverse after treatment discontinuation suggesting acute hemodynamic changes play a role in the renal function changes observed with empagliflozin.

Table 3 Changes from Baseline in Serum Creatinine and eGFRa in the Pool of Four 24-week Placebo-Controlled Studies and Renal Impairment Study

  Pool of 24-Week Placebo-Controlled Studies
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
Baseline Mean N 825 830 822
Creatinine (mg/dL) 0.84 0.85 0.85
eGFR (mL/min/1.73 m2) 87.3 87.1 87.8
Baseline Mean N 825 830 822
Creatinine (mg/dL) 0.84 0.85 0.85
eGFR (mL/min/1.73 m2) 87.3 87.1 87.8
Week 12 Change N 771 797 783
Creatinine (mg/dL) 0.00 0.02 0.01
eGFR (mL/min/1.73 m2) -0.3 -1.3 -1.4
Week 24 Change N 708 769 754
Creatinine (mg/dL) 0.00 0.01 0.01
eGFR (mL/min/1.73 m2) -0.3 -0.6 -1.4
  Moderate Renal Impairmentb
Placebo   Empagliflozin 25 mg
Baseline Mean N 187 - 187
Creatinine (mg/dL) 1.49 - 1.46
eGFR (mL/min/1.73 m2) 44.3 - 45.4
Week 12 Change N 176 - 179
Creatinine (mg/dL) 0.01 - 0.12
eGFR (mL/min/1.73 m2) 0.1 - -3.8
Week 24 Change N 170 - 171
Creatinine (mg/dL) 0.01 - 0.10
eGFR (mL/min/1.73 m2) 0.2 - -3.2
Week 52 Change N 164 - 162
Creatinine (mg/dL) 0.02 - 0.11
eGFR (mL/min/1.73 m2) -0.3 - -2.8
Post-treatment Changec N 98 - 103
Creatinine (mg/dL) 0.03 - 0.02
eGFR (mL/min/1.73 m2) 0.16 - 1.48
aObserved cases on treatment.
bSubset of patients from renal impairment study with eGFR 30 to less than 60 mL/min/1.73 m2.
cApproximately 3 weeks after end of treatment.

Hypoglycemia

The incidence of hypoglycemia by study is shown in Table 4. The incidence of hypoglycemia increased when empagliflozin was administered with insulin or sulfonylurea [see WARNINGS AND PRECAUTIONS].

Table 4 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% 0%
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% 0% 0%
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 WARNINGS AND PRECAUTIONS and 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.

Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see WARNINGS AND PRECAUTIONS].

Laboratory Tests

Empagliflozin

Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see WARNINGS AND PRECAUTIONS]. 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

In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of empagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Read the entire FDA prescribing information for Synjardy (Empagliflozin and Metformin Hydrochloride Tablets)

SLIDESHOW

Type 2 Diabetes Diagnosis, Treatment, Medication See Slideshow
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© Synjardy Patient Information is supplied by Cerner Multum, Inc. and Synjardy Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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