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Synjardy XR

  • Generic Name: empagliflozin and metformin hydrochloride extended-release
  • Brand Name: Synjardy XR Extended-release Tablets

Synjardy XR Extended-release Tablets (Empagliflozin and Metformin Hydrochloride Extended-release) side effects drug center

 

PROFESSIONAL

CONSUMER

SIDE EFFECTS

 

Synjardy XR Side Effects Center

What Is Synjardy XR?

Synjardy XR (empagliflozin and metformin hydrochloride extended-release) tablets, for oral use 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 when treatment with both empagliflozin and metformin is appropriate.

What Are Side Effects of Synjardy XR?

Common side effects of Synjardy XR include:

Dosage for Synjardy XR

The starting dose of Synjardy XR is individualized based on the patient's current regimen. The maximum recommended total daily dose is 25 mg empagliflozin and 2000 mg metformin.

What Drugs, Substances, or Supplements Interact with Synjardy XR?

Synjardy XR may interact with topiramate or other carbonic anhydrase inhibitors, ranolazine, vandetanib, dolutegravir, cimetidine, alcohol, diuretics, insulin or insulin secretagogues, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. Tell your doctor all medications and supplements you use.

Synjardy XR During Pregnancy or Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant before using Synjardy XR. Synjardy XR is not recommended for use during the second and third trimesters; it may harm a fetus. It is unknown if Synjardy XR passes into breast milk. Because of the potential for harm to a nursing infant, breastfeeding while using Synjardy XR is not recommended.

Additional Information

Our Synjardy XR (empagliflozin and metformin hydrochloride extended-release) tablets, for oral use Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

 

Synjardy XR Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Seek medical attention right away if you have signs of a rare but serious genital infection (penis or vagina): burning, itching, odor, discharge, pain, tenderness, redness or swelling of the genital or rectal area, fever, not feeling well. These symptoms may get worse quickly.

Call your doctor at once if you have:

  • little or no urination;
  • dehydration symptoms--dizziness, weakness, feeling light-headed (like you might pass out);
  • ketoacidosis (too much acid in the blood)--nausea, vomiting, stomach pain, confusion, unusual drowsiness, or trouble breathing;
  • lactic acidosis--unusual muscle pain, trouble breathing, stomach pain, vomiting, irregular heart rate, dizziness, feeling cold, or feeling very weak or tired; or
  • signs of a bladder infection--pain or burning when you urinate, increased urination, blood in your urine, fever, pain in your pelvis or back.

Side effects may be more likely to occur in older adults.

Common side effects may include:

  • headache;
  • stomach pain, gas, indigestion, nausea, vomiting, diarrhea;
  • weakness; or
  • runny nose, sore throat.

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.

Read the entire detailed patient monograph for Synjardy XR (Empagliflozin and Metformin Hydrochloride Extended-release)

 

Synjardy XR Professional Information

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

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.

Read the entire FDA prescribing information for Synjardy XR (Empagliflozin and Metformin Hydrochloride Extended-release)

&Copy; Synjardy XR Patient Information is supplied by Cerner Multum, Inc. and Synjardy XR Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.