Synjardy XR (empagliflozin and metformin extended-release)

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.

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.

If metformin-associated lactic acidosis is suspected, immediately discontinue Synjardy XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

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:

• headache,
• stomach pain,
• gas,
• indigestion,
• nausea,
• vomiting,
• diarrhea,
• weakness,
• runny nose, and
• sore throat

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.

Prior To Initiation Of Synjardy XR

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

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.

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.

Table 4 : Clinically Relevant Interactions with Synjardy XR

• Based on animal data showing adverse renal effects, Synjardy XR is not recommended during the second and third trimesters of pregnancy.
• Limited available data with Synjardy XR or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.
• Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk.
• There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.
• There is no information regarding the presence of Synjardy XR or empagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk.