Dosage & Administration
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Synjardy Prescribing Information
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 (5.1)].
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 (2.1), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].
If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].
SYNJARDY
SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.
SYNJARDY XR
SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Empagliflozin
Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:
- Cardiovascular (CV) death in adults with established CV disease.
- CV death and hospitalization for heart failure in adults with heart failure.
- Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression.
Limitations of Use
- SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2)].
- Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.
- Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease [see Clinical Studies (14.5)]. Empagliflozin is not expected to be effective in these populations.
Testing Prior to Initiation of SYNJARDY or SYNJARDY XR
- Assess renal function before initiating SYNJARDY or SYNJARDY XR and as clinically indicated [see Warnings and Precautions (5.1, 5.3)].
- Assess volume status. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5, 8.6)].
Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults
- When switching to SYNJARDY or SYNJARDY XR from:
- Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin HCl and a total daily empagliflozin dosage of 10 mg.
- Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin and a total daily metformin HCl dosage of 1,000 mg.
- Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily dosages of each component.
- Recommended dosage of SYNJARDY or SYNJARDY XR:
- The recommended total daily dosage of empagliflozin is 10 mg.
- For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25 mg in patients tolerating 10 mg daily and metformin HCl may be increased to a maximum total daily dosage of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1)].
- Take SYNJARDY orally twice daily with meals.
- Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not split, crush, dissolve, or chew.
Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and Older
- Individualize the dosage of SYNJARDY based on the patient's current regimen.
- Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg.
- Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1)].
Dosage Recommendations in Patients with Renal Impairment
- Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2, due to the metformin HCl component.
- SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.6)].
Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue SYNJARDY or 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 or SYNJARDY XR if renal function is stable [see Warnings and Precautions (5.1)].
Temporary Interruption for Surgery
Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
Recommendations Regarding Missed Dose
- If a dose is missed, instruct patients to take the dose as soon as possible.
- Advise patients not to double up the next dose.
SYNJARDY Tablets:
| Empagliflozin Strength | Metformin HCl Strength | Color/Shape | Tablet Markings |
|---|---|---|---|
| 5 mg | 500 mg | orange yellow, oval, biconvex, film-coated tablet | Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "500". |
| 5 mg | 1,000 mg | brownish yellow, oval, biconvex, film-coated tablet | Boehringer Ingelheim company symbol and "S5" debossed on one side; the other side is debossed with "1000". |
| 12.5 mg | 500 mg | pale brownish purple, oval, biconvex, film-coated tablet | Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "500". |
| 12.5 mg | 1,000 mg | dark brownish purple, oval, biconvex, film-coated tablet | Boehringer Ingelheim company symbol and "S12" debossed on one side; the other side is debossed with "1000". |
SYNJARDY XR Tablets:
| Empagliflozin Strength | Metformin HCl Extended - Release Strength | Color/Shape | Tablet Markings |
|---|---|---|---|
| 5 mg | 1,000 mg | olive green, oval, biconvex, film-coated tablet | Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S5" on the top line and "1000 M" on the bottom line. |
| 10 mg | 1,000 mg | orange, oval, biconvex, film-coated tablet | Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S10" on the top line and "1000 M" on the bottom line. |
| 12.5 mg | 1,000 mg | blue, oval, biconvex, film-coated tablet | Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S12" on the top line and "1000 M" on the bottom line. |
| 25 mg | 1,000 mg | light green, oval, biconvex, film-coated tablet | Printed on one side in black ink with the Boehringer Ingelheim company symbol and "S25" on the top line and "1000 M" on the bottom line. |
Pregnancy
Risk Summary
Based on animal data showing adverse renal effects from empagliflozin, SYNJARDY and SYNJARDY XR are not recommended during the second and third trimesters of pregnancy.
The limited available data with SYNJARDY, 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 HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).
In animal studies, empagliflozin, a component of SYNJARDY and SYNJARDY XR, resulted in adverse renal changes in rats when administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when metformin HCl was administered to pregnant rats or rabbits (see Data).
The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Human Data
Published data from postmarketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Animal Data
Empagliflozin: Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.
In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.
In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).
Metformin HCl: Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of approximately 2- and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m2) for rats and rabbits, respectively.
Empagliflozin and Metformin HCl: No adverse developmental effects were observed when empagliflozin and metformin HCl were coadministered to pregnant rats during the period of organogenesis at exposures of approximately 35- and 14-times the clinical AUC exposure of empagliflozin associated with the 10 mg and 25 mg doses, respectively, and 4-times the clinical AUC exposure of metformin HCl associated with the 2,000 mg dose.
Lactation
Risk Summary
There is limited information regarding the presence of SYNJARDY, SYNJARDY XR, or its components (empagliflozin or metformin HCl) 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 (see Data). Empagliflozin is present in the milk of lactating rats (see Data). Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.
Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of SYNJARDY or SYNJARDY XR is not recommended while breastfeeding.
Data
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants.
Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
Pediatric Use
SYNJARDY
The safety and effectiveness of SYNJARDY as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of SYNJARDY for this indication is supported by evidence from a 26-week double-blind, placebo-controlled clinical trial of empagliflozin, with a double-blind active treatment safety extension period of up to 52 weeks in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].
The safety profile of pediatric patients treated with empagliflozin was similar to that observed in adults with type 2 diabetes mellitus, with the exception of hypoglycemia risk which was higher in pediatric patients treated with empagliflozin regardless of concomitant insulin use [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].
Use of SYNJARDY for this indication is also supported by evidence from adequate and well-controlled studies of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical study using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus [see Clinical Studies (14)]. In this study, adverse reactions were similar to those described in adults.
The safety and effectiveness of SYNJARDY have not been established in pediatric patients less than 10 years of age.
SYNJARDY XR
Safety and effectiveness of SYNJARDY XR have not been established in pediatric patients.
Geriatric Use
Assess renal function more frequently in SYNJARDY or SYNJARDY XR-treated geriatric patients because there is a greater risk of empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of metformin-associated lactic acidosis in geriatric patients [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.3)].
The recommended dosage for the metformin HCl component of SYNJARDY or SYNJARDY XR in geriatric patients should usually start at the lower end of the dosage range.
Empagliflozin
In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.
In the EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials, no overall differences in safety and effectiveness have been observed between patients 65 years of age and older and younger adult patients. EMPEROR-Reduced included 1,188 (64%) patients treated with empagliflozin 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2,403 (80%) patients treated with empagliflozin 65 years of age and older, and 1,281 (43%) patients 75 years of age and older. EMPA-KIDNEY included 1,803 (55%) patients treated with empagliflozin 65 years of age and older, and 758 (23%) patients 75 years of age and older.
Metformin HCl
Clinical studies of metformin HCl did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.
Renal Impairment
SYNJARDY or SYNJARDY XR should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2 due to the metformin HCl component and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).
Empagliflozin
The glucose lowering benefit of empagliflozin 25 mg decreased in adult patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)]. In the trial of pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, patients with an eGFR less than 60 mL/min/1.73 m2 were not enrolled.
Metformin HCl
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment [see Warnings and Precautions (5.1)].
Hepatic Impairment
Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. SYNJARDY and SYNJARDY XR are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].
SYNJARDY and SYNJARDY XR are contraindicated in patients with:
- severe renal impairment (eGFR less than 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].
- acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
- hypersensitivity to empagliflozin, metformin HCl or any of the excipients in SYNJARDY or SYNJARDY XR, reactions such as angioedema have occurred [see Warnings and Precautions (5.9)].