Synjardy XR

Pregnancy

There are no adequate and well-controlled studies in pregnant women with empagliflozin/metformin or its individual components

Animal studies

• Based on results from animal studies, empagliflozin may affect renal development and maturation
• In studies conducted in rats, empagliflozin crosses the placenta and reaches fetal tissues; during pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters

Lactation

Unknown if distributed in human breast milk As individual components, both empagliflozin and metformin were secreted in the milk of lactating rats

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Synjardy XR, there are no specific foods that you must exclude from your diet when receiving this medication.

Alcohol in combination with metformin may increase the risk of developing lactic acidosis. Avoid excessive alchol use while taking Synjardy XR. Contact your doctor or pharmacist if you have any questions regarding alcohol use and Synjardy XR. 

Before taking Synjardy XR, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Synjardy XR or to any of its ingredients
• have 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 short term “binge” drinking
• are going to get an injection of dye or contrast agents for an x-ray procedure.
• have a history of urinary tract infections or problems with urination
• 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 
• are a premenopausal woman (before the “change of life”), who does not have periods regularly or at all if you are not planning to become pregnant. This is because this medication may increase your chance of becoming pregnant.
• are breastfeeding or plan to breastfeed 

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

• Take Synjardy XR exactly as prescribed.
• Synjardy XR comes in tablet form and is taken once daily with a meal in the morning. 
• Take this medication with food to reduce risk of stomach upset.
• Swallow the tablet whole; do not split, crush, dissolve, or chew.
• 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.
• If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take 2 doses of Synjardy XR at the same time.

• Store Synjardy XR at room temperature. 
• Keep this and all medicines out of reach of children. 

Tell your doctor about all your current medicines and any you start or stop using, especially:

• blood pressure medicine;

• a diuretic or "water pill";

• insulin or other oral diabetes medications; or

• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with empagliflozin and metformin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

It is very important that your doctor check your progress at regular visits, especially during the first few weeks that you take this medicine. Blood and urine tests may be needed to check for unwanted effects.

Under certain conditions, too much metformin can cause a serious condition called lactic acidosis. Lactic acidosis usually occurs when other serious health problems are present, such as a heart attack or kidney failure. The symptoms of lactic acidosis include: abdominal or stomach discomfort, decreased appetite, diarrhea, fast or shallow breathing, a general feeling of discomfort, muscle pain or cramping, and unusual sleepiness, tiredness, or weakness. If you have more than one of these symptoms together, you should get immediate emergency medical help.

Dizziness, lightheadedness, or fainting may occur with this medicine. This is more common if you have kidney disease, low blood pressure, or if you are taking a diuretic (water pill). Taking plenty of fluids each day may help. Drink plenty of water during exercise or in hot weather. Check with your doctor if you have severe nausea, vomiting, or diarrhea that does not stop. This may cause you to lose too much water.

Ketoacidosis (high ketones and acid in the blood) may occur while you are using this medicine. This can be life-threatening and requires immediate medical attention. Your doctor may give you insulin, fluid, and carbohydrate replacement to treat this condition. Tell your doctor right away if you have nausea, vomiting, trouble breathing, increased thirst or urination.

Tell your doctor if you have bloody urine, decrease in how much or how often you urinate, painful or difficult urination, lower back or side pain, fever, chills, or swelling of the face, finger, or lower legs. These may be symptoms of a serious kidney problem.

Let your doctor or dentist know you are taking this medicine. Your doctor may advise you to stop taking this medicine before you have major surgery or diagnostic tests, especially tests that use a contrast dye.

Make sure any doctor or dentist who treats you knows that you are using this medicine. This medicine may affect the results of certain medical tests (eg, urine glucose tests may not be accurate).

This medicine can cause hypoglycemia (low blood sugar). However, low blood sugar can occur if you delay or miss a meal or snack, exercise more than usual, drink alcohol, cannot eat because of nausea or vomiting, or take certain medicines. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms of low blood sugar. Talk to your doctor about the best way to treat low blood sugar.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your diabetes medicine, overeat or do not follow your diet plan, have a fever or infection, or do not exercise as much as usual. High blood sugar can be very serious and must be treated right away. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat high blood sugar.

This medicine may cause vaginal yeast infections in women and yeast infections of the penis in men. This is more common in patients who have a history of genital yeast infections or in men who are not circumcised. Women may have a vaginal discharge, itching, or odor. Men may have redness, itching, swelling, or pain around the penis, or a discharge with a strong odor from the penis. Check with your doctor right away if you have any of these symptoms.

This medicine may increase risk of having urinary tract infections, including pyelonephritis or urosepsis. Check with your doctor right away if you have bladder pain, bloody or cloudy urine, difficult, burning, or painful urination, or lower back or side pain.

This medicine may cause some women who do not have regular monthly periods to ovulate. This can increase the chance of pregnancy. If you are a woman of childbearing potential, you should discuss birth control options with your doctor.

This medicine may make you dizzy. Do not drive or do anything else that could be dangerous until you know how this medicine affects you. Stand up slowly if you feel dizzy.

Limit the amount of alcohol you drink while you are using this medicine. Heavy alcohol use can increase your chances of serious side effects.

There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says you have diabetes with a list of all your medicines.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

  Recommended Dosage

• In patients with volume depletion not previously treated with empagliflozin, correct this condition before initiating Synjardy XR [see Warnings and Precautions (5.2)].
• Individualize the starting dose of Synjardy XR based on the patient’s current regimen: - In patients on metformin hydrochloride, switch to Synjardy XR containing a similar total daily dose of metformin hydrochloride 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 hydrochloride extended-release 1000 mg; - In patients already treated with empagliflozin and metformin hydrochloride, switch to Synjardy XR containing the same total daily doses of empagliflozin and a similar total daily dose of metformin hydrochloride.
• Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of metformin hydrochloride 2000 mg and empagliflozin 25 mg [see Dosage and Administration (2.2)].
• The dose of metformin hydrochloride should be gradually escalated to reduce the gastrointestinal side effects due to metformin hydrochloride [see Dosage Forms and Strengths (3)].
• Take Synjardy XR orally once daily with a meal in the morning
• Swallow Synjardy XR tablets whole.  Do not split, crush, dissolve, or chew before swallowing.  There have been reports of incompletely dissolved tablets being eliminated in the feces for other tablets containing metformin hydrochloride extended-release.  If a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control.
• 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.

2.2  Recommended Dosage in Patients with Renal Impairment

• Assess renal function prior to initiation of Synjardy XR and periodically, thereafter.
• Synjardy XR is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1, 5.4)].

  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 between 45 and 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 (5.1)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Synjardy XR
No animal studies have been conducted with the combination of empagliflozin and metformin hydrochloride to evaluate carcinogenesis, mutagenesis, or impairment of fertility.  General toxicity studies in rats up to 13 weeks were performed with the combined components.  These studies indicated that no additive toxicity is caused by the combination of empagliflozin and metformin.

Empagliflozin
Carcinogenesis
Carcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats.  Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg).  In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from a 25 mg clinical dose.  Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the exposure from a 25 mg clinical dose).  Renal tubule adenomas and carcinomas were observed in male mice at 1000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg.  These tumors may be associated with a metabolic pathway predominantly present in the male mouse kidney.

Mutagenesis
Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.

Impairment of Fertility
Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).

Metformin hydrochloride
Carcinogenesis
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively.  These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg/kg/day based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats.  There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

Mutagenesis
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (Salmonella typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Impairment of Fertility
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the MRHD based on body surface area comparisons.

  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).

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).

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).

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.

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

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.  However, the effectiveness of Synjardy XR on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease has not been established.  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 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 nonfatal myocardial infarction (MI) or a nonfatal 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 time to 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 Figure 4 and 5).  Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.

Figure 4     Estimated Cumulative Incidence of First MACE

Figure 5      Estimated Cumulative Incidence of Cardiovascular Death

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).