Synjardy

Your doctor may perform kidney function tests before you start taking empagliflozin and metformin.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take this medicine with food to prevent upset stomach.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

Your doctor may have you take extra vitamin B12 while you are taking empagliflozin and metformin. Take only the amount of vitamin B12 that your doctor has prescribed.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medicine, which can lead to severely low blood pressure or a serious electrolyte imbalance.

Empagliflozin and metformin can cause positive results with certain lab tests for glucose (sugar) in the urine. Tell any doctor who treats you that you are using empagliflozin.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, pale skin, irritability, dizziness, feeling shaky, or trouble concentrating. Always keep a source of sugar with you in case you have low blood sugar. Sugar sources include fruit juice, hard candy, crackers, raisins, and non-diet soda. Be sure your family and close friends know how to help you in an emergency.

If you have severe hypoglycemia and cannot eat or drink, use a glucagon injection. Your doctor can prescribe a glucagon emergency injection kit and tell you how to use it.

Also watch for signs of high blood sugar (hyperglycemia) such as increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, and weight loss.

Check your blood sugar carefully during times of stress, travel, illness, surgery or medical emergency, vigorous exercise, or if you drink alcohol or skip meals. These things can affect your glucose levels and your dose needs may also change. Do not change your medication dose or schedule without your doctor's advice.

Empagliflozin and metformin is only part of a treatment program that may also include diet, exercise, weight control, blood sugar testing, and special medical care. Follow your doctor's instructions very closely.

Store at room temperature, away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of metformin may cause lactic acidosis. Get emergency medical help if you have any of these symptoms of lactic acidosis: weakness, increasing sleepiness, slow heart rate, cold feeling, muscle pain, shortness of breath, stomach pain, feeling light-headed, and fainting.

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Serious side effects have been reported with Synjardy. See the “Synjardy Precautions” section.

Common side effects of Synjardy include the following:

• runny or stuffy nose
• diarrhea
• nausea/vomiting
• flatulence
• abdominal discomfort
• indigestion
• asthenia
• headache

Synjardy may also cause urinary tract infections and female genital yeast infections.

This is not a complete list of Synjardy side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If you take too much Synjardy, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Synjardy is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nose or throat irritation.
• Gas.
• Stomach pain.
• Feeling tired or weak.
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

Synjardy is contraindicated in patients with:

• Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end stage renal disease, or dialysis [see Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.6)].
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1)].
• History of serious hypersensitivity reaction to empagliflozin or metformin.

 Mechanism of Action

Synjardy
Synjardy combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin, a member of the biguanide class.

Empagliflozin
Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Metformin
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. It is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike SUs, metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.6)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

 Pharmacodynamics

Empagliflozin
Urinary Glucose Excretion
In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily [see Clinical Studies (14)].

Urinary Volume
In a 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day 1 and 135 mL on Day 5 of empagliflozin 25 mg once daily treatment.

Cardiac Electrophysiology
In a randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered a single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

 Pharmacokinetics

Synjardy
The results of a bioequivalence study in healthy subjects demonstrated that Synjardy (empagliflozin/metformin hydrochloride) 5 mg/500 mg, 5 mg/1000 mg, 12.5 mg/500 mg, and 12.5 mg/1000 mg combination tablets are bioequivalent to coadministration of corresponding doses of empagliflozin and metformin hydrochloride as individual tablets.

Administration of 12.5 mg empagliflozin/1000 mg metformin hydrochloride under fed conditions resulted in a 9% decrease in AUC and a 28% decrease in Cmax for empagliflozin, when compared to fasted conditions. For metformin, AUC decreased by 12% and Cmax decreased by 26% compared to fasting conditions. The observed effect of food on empagliflozin and metformin is not considered to be clinically relevant.

Empagliflozin
Absorption
The pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol·h/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.

Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.

Distribution
The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.

Metabolism
No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.

Elimination
The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.

Metformin
Absorption
The absolute bioavailability of a metformin hydrochloride 500-mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.

Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower Cmax, a 25% lower AUC, and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution
The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins, in contrast to SUs, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin tablets, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Elimination
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations
Renal Impairment
Synjardy: Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of Synjardy in renally impaired patients have not been performed [see Contraindications (4) and Warnings and Precautions (5.4)].

Empagliflozin: In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and subjects with kidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.

Metformin hydrochloride: In patients with decreased renal function (based on measured eGFR), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in eGFR [see Contraindications (4) and Warnings and Precautions (5.1)].

Hepatic Impairment
Synjardy: Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of Synjardy in hepatically impaired patients have not been performed [see Warnings and Precautions (5.1)].

Empagliflozin: In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.

Metformin hydrochloride: No pharmacokinetic studies of metformin hydrochloride have been conducted in patients with hepatic impairment.

Effects of Age, Body Mass Index, Gender, and Race
Empagliflozin: Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have a clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations (8.5)].

Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Caucasians (n=249), Blacks (n=51), and Hispanics (n=24).

Geriatric
Synjardy: Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of Synjardy in geriatric patients have not been performed [see Warnings and Precautions (5.2, 5.4) and Use in Specific Populations (8.5)].

Empagliflozin: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based on a population pharmacokinetic analysis [see Use in Specific Populations (8.5)].

Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Pediatric
Studies characterizing the pharmacokinetics of empagliflozin or metformin after administration of Synjardy in pediatric patients have not been performed.

Drug Interactions
Pharmacokinetic drug interaction studies with Synjardy have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin.

Empagliflozin
In vitro Assessment of Drug Interactions: Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated.

Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.

In vivo Assessment of Drug Interactions: No dose adjustment of empagliflozin is recommended when coadministered with commonly prescribed medicinal products based on results of the described pharmacokinetic studies.  Empagliflozin pharmacokinetics were similar with and without coadministration of metformin hydrochloride, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes (see Figure 1).  The observed increases in overall exposure (AUC) of empagliflozin following coadministration with gemfibrozil, rifampicin, or probenecid are not clinically relevant.  In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion.  The relevance of this observation to patients with renal impairment is unknown.

Figure 1  Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% - 125%)]

aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin, 10 mg, single dose

Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered with empagliflozin (see Figure 2).

Figure 2  Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% - 125%)]

aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon®; gadministered as ramipril

Metformin hydrochloride

Synjardy (empagliflozin and metformin hydrochloride) tablets are available in the following strengths and packages:

Storage
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Store in a safe place out of reach of children.

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Applies to empagliflozin / metformin: oral tablet, oral tablet extended release

General

Empagliflozin: The most frequently reported side effects included urinary tract infections and female genital mycotic infections.

Metformin: The most frequently reported side effects included diarrhea, nausea, vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.[Ref]

Cardiovascular

Empagliflozin is known to cause osmotic diuresis, leading to intravascular volume contraction and adverse reactions related to volume depletion. Adverse reactions related to volume depletion such as decreased ambulatory/systolic blood pressure, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope were reported in 0.5% and 0.3% of patients receiving empagliflozin 10 mg (n=999) or 25 mg (n=977) orally once a day, respectively.[Ref]

Empagliflozin:
Uncommon (0.1% to 1%): Hypotension, orthostatic hypotension, syncope, decreased systolic blood pressure, decreased ambulatory blood pressure[Ref]

Genitourinary

Empagliflozin-Metformin:
Common (1% to 10%): Urinary tract infections

Empagliflozin:
Common (1% to 10%): Urinary tract infections, female genital mycotic infections, male genital mycotic infections, increased urination (e.g., polyuria, pollakiuria, and nocturia)
Uncommon (0.1% to 1%): Dysuria
Rare (less than 0.1%): Phimosis
Postmarketing reports: Urosepsis, pyelonephritis[Ref]

During a 24 week study of empagliflozin in combination with metformin plus a sulfonylurea, urinary tract infections (UTIs) were reported in 9.4% and 6.9% of patients receiving empagliflozin 10 mg (n=224) or 25 mg (n=217) once a day, respectively. Pooled data from 5 studies showed the incidence of UTIs (e.g., UTI, asymptomatic bacteriuria, and cystitis), was increased in empagliflozin-treated patients compared to placebo, more frequent in females compared to males, and more likely to occur in patients with a history of chronic or recurrent UTIs. Treatment discontinuation due to UTIs occurred in 0.2% and 0.1% of patients receiving empagliflozin 10 mg or 25 mg once a day, respectively.[Ref]

Metabolic

The frequency of hypoglycemia depended on the type of background therapy used. When empagliflozin was used as monotherapy, hypoglycemia was reported in 0.4% of patients taking the 10 mg and 25 mg doses. In combination with metformin, hypoglycemia was reported in 1.8% taking 10 mg and 1.4% taking 25 mg. In combination with metformin and a sulfonylurea, hypoglycemia was reported in 16.1% taking the 10 mg dose and 11.5% taking the 25 mg dose. In combination with basal insulin, hypoglycemia was reported in 19.5% taking the 10 mg dose and 28.4% taking the 25 mg dose.

Twenty reports of acidosis, including diabetic ketoacidosis (DKA), ketoacidosis, or ketosis in patients treated with SGLT-2 inhibitors have been identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database during the period March 2013 through 06 June 2014. All patients required emergency room treatment or hospitalization. These cases were not typical of ketoacidosis or DKA in that they occurred in patients with type 2 diabetes and their blood sugar levels were only slightly increased. Some factors identified as potentially triggering the acidosis included major illness, reduced food and fluid intake, and reduced insulin dose.[Ref]

Empagliflozin-Metformin:
Very common (10% or more): Hypoglycemia (15.6%)

Empagliflozin:
Common (1% to 10%): Dyslipidemia, polydipsia, increased LDL-C
Uncommon (0.1% to 1%): Dehydration, hypovolemia, hypoglycemia
Frequency not reported: Increased serum creatinine
Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis

Metformin:
Very rare (less than 0.01%): Lactic acidosis[Ref]

Dermatologic

Empagliflozin-Metformin:
Common (1% to 10%): Pruritus

Metformin:
Very rare (less than 0.01%): Erythema, urticaria[Ref]

Gastrointestinal

Empagliflozin:
Common (1% to 10%): Nausea

Metformin:
Common (1% to 10%): Nausea, vomiting, diarrhea, flatulence, abdominal discomfort, indigestion[Ref]

Hematologic

Empagliflozin:
Common (1% to 10%): Increased hematocrit

Metformin:
Common (1% to 10%): Subnormal vitamin B12 levels
Postmarketing reports: Hematologic reactions possibly related to subnormal Vitamin B12 levels[Ref]

Hepatic

Metformin:
Very rare (less than 0.01%): Hepatitis, abnormal liver function tests[Ref]

Musculoskeletal

Empagliflozin:
Common (1% to 10%): Arthralgia[Ref]

Nervous system

Metformin:
Common (1% to 10%): Headache, taste disturbances
Postmarketing reports: Neurologic reactions possibly related to subnormal Vitamin B12 levels[Ref]

Renal

Postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, have been received for patients treated with SGLT2 inhibitors including empagliflozin. Some reports involved patients younger than 65 years old.[Ref]

Empagliflozin:
Frequency not reported: Decreased eGFR
Postmarketing reports: Acute Kidney Injury[Ref]

Respiratory

Empagliflozin-Metformin:
Common (1% to 10%): Nasopharyngitis

Empagliflozin:
Common (1% to 10%): Upper respiratory tract infection[Ref]

Other

Metformin:
Common (1% to 10%): Asthenia[Ref]

Some side effects of Synjardy may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.