Empagliflozin-metFORMIN

Empagliflozin and metformin are oral diabetes medicines that help control blood sugar levels. Empagliflozin works by helping the kidneys get rid of glucose from your bloodstream. Metformin lowers glucose production in the liver and also causes your intestines to absorb less glucose.

Empagliflozin and metformin is a combination medicine used together with diet and exercise to treat type 2 diabetes. Empagliflozin is not for treating type 1 diabetes.

Empagliflozin and metformin may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have moderate to severe kidney disease, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin). Empagliflozin and metformin is not for treating type 1 diabetes.

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking empagliflozin and metformin.

This medicine may cause a serious condition called lactic acidosis. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

You should not use this medicine if you are allergic to empagliflozin (Jardiance, Glyxambi) or metformin (Glucophage, Actoplus Met, Avandamet, Fortamet, Glucovance, Janumet, Jentadueto, Kazano, Kombiglyze, Metaglip, PrandiMet, Riomet), or if you have:

• moderate to severe kidney disease (or if you are on dialysis); or
• if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking empagliflozin and metformin.

Some people taking metformin develop a serious condition called lactic acidosis. This may be more likely if you have liver or kidney disease, congestive heart failure, a severe infection, if you are dehydrated, or if you drink large amounts of alcohol. Talk with your doctor about your risk.

To make sure empagliflozin and metformin is safe for you, tell your doctor if you have:

• liver or kidney disease;
• low blood pressure;
• a history of bladder infections or urination problems;
• high cholesterol levels;
• a history of heart attack or stroke;
• if you are on a low-salt diet;
• if you take blood pressure medicine such as a diuretic (water pill); or
• if you are 80 or older and your kidneys have not been tested.

It is not known whether empagliflozin and metformin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether this medicine passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Empagliflozin and metformin is not approved for use by anyone younger than 18 years old.

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

Early symptoms of lactic acidosis may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;
• dehydration symptoms--feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin;
• signs of a kidney problem--little or no urinating; painful or difficult urination; swelling in your feet or ankles; feeling tired or short of breath;
• signs of a bladder infection--pain or burning when you urinate, urine that looks cloudy, pain in pelvis or back; or
• signs of a genital infection (penis or vagina)--pain, burning, itching, rash, redness, odor, or discharge.

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

Common side effects may include:

• bladder infection or genital infection;
• headache;
• stomach pain, gas, indigestion, nausea, vomiting, diarrhea;
• weakness; or
• cold symptoms such as stuffy nose, sneezing, 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.

1-10%

Urinary tract infection (7.6-9.3%)

Decreased vitamin B12 levels (7%)

Increased LDL-C (4.6-6.5%)

Female genital mycotic infections (5.4-6.4%)

Dyslipidemia (2.9-3.9%)

Increased urination (3.2-3.4%)

Male genital mycotic infections (1.6-3.1%)

Nausea (1.1-2.3%)

Hypoglycemia, with monotherapy (1.4-1.8%)

<1%

Volume depletion

Impaired renal function

Mechanism of Action

Empagliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

Metformin: Decreases hepatic glucose production; decreases GI glucose absorption; increases target cell insulin sensitivity

Pharmacokinetics

Empagliflozin

• Peak plasma time: 1.5 hr
• Peak plasma concentration: 259 nmol/L
• AUC: 1870 nmol·h/L
• Protein bound: 86.2%
• Vd: 73.8 L
• Red blood cell partitioning: 36.8%
• Metabolism: Primary route of metabolism is glucuronidation by the uridine 5'-diphospho-glucuronosyl transferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9
• Half-life: 12.4 hr
• Excretion: 54.4% urine; 41.2% feces

Metformin

• Bioavailability: 50-60% (fasting)
• Protein bound: Negligible
• Vd: 654 L
• Red blood cell partitioning: Partitions into erythrocytes, most likely as a function of time
• Metabolism: Does not undergo hepatic metabolism nor biliary excretion
• Half-life: 17.6 hr (blood); 6.2 hr (plasma)
• Excretion: 90% urine

Oral Administration

When initiating, gradually increase dose to avoid GI adverse effects from metformin

Take with meal(s)

Extended-release

• Swallow extended-release 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 extended-release; if a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control
• 10 mg/1000 mg XR and 25 mg/1000 mg XR tablets should be taken as a single tablet once daily
• 5 mg/1000 mg XR and 12.5 mg/1000 mg XR tablets should be taken as 2 tablets together once daily

Storage

Controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86°F)

Empagliflozin/metformin is a prescription medication used to treat type 2 diabetes. It is a combination of two medications in one tablet. Empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney. Metformin, a commonly prescribed initial treatment for T2D, lowers glucose production by the liver and its absorption in the intestine.

Empagliflozin/metformin comes in tablet form in several dosage strengths. It is taken twice daily with meals.

This medication is also available in an extended-release tablet and is taken once a day with a meal in the morning. Swallow the extended-release tablet whole; do not split, crush, dissolve, or chew.

The most common side effects include stuffy or runny nose and sore throat, urinary tract infections, female genital infections, diarrhea, headache, nausea, and vomiting.

Serious side effects have been reported with empagliflozin/metformin. See the “Empagliflozin/metformin Precautions” section.

Common side effects of empagliflozin/metformin include the following:

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

This medication may also cause urinary tract infections and female genital yeast infections.

This is not a complete list of empagliflozin/metformin 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.

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

• beta-blockers such as metoprolol (Toprol XL, Lopressor), carvedilol (Coreg), bisoprolol (Zebeta) betaxolol (Kerlone), nebivolol (Bystolic), propranolol (Inderal)
• cough and cold products containing decongestants
• calcium channel blockers
• cimetidine (Tagamet)
• corticosteroids
• digoxin (Lanoxin)
• diuretics such as acetazolamide (Diamox), amiloride (Midamor), bumetanide (Bumex), chlorothiazide (Diuril), chlorthalidone (Thalitone), ethacrynic acid (Edecrin), furosemide (Lasix), hydrochlorothiazide (Microzide, HCTZ), metolazone (Zaroxolyn), or torsemide (Demadex)
• estrogens
• Insulin or insulin-releasing drugs that can lower blood sugar such as glipizide (Glucotrol), glimepiride (Amaryl), repaglinide (Prandin), and nateglinide (Starlix)
• isoniazid (INH, Nydrazid)
• morphine
• niacin (nicotinic acid, Niaspan)
• nifedipine
• oral contraceptives
• oral steroids
• phenothiazines such as promethazine (Phenergan)
• phenytoin (Dilantin)
• procainamide
• quinidine
• quinine
• ranitidine
• thyroid medicines such as levothyroxine (Levothroid, Levoxyl, Synthroid)
• triamterene
• trimethoprim
• vancomycin

This is not a complete list of empagliflozin/metformin drug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Empagliflozin/metformin falls into category C. There are no well-controlled studies that have been done in pregnant women. Empagliflozin/metformin should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.