Glyxambi

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

Stop taking this medicine and call your doctor at once if you have:

• severe or ongoing pain in your joints;
• a light-headed feeling, like you might pass out;
• ketoacidosis (too much acid in the blood)--nausea, vomiting, stomach pain, confusion, unusual drowsiness, or trouble breathing;
• pancreatitis--severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate;
• dehydration symptoms--feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin;
• 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.

Common side effects may include:

• urination problems;
• sinus pain; 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.

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

Common side effects of Glyxambi include the following:

• Urinary tract infections (UTIs)
• Increased frequency of urination 
• Low blood sugars
• Headaches
• Back and joint pain
• Upper respiratory infections
• Genital fungal infections (yeast infections)
• Increases in LDL cholesterol (bad cholesterol)

This is not a complete list of 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.

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 Glyxambi, there are no specific foods that you must exclude from your diet when receiving this medication.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

The recommended dose of Glyxambi is is 10 mg empagliflozin/5 mg linagliptin once daily. The maximum dose is 25 mg empagliflozin/5 mg linagliptin once daily.

• Store Glyxambi at room temperature.
• Keep this and all medicines out of the reach of children.

Empagliflozin and linagliptin combination is used together with proper diet and exercise to treat high blood sugar levels caused by type 2 diabetes. It is also used to lower risk of death in patients with type 2 diabetes and heart disease. Empagliflozin works in the kidneys to prevent absorption of glucose (blood sugar). Linagliptin helps to control blood sugar levels by increasing substances in the body that make the pancreas release more insulin. It also signals the liver to stop producing sugar (glucose) when there is too much sugar in the blood. This medicine does not help patients who have insulin-dependent or type 1 diabetes.

This medicine is available only with your doctor's prescription.

Carefully follow the special meal plan your doctor gave you. This is the most important part of controlling your diabetes, and will help the medicine work properly. Exercise regularly and test for sugar in your blood or urine as directed.

This medicine comes with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

You may take this medicine with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For type 2 diabetes:
    • Adults—1 tablet once a day, taken in the morning. Each tablet contains 10 milligrams (mg) of empagliflozin and 5 mg of linagliptin. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 25 mg of empagliflozin and 5 mg of linagliptin.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• 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.

 Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue Glyxambi and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Glyxambi.

 Heart Failure

An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of Glyxambi prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of Glyxambi.

 Hypotension

Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating empagliflozin [see Adverse Reactions (6.1)] particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Before initiating Glyxambi, assess for volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see Use in Specific Populations (8.5)].

 Ketoacidosis

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. Glyxambi is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

Patients treated with Glyxambi who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with Glyxambi may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, Glyxambi should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.

In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating Glyxambi, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with Glyxambi consider monitoring for ketoacidosis and temporarily discontinuing Glyxambi in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

 Acute Kidney Injury and Impairment in Renal Function

Empagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.1)] and can cause renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.

Before initiating Glyxambi, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing Glyxambi in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue Glyxambi promptly and institute treatment.

Empagliflozin increases serum creatinine and decreases eGFR.  Patients with hypovolemia may be more susceptible to these changes.  Renal function abnormalities can occur after initiating Glyxambi [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of Glyxambi and monitored periodically thereafter. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Use of Glyxambi is not recommended when eGFR is persistently less than 45 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Use in Specific Populations (8.6)].

 Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].

 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues are known to cause hypoglycemia. The use of empagliflozin or linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with Glyxambi.

 Genital Mycotic Infections

Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop mycotic genital infections. Monitor and treat as appropriate.

 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of Glyxambi). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue Glyxambi, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with Glyxambi.

 Increased Low-Density Lipoprotein Cholesterol (LDL-C)

Increases in LDL-C can occur with empagliflozin [see Adverse Reactions (6.1)]. Monitor and treat as appropriate.

 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.

 Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving Glyxambi. If bullous pemphigoid is suspected, Glyxambi should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glyxambi.

 Drug Interactions with Empagliflozin

Diuretics
Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion [see Warnings and Precautions (5.3)].

Insulin or Insulin Secretagogues
Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia [see Warnings and Precautions (5.7)].

Positive Urine Glucose Test
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

 Drug Interactions with Linagliptin

Inducers of P-glycoprotein or CYP3A4 Enzymes
Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see Clinical Pharmacology (12.3)].

In the event of an overdose with Glyxambi, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of empagliflozin by hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

Glyxambi contains a combination of empagliflozin and linagliptin are oral diabetes medicines that help control blood sugar levels. Empagliflozin works by helping the kidneys get rid of glucose from your bloodstream. Linagliptin works by regulating the levels of insulin your body produces after eating.

Glyxambi is used together with diet and exercise improve blood sugar control in adults with type 2 diabetes. This medicine is not for treating type 1 diabetes.

Glyxambi is also used to lower the risk of death from heart attack, stroke, or heart failure in adults with type 2 diabetes who also have heart disease.

You should not use Glyxambi if you are allergic to empagliflozin and linagliptin, or if you have:

• severe kidney disease (or if you are on dialysis);

• a history of severe allergic or skin reaction after taking linagliptin; or

• if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

To make sure Glyxambi is safe for you, tell your doctor if you have ever had:

• heart problems;

• kidney disease;

• liver disease;

• a pancreas disorder;

• low blood pressure;

• gallstones;

• high cholesterol or triglycerides (a type of fat in the blood);

• alcoholism;

• genital infection (penis or vagina);

• if you are on a low salt diet; or

• if you are 65 or older.

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

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

Take the missed dose as soon as you remember. 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 / linagliptin: oral tablet, tablet oral

Along with its needed effects, empagliflozin / linagliptin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking empagliflozin / linagliptin:

• Bladder pain
• bloody or cloudy urine
• difficult, burning, or painful urination
• frequent urge to urinate
• lower back or side pain

• Anxiety
• bloating
• blurred vision
• chills
• cold sweats
• confusion
• constipation
• cool, pale skin
• darkened urine
• depression
• dizziness
• dry mouth
• fast heartbeat
• fever
• flushed, dry skin
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• indigestion
• large, hard skin blisters
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• loss of consciousness
• nausea
• nightmares
• pains in the stomach, side, or abdomen, radiating to the back
• seizures
• severe joint pain
• shakiness
• slurred speech
• stomach pain
• sweating
• troubled breathing
• unexplained weight loss
• unusual tiredness or weakness
• vomiting
• yellow eyes or skin

Some side effects of empagliflozin / linagliptin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Body aches or pain
• difficulty with breathing
• ear congestion
• headache
• loss of voice
• runny or stuffy nose
• sneezing
• sore throat

• Discharge with a strong odor from the penis
• redness, itching, swelling, or pain around the penis
• vaginal discharge, itching, or odor