Metformin and saxagliptin

You should not use this medicine if you have severe kidney disease or diabetic ketoacidosis (call your doctor for treatment with insulin).

Some people develop lactic acidosis while taking metformin. Early symptoms may get worse over time and this condition can be fatal. Stop taking this medicine and get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, trouble breathing, stomach pain, nausea, and feeling very weak or tired.

You should not use this medicine if you are allergic to metformin or saxagliptin (Onglyza), or if you have severe kidney disease or diabetic ketoacidosis (call your doctor for treatment with insulin).

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 heart attack or stroke, a severe infection, if you are 65 or older, if you are dehydrated, or if you drink a lot of alcohol. Talk with your doctor about your risk.

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

• kidney disease (your kidney function may need to be checked before you take this medicine);

• liver disease;

• heart disease;

• pancreatitis;

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

• gallstones;

• a history of alcoholism; or

• if you are over 80 years old and have not recently had your kidney function checked.

If you need to have surgery or any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and saxagliptin. Be sure your caregivers know ahead of time that you are using this medication.

This medicine is not expected to 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.

This medicine is not approved for use by anyone younger than 18 years old.

Avoid drinking alcohol. It lowers blood sugar and may increase your risk of lactic acidosis.

Applies to metformin / saxagliptin: oral tablet extended release

Along with its needed effects, metformin / saxagliptin 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 metformin / saxagliptin:

• Anxiety
• bladder pain
• bloody or cloudy urine
• blurred vision
• body aches or pain
• chills
• cold sweats
• confusion
• cool, pale skin
• cough
• depression
• difficult, burning, or painful urination
• difficulty with breathing
• dizziness
• ear congestion
• fast heartbeat
• fever
• frequent urge to urinate
• headache
• increased hunger
• loss of voice
• lower back or side pain
• nasal congestion
• nausea
• nightmares
• runny nose
• seizures
• shakiness
• slurred speech
• sneezing
• sore throat
• unusual tiredness or weakness

• Cough or hoarseness

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• constipation
• darkened urine
• difficulty with swallowing
• hives or skin rash
• 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
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pinpoint red spots on the skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• tightness in the chest
• unusual bleeding or bruising
• vomiting
• yellow eyes or skin

Some side effects of metformin / saxagliptin 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:

• Diarrhea
• muscle aches

• Abdominal or stomach pain
• itching
• pain or tenderness around the eyes and cheekbones
• redness of the skin
• weakness
• welts

Individualize dose based patient's current regimen, effectiveness, and tolerability; gradual dose titration of metformin is advised to reduce gastrointestinal side effects.

Saxagliptin-Metformin XR:
Usual dose: 1 tablet orally once a day with the evening meal
Maximum dose: saxagliptin 5 mg-metformin 2000 mg orally once a day
Maximum dose with concomitant strong CYP450 3A4/5 inhibitors: saxagliptin 2.5-metformin 1000 mg orally once a day

-Patients not currently treated with metformin: Initial dose saxagliptin 5 mg-metformin 500 mg orally once daily
-Patients currently treated with metformin: Initial dose: saxagliptin 5 mg plus the dose of metformin that is already being taken, or the nearest therapeutically appropriate dose.

Comments:
-Patients requiring saxagliptin 2.5 mg per day AND are either metformin-naive or require a dose of metformin greater than 1000 mg per day should use the individual components.
-Following a switch from metformin immediate-release to metformin extended release, glycemic control should be closely monitored and dosage adjustments made according.
-When used in combination with a sulfonylurea or insulin, a lower dose of the sulfonylurea or insulin may be considered to reduce the risk of hypoglycemia.
-Note: There are saxagliptin-metformin combination products available internationally that contain immediate-release metformin; saxagliptin-metformin products containing immediate-release metformin should be dosed twice a day.

Use: An adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both saxagliptin and metformin is appropriate.

Renal impairment: Contraindicated (e.g. serum creatinine levels 1.5 mg/dL or greater in men; 1.4 mg/dL or greater in women, or abnormal CrCl)

New Metformin Renal Dosing: Obtain eGFR prior to initiating therapy:
-eGFR less than 30 mL/min/1.73 m2: Use is contraindicated
-eGFR 30 to 45 mL/min/1.73 m2: Initiating therapy is not recommended
-eGFR that falls below 30 mL/min/1.73 m2 during therapy: Discontinue therapy
-eGFR that falls below 45 mL/min/1.73 m2 during therapy: Assess risks versus benefit of continued therapy
-eGFR greater than 45 mL/min/1.73 m2: No dose adjustments recommended

Saxagliptin:
Mild renal dysfunction (CrCl more than 50 mL/min): No adjustment recommended.
Moderate or severe renal dysfunction (CrCl 50 mL/min or less): 2.5 mg orally once a day, regardless of meals

IODINATED CONTRAST PROCEDURE:
-For patients with eGFR between 30 and 60 mL/min/1.73 m2: Stop this drug at the time of, or before imaging procedure; re-evaluate eGFR 48 hours after procedure; restart therapy only if renal function is stable.

-Use is contraindicated in conditions that may result in renal impairment such as cardiovascular collapse (shock), acute myocardial infarction, and septicamia; regular renal function monitoring is recommended to reduce the risk of developing lactic acidosis
-Treatment should not be initiated in patients 80 years or older unless measurement of CrCl demonstrates that renal function is not reduced.