Metformin and pioglitazone

Metformin/pioglitazone is a prescription medication used to treat type 2 diabetes.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

Congestive Heart Failure

Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET, cause or exacerbate congestive heart failure in some patients.

After initiation of ACTOPLUS MET, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of ACTOPLUS MET must be considered.

ACTOPLUS MET is not recommended in patients with symptomatic heart failure.

Initiation of ACTOPLUS MET in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

Lactic Acidosis

Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, ACTOPLUS MET should be discontinued and the patient hospitalized immediately.

You should not use this medicine if you are allergic to metformin or pioglitazone, or if you have:

• severe or uncontrolled heart failure;

• kidney problems;

• active bladder cancer;

• metabolic acidosis; or

• 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 metformin and pioglitazone. Be sure your caregivers know ahead of time that you are using this medication.

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 metformin and pioglitazone is safe for you, tell your doctor if you have:

• congestive heart failure or heart disease;

• fluid retention;

• a history of bladder cancer;

• a history of heart attack or stroke;

• liver disease; or

• if you are 80 years or older.

This medication may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

Taking metformin and pioglitazone may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with this medicine.

Follow your doctor's instructions about using this medicine if you are pregnant. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy.

Some women using metformin and pioglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

Women may be more likely than men to have bone fractures in the upper arm, hand, or foot while taking medicine that contains pioglitazone. Talk with your doctor if you are concerned about this possibility.

It is not known whether metformin and pioglitazone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Metformin and pioglitazone should not be given to a child.

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

Tell your doctor if you use insulin. Taking metformin and pioglitazone while you are using insulin may increase your risk of serious heart problems.

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

• gemfibrozil;

• morphine;

• ranitidine;

• an antibiotic--rifampin, trimethoprim, vancomycin; or

• heart or blood pressure medication--digoxin, nifedipine, procainamide, quinidine.

You may be more likely to have hyperglycemia (high blood sugar) if you also take other drugs that can raise blood sugar, such as:

• isoniazid;

• diuretics (water pills);

• steroids (prednisone and others);

• niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others);

• phenothiazines (Compazine and others);

• thyroid medicine (Synthroid and others);

• birth control pills and other hormones; and

• diet pills or medicines to treat asthma, colds or allergies.

These lists are not complete and many other medicines can increase or decrease the effects of metformin and pioglitazone on lowering your blood sugar. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here. Give a list of all your medicines to any healthcare provider who treats you.

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

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

• Bladder pain
• bloody or cloudy urine
• difficult, burning, or painful urination
• frequent urge to urinate
• lower back or side pain
• swelling of the face, fingers, feet, or lower legs
• weight gain

• Pain or swelling in the arms or legs without any injury
• pale skin
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Abdominal or stomach discomfort
• anxiety
• blurred vision
• chills
• cold sweats
• coma
• confusion
• cool, pale skin
• decreased appetite
• depression
• diarrhea
• dizziness
• fast heartbeat
• fast, shallow breathing
• general feeling of discomfort
• headache
• increased hunger
• muscle pain or cramping
• nausea
• nightmares
• seizures
• shakiness
• sleepiness
• slurred speech

Some side effects of metformin / pioglitazone 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
• cough
• ear congestion
• fever, sneezing, or sore throat
• loss of voice
• runny nose
• stuffy nose

Individualize dose based on safety, efficacy, and prior therapy
-All doses provided as pioglitazone/metformin

Immediate-release (IR):
Initial dose: 15 mg/500 mg IR orally twice a day or 15 mg/850 mg IR orally once a day
-For patients inadequately control on metformin monotherapy: May initiate with 15 mg/850 mg IR orally twice a day (depending on previous metformin dose)
-For patients with NYHA Class I or Class II CHF: Initial dose: 15 mg/500 mg IR or 15 mg/850 mg IR orally once a day
Maintenance dose: Gradually titrate dose based on safety and efficacy
Maximum dose: Pioglitazone 45 mg/Metformin 2550 mg per day

Extended-release (XR):
Initial dose: 15 mg/1000 mg XR or 30 mg/1000 mg XR orally once a day
-For patients inadequately control on pioglitazone or metformin monotherapy: 15 mg/1000 mg XR twice a day (depending on previous metformin dose) or 30 mg/1000 mg XR orally once a day
Maintenance dose: Gradually titrate dose based on safety and efficacy
Maximum dose: Pioglitazone 45 mg/Metformin 2000 mg per day

Comments:
-Initial doses for patients receiving combination therapy as separate tablets should be as close as possible to current regimen.
-Take with meals and gradually titrate metformin doses to reduce gastrointestinal side effects; metformin doses above 2000 mg may be better tolerated given 3 times a day.
-After initiation of therapy, and with each dose increase, carefully monitor for adverse reactions related to fluid retention.
-If hypoglycemia occurs with concomitant use of insulin or insulin secretagogue, the insulin or insulin secretagogue dose should be reduced.

Use: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate.

-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

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

Administration advice:
-Take with food
-Swallow whole with a glass of water
-Extended-release product should not be chewed, cut, or crushed; the tablet shell may be seen in the stool

General:
-This drug may need to be temporarily stopped prior to radiologic studies utilizing iodinated contrast materials and for surgical procedures when restricted food or fluid intake is expected; may resume once adequate renal function is confirmed.
-This drug should not be used in patients with symptomatic heart failure.
-Hypoglycemia may occur if used in combination with other hypoglycemic agents, especially insulin or insulin secretagogues; dose reduction of concomitant drug may be necessary.
-Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin and therefore would not be effective in patients with type 1 diabetes or diabetic ketoacidosis and should not be used in treat these conditions.

Monitoring:
-Observe closely for signs and symptoms of heart failure especially at therapy initiation and with each increase in dose
-Hepatic: Liver function tests (ALT, AST, total bilirubin, and alkaline phosphatase) should be obtained prior to initiating therapy and promptly if signs or symptoms of liver injury develop; routine monitoring in patients without liver disease is not recommended.
-Renal: Assess renal function baseline, repeat at least annually and more often as clinically indicated.
-Hematologic: Measure hematologic parameters at baseline, and annually
-Monitor glycemic control

Patient advice:
-Patients should understand the importance of diet and exercise in the management of their diabetes; they should understand during periods of stress, medication requirements may change and they should seek medical advice promptly.
-Patients should understand the management of low and high blood sugars, especially if they are on insulin or other medications that may affect blood sugars.
-This drug may cause edema; patients experiencing rapid weight gain, shortness of breath or other symptoms of heart failure should notify their health care professional promptly.
-Premenopausal anovulatory women may be at risk for pregnancy while on this drug; pregnancy risk should be discussed with patient and adequate contraception offered.
-Patients with unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should be advised to report these symptoms to their health care professional; while gastrointestinal symptoms might be common when initiating treatment, gastrointestinal problems after initiation should be reported.
-Inform patients about the risk of lactic acidosis, conditions that might predispose them to its occurrence, and symptoms to watch for and report.
-Advise patient that this drug will need to be temporarily stopped if undergoing radiologic studies with intravascular iodinated contrast materials or surgical procedures that will limit food or fluid intake.
-Advise patients on the risks of excessive alcohol intake.
-Patients should be instructed to report hematuria, dysuria, or urinary urgency promptly.