Pioglitazone/metformin

What is Pioglitazone/metformin?

• Pioglitazone/metformin (Actoplus met) is a thiazolidinedione and biguanide combination product used to improve glycemic control in adults with type 2 diabetes.

Pioglitazone

Metformin

What are the uses of this medicine?

• Pioglitazone/metformin (Actoplus met) contains two prescription diabetes medicines called pioglitazone and metformin hydrochloride. Pioglitazone and metformin hydrochloride tablets can be used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

Limitations of Use:

• Pioglitazone and metformin hydrochloride tablets are not for people with type 1 diabetes.
• Pioglitazone and metformin hydrochloride tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

How does this medicine work?

• Pioglitazone and metformin hydrochloride combines two antidiabetic medications with different mechanisms of action to improve glycemic control in adults with type 2 diabetes: pioglitazone, a thiazolidinedione, and metformin hydrochloride, a biguanide.
• Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone: Pioglitazone (pye" oh gli' ta zone) is a thiazolidinedione thought to act by engagement of PPAR-? receptors which induce multiple genes involved in glucose and fatty acid metabolism.

Metformin hydrochloride:

• Metformin (met for' min) is a biguanine and acts as an insulin sensitizing agent, probably through activation of adenosine monophosphate dependent (AMP) kinase in liver and muscle tissue.
• Metformin is often associated with weight loss making it a preferred, first line agent for management of overweight patients with type 2 diabetes.
• Initial concerns about the possibility that metformin (like the related biguanine phenformin) could induce lactic acidosis have been largely resolved, although the agent is contraindicated in patients with renal dysfunction because of this reason and should be used with caution in patients with significant liver disease.

Who Should Not Use this medicine ?

This medicine cannot be used in patients who:

• have severe heart failure
• are allergic to pioglitazone, metformin, or any of the ingredients in pioglitazone and metformin hydrochloride tablets.
• have severe kidney problems
• have a condition called metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin

What drug interactions can this medicine cause?

• The maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors.
• CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. The maximum recommended daily dose of 45 mg for pioglitazone
• Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring.
• Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use.
• Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.
• Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction.
• Topiramate may decrease pioglitazone concentrations. When pioglitazone and metformin hydrochloride and topiramate are used concomitantly, monitor patients for adequate glycemic control.

Is this medicine FDA approved?

Initial U.S. Approval: 2005

How should this medicine be used?

Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR):

• Do not use in patients with eGFR below 30 mL/min/1.73 m2
• Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2
• Assess risk/benefit of continuing pioglitazone and metformin hydrochloride tablets if eGFR falls below 45 mL/min/1.73 m2
• Discontinue if eGFR falls below 30 mL/min/1.73 m2

• Pioglitazone and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.

Recommended dosage: If therapy with a combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is:

• 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

• for patients with New York Heart Association (NYHA) Class I or Class II congestive heart failure: 15 mg/500 mg or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

• for patients inadequately controlled on metformin monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once or twice daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

• for patients inadequately controlled on pioglitazone monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,

• for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: Pioglitazone and metformin hydrochloride tablets should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.

• Pioglitazone and metformin hydrochloride tablets may be titrated up to a maximum daily dose of 45 mg of pioglitazone and 2550 mg of metformin.

• Metformin doses above 2000 mg may be better tolerated given three times a day.
• Monitor patients for adverse events related to fluid retention after initiation and dose increases.
• Obtain liver tests before initiation. If abnormal, use caution when treating with pioglitazone and metformin hydrochloride tablets, investigate the probable cause, treat (if possible), and follow appropriately.

Concomitant Use with Strong CYP2C8 Inhibitors:

• Coadministration of pioglitazone (one of the ingredients in pioglitazone and metformin hydrochloride tablets) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone and metformin hydrochloride tablets are 15 mg/850 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors.

Administration:

• Pioglitazone and metformin hydrochloride tablets may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled
• Take pioglitazone and metformin hydrochloride tablets with meals to lower your chance of an upset stomach
• If you miss a dose of pioglitazone and metformin hydrochloride tablets, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day
• If you take too much pioglitazone and metformin hydrochloride, call your doctor or go to the nearest hospital emergency room right away
• If your body is under stress such as from a fever, infection, accident, or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away
• Stay on your diet and exercise programs and test your blood sugar regularly while taking pioglitazone and metformin hydrochloride tablets.
• Your doctor should do certain blood tests before you start and while you take pioglitazone and metformin hydrochloride tablets
• Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with pioglitazone and metformin hydrochloride tablets
• Your doctor should check your eyes regularly while you take pioglitazone and metformin hydrochloride tablets

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As Tablets: 15 mg pioglitazone/500 mg metformin hydrochloride and 15 mg pioglitazone/850 mg metformin hydrochloride

This medicine is available in fallowing brand namesː

• Actoplus met ; Actoplus met xr

What side effects can this medication cause?

The most common side effects of this medicine include:

• cold-like symptoms (upper respiratory tract infection)
• swelling (edema)
• diarrhea
• headache
• increased weight

Pioglitazone and metformin hydrochloride tablets may cause serious side effects, including:

• new or worse heart failure
• lactic acidosis
• hypoglycemia
• liver problems
• bladder cancer
• fractures
• macular edema
• release of an egg from an ovary in a woman (ovulation) leading to pregnancy
• anemia

What special precautions should I follow?

• Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone and metformin hydrochloride must be considered.
• There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue pioglitazone and metformin hydrochloride and report these symptoms to their healthcare provider.
• Edema was reported more frequently in patients treated with pioglitazone. Patients treated with pioglitazone and metformin hydrochloride should be monitored for signs and symptoms of congestive heart failure.
• Patients receiving pioglitazone and metformin hydrochloride in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia.
• Fatal and nonfatal hepatic failure in patients taking pioglitazone. In patients with abnormal liver tests, pioglitazone and metformin hydrochloride should be initiated with caution.
• This medicine may increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer.
• Increased incidence of fractures in female patients was observed. Apply current standards of care for assessing and maintaining bone health.
• Macular edema was observed in postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes.
• Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone and metformin hydrochloride.

What to do in case of emergency/overdose?

Symptoms of overdosage may include: Pioglitazone overdose:

• In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

Metformin hydrochloride overdose:

• Hypoglycemia
• Lactic acidosis

Management of overdosage:

• In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
• Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.
• Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.

Can this medicine be used in pregnancy?

• Limited data with pioglitazone and metformin hydrochloride or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage.
• There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Can this medicine be used in children?

• Safety and effectiveness of pioglitazone and metformin hydrochloride in pediatric patients have not been established.

What are the active and inactive ingredients in this medicine?

• Active Ingredients: pioglitazone hydrochloride and metformin hydrochloride
• Inactive Ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.

Who manufactures and distributes this medicine?

Finished drug product manufactured by

• Lek Pharmaceuticals d.d., SI-1526 Ljubljana, Slovenia for
• Sandoz Inc., Princeton, NJ

What should I know about storage and disposal of this medication?

• Store pioglitazone and metformin hydrochloride tablets at 68°F to 77°F (20°C to 25°C).
• Keep pioglitazone and metformin hydrochloride tablets in the original container and protect from light.
• Keep the pioglitazone and metformin hydrochloride tablets bottle tightly closed and keep tablets dry.

• Dailymed label info on Pioglitazone/metformin
• FDA Pioglitazone/metformin

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