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Metformin / Pioglitazone Dosage

Applies to the following strength(s): 500 mg-15 mg ; 850 mg-15 mg ; 1000 mg-30 mg ; 1000 mg-15 mg

The information at Drugs.com is not a substitute for medical advice. Always consult your doctor or pharmacist.

Usual Adult Dose for Diabetes Type 2

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.

Renal Dose Adjustments

-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.

Liver Dose Adjustments

Avoid use in patients with clinical or laboratory evidence of hepatic disease

Liver function tests (ALT, AST, alkaline phosphatase, and total bilirubin) should be obtained prior to therapy
-If ALT is greater than 3 times the upper limit of normal (ULN) and total bilirubin greater than 2 x ULN without alternative etiologies: Therapy should not be initiated
-For lesser elevations or in patients with an alternate probable cause, may initiate with caution
-Promptly measure liver tests in patients reporting symptoms indicative of liver injury; if abnormal, interrupt therapy and investigate cause; therapy should not be restarted without another explanation for liver test abnormalities.

Dose Adjustments

Elderly: Renal function should be assessed more frequently in elderly patients.

New York Heart Association (NYHA) Class I or Class II Heart Failure:
-Initial dose (IR): pioglitazone 15 mg/metformin 500 mg immediate-release (IR) or pioglitazone 15 mg/metformin 850 mg IR orally once a day; titrate as needed, after assessing adequacy of response and tolerability.
-Initial dose (XR): pioglitazone 15 mg/metformin 1000 mg extended-release (XR) or pioglitazone 30 mg/metformin 1000 mg XR orally once a day; titrate as needed, after assessing adequacy of response and tolerability.

IODINATED CONTRAST PROCEDURES:
-Stop therapy at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
-Re-evaluate eGFR 48 hours after procedure; restart therapy only if renal function is stable.

Concomitant use with Strong CYP450 2C8 Inhibitors:
-Immediate-release (IR): Maximum dose: pioglitazone 15 mg/metformin 850 mg IR orally once a day
-Extended-release (XR): Maximum dose: pioglitazone 15 mg/metformin 1000 mg XR orally once a day

Hypoglycemia:
-If hypoglycemia occurs in a patient concomitantly receiving an insulin secretagogue such as a sulfonylurea: the dose of the insulin secretagogue should be reduced.
-If hypoglycemia occurs in a patient concomitantly receiving insulin: decrease the insulin dose by 10% to 25%, further adjustments to the insulin dose should be based on glycemic response.

Therapeutic drug monitoring/range: Steady-state plasma concentrations of metformin are achieved within 24 to 48 hours and are generally less than 1 mcg/mL. Metformin levels greater than 5 mcg/mL have been implicated as the cause of lactic acidosis.

Precautions

US BOXED WARNING(S): Congestive Heart Failure and Lactic Acidosis:
-CONGESTIVE HEART FAILURE: Thiazolidinediones, including pioglitazone, may cause or exacerbate congestive heart failure in some patients.
-After initiation of therapy and with any dosage increase, observe patients carefully for signs and symptoms of heart failure including excessive, rapid weight gain, dyspnea, and/or edema; if signs and symptoms of heart failure develop, manage in accordance to current standards of care.
-Drug discontinuation or dosage reduction should be considered in patients showing signs and symptoms of heart failure; this drug is not recommended in patients with symptomatic heart failure.
-Initiation in patients with established NYHA Class III or IV heart failure is contraindicated.
LACTIC ACIDOSIS:
-Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle accompanied only by symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L) anion gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.
-Risk factors include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, radiological studies with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
-Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the prescribing information.
-If metformin-associated lactic acidosis is suspected, immediately discontinue this drug and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

-Metformin is contraindicated in patients with renal failure.
-Metformin may be removed from the system following prolonged hemodialysis;venovenous hemofiltration has been used successfully following metformin overdose.

Other Comments

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.

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