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Pioglitazone Hydrochloride / Metformin Hydrochloride
Pronunciation: pye-oh-GLI-ta-zone HYE-droe-KLOR-ide/met-FOR-min HYE-droe-KLOR-ide
Class: Antidiabetic combination
- Tablets, oral pioglitazone 15 mg/metformin 500 mg
- Tablets, oral pioglitazone 15 mg/metformin 850 mg
ActoPlus Met XR
- Tablets, ER, oral pioglitazone 15 mg/metformin 1,000 mg ER
- Tablets, ER, oral pioglitazone 30 mg/metformin 1,000 mg ER
Pioglitazone, a thiazolidinedione, increases insulin sensitivity in the liver, skeletal muscle, and adipose tissues. Metformin, a biguanide, decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Indications and Usage
As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and metformin or who have inadequate glycemic control on a thiazolidinedione alone or metformin alone.
Renal disease or dysfunction (eg, serum creatine levels 1.5 mg/dL or higher in men, 1.4 mg/dL or higher in women, abnormal CrCl), which may result from conditions such as CV collapse (shock), acute MI, and septicemia; acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma; patients undergoing radiologic studies involving IV administration of iodinated contrast materials; hypersensitivity to any component of the product; patients with established New York Heart Association (NYHA) class III or IV heart failure.
Dosage and AdministrationAdults
PO Starting dose is based on patient's current regimen of pioglitazone and/or metformin.Immediate Release
Pioglitazone 15 mg/metformin 500 mg or pioglitazone 15 mg/metformin 850 mg once or twice daily with food, not to exceed pioglitazone 45 mg/metformin 2,550 mg per day.ER
Pioglitazone 15 mg/metformin 1,000 mg ER or pioglitazone 30 mg/metformin 1,000 mg ER once daily with the evening meal, not to exceed pioglitazone 45 mg/metformin 2,000 mg ER per day.
- Administer with food.
- ER tablets must be swallowed whole and not chewed, crushed, or cut.
- Elderly, debilitated, and malnourished patients should not be titrated to the maximum dose.
- Do not initiate treatment if a patient exhibits clinical evidence of active liver disease or increased serum transaminase levels at the start of therapy.
Store tablets at 59° to 86°F. Protect from moisture and humidity.
Effect of metformin on lactate metabolism may be potentiated. Warn patients against excessive alcohol intake, short- or long-term, while receiving metformin.Atorvastatin
Concurrent use may decrease pioglitazone and atorvastatin serum concentrations. Coadminister with caution.Cationic drugs (eg, amiloride, digoxin, quinidine)
May increase metformin serum levels by competing for tubular secretion. Careful patient monitoring and dose adjustment of metformin and/or the interfering drug are recommended in patients who are taking cationic medications excreted via the proximal renal tubular secretory system.Cimetidine
Metformin serum levels may be elevated, increasing pharmacologic effects and adverse reactions. Closely monitor renal function. Metformin dosage reduction may be needed.CYP2C8 inducers (eg, rifamycins [eg, rifabutin, rifampin, rifapentine])
Rifampin administration may reduce plasma concentrations and half-life while increasing Cl of pioglitazone, possibly resulting in decreased glycemic control. Closely monitor blood glucose concentrations when starting or stopping CYP2C8 inducers.CYP2C8 inhibitors (eg, fluvoxamine, gemfibrozil, ketoconazole, trimethoprim)
Inhibition of pioglitazone metabolism. Plasma concentration of pioglitazone may be elevated, increasing hypoglycemic and other adverse reactions (eg, edema). Closely monitor blood glucose concentrations when starting or stopping CYP2C8 inhibitors.CYP3A4 substrates
Pioglitazone may be a weak inducer of CYP3A4, which may decrease serum levels of other drugs metabolized by this isozyme.Drugs that cause hyperglycemia (eg, calcium channel blockers, corticosteroids, diuretics, estrogens, isoniazid, nicotinic acid, oral contraceptives, phenothiazines, phenytoin, sympathomimetics, thyroid products)
May lead to loss of glycemic control. Closely monitor the patient to maintain adequate glycemic control.Furosemide
May increase metformin serum levels; metformin may reduce furosemide levels. Coadminister with caution and closely monitor the patient.Hormonal contraceptives
Coadministration of pioglitazone with a hormonal contraceptive (ie, ethinyl estradiol/norethindrone) decreased the ethinyl estradiol AUC and C max . The clinical relevance is unknown.Insulin
Risk of edema may be increased, even after several months of combined therapy.Iodinated contrast material
May cause acute renal failure and has been associated with lactic acidosis in patients receiving metformin. Withhold pioglitazone/metformin therapy prior to and for 48 h after procedures using iodinated contrast material.Midazolam
Midazolam C max and AUC may be reduced, decreasing the pharmacologic effect.Nifedipine
Concurrent use of pioglitazone and nifedipine ER may decrease nifedipine concentrations. Clinical importance is unknown. Coadministration may also increase plasma metformin C max and AUC and increase the amount excreted in the urine. Nifedipine appears to enhance the absorption of metformin.
Unless otherwise stated, the following adverse reactions were reported with combined use of pioglitazone plus metformin.
Dizziness, headache (5%).
Pharyngitis, tooth disorder (pioglitazone) (5%); macular edema (pioglitazone) (postmarketing).
Diarrhea, nausea (6%).
Anemia (2% or less); Hgb decreased (pioglitazone).
Decreased serum vitamin B 12 levels (metformin) (7%).
Weight gain (7%).
Myalgia (pioglitazone) (5%).
Upper respiratory tract infection (14%); sinusitis (5%).
Lower limb edema (11%); edema/peripheral edema (6%).
WarningsCongestive heart failure
Pioglitazone may cause or exacerbate CHF in some patients. Observe patients carefully for signs or symptoms of heart failure after starting or increasing the dose of pioglitazone. If signs or symptoms develop, manage the heart failure according to the current standards of care. Also, consider discontinuation or dose reduction of pioglitazone. Treatment with pioglitazone is not recommended in patients with symptomatic heart failure. Use in patients with established NYHA class III or IV heart failure is contraindicated.Lactic acidosis
Lactic acidosis can occur because of metformin accumulation. Risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute CHF. The onset is often subtle with symptoms such as malaise, myalgias, respiratory distress, somnolence, nonspecific abdominal distress, and laboratory abnormalities such as low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, discontinue the medication and hospitalize the patient immediately.
Obtain periodic fasting blood glucose and hemoglobin A 1c (HbA 1c ) concentrations to monitor therapeutic response. Assess liver enzymes prior to initiation of therapy and periodically thereafter. Monitor all patients for signs and symptoms associated with fluid retention (eg, edema, heart failure). Assess renal function before starting therapy and at least annually thereafter. Monitor renal function more frequently in elderly patients and patients in whom renal function impairment is anticipated. Evaluate hematologic parameters on an annual basis and vitamin B 12 levels at 2- to 3-y intervals in patients at risk of deficiency. For detection of acidosis, evaluate laboratory parameters, such as blood pH, lactate, and electrolytes, in patients with laboratory abnormalities or vague and poorly defined illness. Patients should have regular eye examinations by an ophthalmologist. Promptly refer all patients reporting any visual symptoms to an ophthalmologist.
Category C .
Safety and efficacy not established.
Ensure that initial and maintenance doses are conservative because of the potential for reduced renal function; avoid titration to maximum dose.
Risk of metformin accumulation and lactic acidosis increases with degree of renal function impairment. Patients with serum creatinine levels above the ULN for their age should not receive metformin-containing products.
Do not initiate therapy in patients with clinical evidence of active liver disease or baseline ALT more than 2.5 × ULN. Initiate or continue therapy in patients with mildly elevated liver enzymes (ALT less than 2.5 × ULN) with caution; discontinue therapy in these patients if ALT increases to more than 3 × ULN and persists, or if the patient develops jaundice.
Special Risk Patients
Do not titrate elderly, debilitated, and malnourished patients to the maximum dose. Do not initiate treatment if a patient exhibits clinical evidence of active liver disease or increased serum transaminase levels at the start of therapy.
Pioglitazone may cause fluid retention. Use with caution in patients with edema or at risk of heart failure.
Increased incidence of bone fracture has been observed in women taking pioglitazone.
Decreases in Hgb (2% to 4%) have been reported in patients receiving pioglitazone.
Risk of hypoglycemia increases when used with other oral hypoglycemic agents or insulin; reduction in the dose of the concomitant agent may be necessary.Type 1 diabetes
Do not use in these patients.
CV shock and other conditions characterized by hypoxemia have been associated with lactic acidosis and also may cause prerenal azotemia. Promptly discontinue therapy if such events occur.
Intravascular iodinated contrast materials
Can lead to acute alteration of renal function and have been associated with metformin-induced lactic acidosis. Temporarily discontinue pioglitazone/metformin prior to the procedure, and withhold for 48 h after the procedure; restart only after renal function has returned to normal.
Loss of glucose control
Consider temporarily withholding therapy and administering insulin in patients who lose glycemic control as result of fever, trauma, infection, or surgery.
Has been reported during postmarketing experience.
Pioglitazone therapy may result in resumption of ovulation in premenopausal anovulatory women with insulin resistance. Consider contraceptive measures in such patients.
Temporarily suspend therapy for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids). Do not restart until patient's oral intake has resumed and renal function has been evaluated as healthy.
Urinary bladder tumors
Do not use in patients with active bladder cancer. Evaluate benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone/metformin use in patients with a history of bladder cancer.
Vitamin B 12 levels
Metformin may interfere with B 12 absorption from the B 12 -intrinsic factor complex.
Dose-related weight gain has been reported. Assess patients who experience unusually rapid increases in weight for fluid accumulation and volume-related events (eg, edema, heart failure).
- Advise patient to review the Medication Guide carefully before starting therapy and to read and check for new information each time the medication is refilled.
- Advise patient to take the medication with food.
- Inform patients who are taking the pioglitazone/metformin ER that the tablets must be swallowed whole and not chewed, cut, or crushed. The inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.
- Caution patient not to change the dose or stop taking unless advised by health care provider.
- Advise patient that a reduction in blood glucose may be noted within days of starting therapy but that it may take 2 to 3 mo before the full effect is seen.
- Instruct patient that this drug is not a substitute for diet and exercise and to continue to follow prescribed regimens.
- Caution patient to avoid excessive alcohol use during treatment with pioglitazone/metformin.
- Educate patient regarding type 2 diabetes and its management.
- Emphasize the importance of regular daily blood glucose monitoring and periodic HbA 1c tests. Ensure that patient knows their target values for both.
- Educate patient regarding potential long-term complications of diabetes and need for regular general physical and eye examinations.
- Advise patient to carry medical identification that indicates diabetes (eg, card, bracelet).
- Advise patient to report any of the following to health care provider immediately: abdominal pain or nonspecific discomfort, anorexia, dark urine, edema or swelling, general body discomfort, unexplained drowsiness, unexplained fatigue, unexplained muscle aches, unexplained nausea and/or vomiting, unexplained shortness of breath or rapid breathing, unusually rapid increase in weight, vision changes, or yellowing of the skin or eyes.
- Review symptoms of hypoglycemia and hyperglycemia and action plans to undertake if either occurs.
- Advise patient to discuss with health care provider a plan for managing each of the following situations: accidental administration of too little or too much medication, change in physical activity, dosing during intercurrent conditions (eg, infection, sick days, stress, trauma, vomiting), inadequate food intake or a skipped meal, missed doses, travel across time zones.
- Instruct patient to notify health care provider if experiencing hypoglycemic or hyperglycemic episodes.
- Advise patient that blood will be drawn to check blood cell counts, liver function, and renal function prior to starting therapy and then periodically thereafter.
- Caution women that drug can cause resumption of ovulation in premenopausal anovulatory women with insulin resistance. Advise such women to discuss adequate contraceptive measures with their health care provider.
Copyright © 2009 Wolters Kluwer Health.