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|Pioglitazone Hydrochloride/Metformin Hydrochloride

Pioglitazone Hydrochloride/Metformin Hydrochloride

Trade Names:
ActosPlus Met
- Tablets pioglitazone 15 mg and metformin 500 mg
- Tablets pioglitazone 15 mg and metformin 850 mg

Mechanism of Action

Pharmacology

Rosiglitazone, 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

Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with pioglitazone plus metformin or whose diabetes is not adequately controlled with metformin alone, or for those patients who initially responded to pioglitazone alone and require additional glycemic control.

Contraindications

Renal disease or dysfunction (eg, serum creatine levels 1.5 mg/dL or higher in men, 1.4 mg/dL or higher in women, or abnormal Ccr); 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.

Dosage and Administration

PO Starting dose is based on patient"s current regimen of pioglitazone and/or metformin.

Pioglitazone 15 mg and metformin 500 mg or pioglitazone 15 mg and metformin 850 mg once daily or bid, then gradually titrate based on therapeutic response.

Pioglitazone 15 mg and metformin 500 mg bid or pioglitazone 15 mg and metformin 850 mg once daily, then gradually titrate based on therapeutic response.

Pioglitazone 15 mg and metformin 500 mg or pioglitazone 15 mg and metformin 850 mg based on dose of pioglitazone and metformin already being taken.

Pioglitazone 45 mg/day, metformin 2,550 mg/day.

Initiate therapy at lowest dose if used in patients with systolic heart failure (New York Heart Association [NYHA] class 2). Increase dose only after several months of therapy with careful monitoring for weight gain, edema, or signs and symptoms of heart failure exacerbation.

General Advice

• Administer without regard to meals. Administer with food if GI upset occurs.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Protect from moisture and humidity.

Drug Interactions

Effect of metformin on lactate metabolism may be potentiated.

May increase metformin serum levels by competing for tubular secretion.

Metformin serum levels may be elevated, increasing pharmacologic and adverse effects.

Pioglitazone may be a weak inducer of CYP3A4, which may decrease serum levels of other drugs metabolized by this isozyme.

May lead to loss of glycemic control.

May increase metformin serum levels; metformin may reduce furosemide levels.

Risk of edema may be increased, even after several months of combined therapy.

Hormone components may decrease, potentially reducing contraceptive effectiveness.

Adverse Reactions

Unless otherwise stated, the following adverse reactions were reported with combined use of pioglitazone plus metformin.

CNS

Dizziness, headache (at least 5%).

EENT

Pharyngitis, tooth disorder (pioglitazone) (at least 5%).

GI

Diarrhea, nausea (at least 5%).

Genitourinary

UTI (at least 5%).

Hematologic

Anemia (less than 2%).

Lab Tests

Decreased serum vitamin B ₁₂ levels (metformin) (at least 5%).

Metabolic-Nutritional

Increased weight (at least 5%).

Musculoskeletal

Myalgia (pioglitazone) (at least 5%).

Respiratory

Sinusitis, upper respiratory tract infection (at least 5%).

Miscellaneous

Edema/peripheral edema, lower limb edema (at least 5%).

Precautions

Pregnancy

Category C . Not recommended for use in pregnant patients.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Initial and maintenance doses should be conservative because of potential for reduced renal function; avoid titration to max dose if possible.

Renal Function

Risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. Patients with serum creatinine levels above ULN for age should not receive metformin-containing products.

Hepatic Function

Do not initiate therapy in patients with clinical evidence of active liver disease or baseline ALT more than 2.5 × ULN. Initiation or continuation of therapy in patients with mildly elevated liver enzymes (ALT less than 2.5 × ULN) should proceed with caution; discontinue therapy in these patients if ALT increases to more than 3 × ULN and persists, or if patient develops jaundice.

Cardiac effects

Pioglitazone may cause fluid retention that may lead to or exacerbate heart failure. Discontinue therapy if any deterioration in cardiac status occurs. Pioglitazone is not recommended in patients with NYHA class 3 or 4 cardiac status.

Edema

Pioglitazone may cause fluid retention. Use with caution in patients with edema or at risk of heart failure.

Hematologic

Decreases in hemoglobin (2% to 4%) have been reported in patients receiving pioglitazone.

Hypoglycemia

Risk of hypoglycemia increases when used with other oral hypoglycemic agents or insulin; reduction in dose of concomitant agent may be necessary.

Do not use in these patients.

Hypoxic states

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 therapy at time of or prior to the procedure, and withhold for 48 hr 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.

Ovulation

Pioglitazone therapy may result in resumption of ovulation in premenopausal, anovulatory women with insulin resistance. Consider contraceptive measures in such patients.

Surgical procedures

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 normal.

Vitamin B ₁₂ levels

Metformin may interfere with B ₁₂ absorption from the B ₁₂ -intrinsic factor complex.

Weight gain

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).

Overdosage

Symptoms

Lactic acidosis.

Patient Information

• Explain name, dose, action, potential benefits, and potential side effects of drug.
• Advise patient to review the Patient Information leaflet carefully before starting therapy and to read and check for new information each time the medication is refilled.
• Advise patient to take without regard to meals, but to take with food if GI upset occurs.
• 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 that patient should 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 glycosylated hemoglobin (A _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, Medi-Alert ).
• 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 occur.
• 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 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 health care provider.
• Advise women to notify health care provider if pregnant, planning to become pregnant, or breast-feeding.
• Instruct patient not to take any other prescription or OTC drugs, dietary supplements, or herbal preparations unless advised by health care provider.
• Advise patient that follow-up visits and laboratory tests will be required to monitor therapy and to keep appointments.