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Drugs reference index «Pioglitazone Hydrochloride/Metformin Hydrochloride»

Pioglitazone Hydrochloride / Metformin Hydrochloride

Pronunciation: (pye-oh-GLI-ta-zone HYE-droe-KLOR-ide/met-FOR-min HYE-droe-KLOR-ide)Class: Antidiabetic combination

Trade Names:ActoPlus Met- Tablets pioglitazone 15 mg/metformin 500 mg- Tablets pioglitazone 15 mg/metformin 850 mg

Pharmacology

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

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.

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 CrCl), which may result from 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 class III or IV heart failure.

Dosage and Administration

Adults

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

Patients inadequately controlled on metformin monotherapy

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

Patients who initially responded to pioglitazone monotherapy and need additional glycemic control

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

Patients switching from combination therapy of pioglitazone plus metformin as separate tablets

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

Max dose

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

General Advice

  • Administer without regard to meals. Administer with food if GI upset occurs.
  • Elderly, debilitated, and malnourished patients should not be titrated to the max 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.

Storage/Stability

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

Drug Interactions

Alcohol

Effect of metformin on lactate metabolism may be potentiated.

Cationic drugs (eg, amiloride, digoxin, quinidine)

May increase metformin serum levels by competing for tubular secretion.

Cimetidine, nifedipine

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

CYP3A4 system

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.

Furosemide

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

Gemfibrozil

Pioglitazone plasma concentrations may be elevated, increasing the risk of hypoglycemia and other adverse reactions (eg, peripheral and pulmonary edema).

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 metformin therapy at the time of, prior to, and for 48 h after procedures using iodinated contrast material.

Rifampin

Pioglitazone plasma concentrations may be reduced, decreasing glycemic control.

Adverse Reactions

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

CNS

Dizziness, headache (5%).

EENT

Pharyngitis, tooth disorder (pioglitazone) (5%); macular edema (postmarketing).

GI

Diarrhea, nausea (6%).

Genitourinary

UTI (6%).

Hematologic-Lymphatic

Anemia (2% or less).

Lab Tests

Decreased serum vitamin B 12 levels (metformin) (7%).

Metabolic-Nutritional

Weight gain (7%).

Musculoskeletal

Myalgia (pioglitazone) (5%).

Respiratory

Upper respiratory tract infection (14%); sinusitis (5%).

Miscellaneous

Lower limb edema (11%); edema/peripheral edema (6%).

Precautions

Warnings

CHF

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.

Lactic acidosis

Lactic acidosis can occur because of metformin accumulation during treatment with pioglitazone/metformin; it is fatal in approximately 50% of cases. Lactic acidosis also may occur in association with diabetes mellitus and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis from metformin is usually characterized by metformin plasma levels of more than 5 mcg/mL.

Cases have occurred primarily in diabetic patients with significant renal function impairment, including intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with unstable or acute heart failure who are at risk of hypoperfusion and hypoxemia are at an increased risk of lactic acidosis. The risk of lactic acidosis increases with degree of renal function impairment and age. Risk of lactic acidosis may be reduced by the following: regularly monitoring renal function; using minimum effective dose of metformin; not administering to patients older than 80 yr of age unless measurement of CrCl demonstrates that renal function is not reduced; promptly withholding metformin in presence of any condition associated with hypoxemia, dehydration, or sepsis; avoiding use in patients with clinical or laboratory evidence of hepatic disease; temporarily discontinuing metformin prior to any intravascular radiocontrast study and for any surgical procedure; and having patient avoid excessive alcohol use.

Suspect lactic acidosis in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis.

Lactic acidosis is a medical emergency that must be treated in a hospital setting; discontinue drug and promptly institute general supportive measures. Metformin is dialyzable, and prompt hemodialysis corrects the acidosis and removes accumulated metformin.

Monitor

Obtain periodic fasting blood glucose and 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-yr intervals in patients at risk for deficiency. Patients should have regular eye examinations by an ophthalmologist. Promptly refer all patients reporting any visual symptoms to an ophthalmologist.

Pregnancy

Category C . Not recommended for use in pregnant patients.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Ensure that initial and maintenance doses are 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 function 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. 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 patient develops jaundice.

Special Risk Patients

Do not titrate elderly, debilitated, and malnourished patients to the max 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.

Edema

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

Fractures

Increased incidence of bone fracture has been observed in women taking pioglitazone.

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.

Type 1 diabetes

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 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.

Macular edema

Has been reported during postmarketing experience.

Ovulation

Pioglitazone and metformin 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

  • 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 months 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 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, 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 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 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.

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