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Drugs reference index «Rosiglitazone Maleate/Metformin Hydrochloride»

Rosiglitazone Maleate / Metformin Hydrochloride

Pronunciation: (ROE-zi-GLI-ta-zone MAL-ee-ate/met-FOR-min HYE-droe-KLOR-ide)Class: Antidiabetic combination

Trade Names:Avandamet- Tablets rosiglitazone 2 mg/metformin 500 mg- Tablets rosiglitazone 2 mg/metformin 1,000 mg- Tablets rosiglitazone 4 mg/metformin 500 mg- Tablets rosiglitazone 4 mg/metformin 1,000 mg

Pharmacology

Rosiglitazone

Increases insulin sensitivity.

Metformin

Decreases blood glucose by reducing hepatic glucose production, increases peripheral glucose uptake and utilization, and decreases intestinal absorption of glucose.

Pharmacokinetics

Special Populations

Renal Function Impairment

Plasma and blood half-life of metformin is prolonged and the renal Cl is decreased in proportion to the decrease in CrCl.

Hepatic Function Impairment

Cl of rosiglitzone was significantly lower in patients with moderate to severe liver disease and C max and AUC 0-∞ were increased 2- and 3-fold, respectively.

Indications and Usage

As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with combination rosiglitazone and metformin is appropriate.

Contraindications

Patients with renal disease or renal function impairment that may also result from conditions such as CV collapse, acute MI, and septicemia; acute or chronic metabolic acidosis, with or without coma; known hypersensitivity to any component of the product; established New York Heart Association class III or IV heart failure; temporarily suspend treatment in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.

Dosage and Administration

Base dosage selection of rosiglitazone and metformin on the patient's current doses of rosiglitazone or metformin (max daily dose, rosiglitazone 8 mg/metformin 2,000 mg).

Patients Inadequately Controlled on Metformin MonotherapyAdults

PO Start with rosiglitazone 4 mg daily plus the metformin dose already being taken. If prior therapy consists of metformin 1,000 mg/day, start with 2 mg/500 mg and administer 1 tablet twice daily. If prior therapy consists of metformin 2,000 mg/day, start with 2 mg/1,000 mg and administer 1 tablet twice daily.

Patients Inadequately Controlled on Rosiglitazone MonotherapyAdults

PO Start with metformin 1,000 mg daily plus the rosiglitazone dose already being taken. If prior therapy consists of rosiglitazone 4 mg/day, start with 2 mg/500 mg and administer 1 tablet twice daily. If prior therapy consists of rosiglitazone 8 mg/day, start with 4 mg/500 mg and administer 1 tablet twice daily.

Switching from Separate Doses of Rosiglitazone and Metformin to Combination TherapyAdults

PO Start with the doses of rosiglitazone and metformin already being taken. Increase the dose in increments of rosiglitazone 4 mg and/or metformin 500 mg up to the max recommended total daily dose of 8 mg/2,000 mg.

Drug-Naive PatientsAdults

PO Start with 2 mg/500 mg once or twice daily. Consider a starting dosage of 2 mg/500 mg twice daily for patients with glycosylated hemoglobin (HbA 1c ) more than 11% or fasting plasma glucose more than 270 mg/dL. Increase dose in increments of 2 mg/500 mg per day in divided doses if patient is not adequately controlled after 4 wk (max, 8 mg/2,000 mg per day).

Renal Function ImpairmentAdults

PO Dosage adjustments should be based on careful assessment of renal function.

Hepatic Function ImpairmentAdults

PO Do not initiate treatment in patients exhibiting evidence of active liver disease or increased serum transaminase levels (ALT more than 2.5 × ULN at the start of therapy).

Storage/Stability

Store at 59° to 86°F. Protect from light.

Drug Interactions

Alcohol

The effects of metformin on lactate metabolism may be potentiated.

Cationic drugs (eg, amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin)

Use with caution; may interact with metformin by competing for common renal tubular transport systems.

Cimetidine

Increased metformin plasma levels.

CYP2C8 inducers (eg, rifampin)

Rosiglitazone plasma concentrations may be reduced, decreasing the efficacy.

CYP2C8 inhibitors (eg, azole antifungal agents [ketoconazole], fluvoxamine, gemfibrozil, trimethoprim)

May elevate rosiglitazone plasma levels, increasing the pharmacologic effects and adverse reactions.

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.

Drugs that cause hypoglycemia (eg, beta-adrenergic blockers, chloramphenicol, fluconazole, MAOIs, NSAIDs, probenecid, salicylates, sulfinpyrazone, sulfonamides, urine acidifiers)

May lead to loss of glycemic control.

Furosemide

Metformin plasma levels may be elevated while furosemide levels may be decreased.

Insulin

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

Iodinated contrast material

May cause acute renal failure and has been associated with lactic acidosis in patients receiving metformin.

Nevirapine

Nevirapine plasma concentrations may be reduced, decreasing efficacy.

Nifedipine

Metformin plasma levels may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

CHF (postmarketing).

CNS

Headache (11%); dizziness (8%); fatigue (6%).

Dermatologic

Pruritus, rash, Stevens-Johnson syndrome, urticaria (postmarketing).

EENT

Nasopharyngitis (6%); decreased visual acuity, diabetic macular edema (postmarketing).

GI

Nausea/vomiting (16%); diarrhea (14%); dyspepsia (10%); abdominal pain, constipation, loose stools (5%).

Hematologic-Lymphatic

Anemia (7%); decreased Hgb and Hct.

Hepatic

Hepatic failure, hepatitis and hepatic enzyme elevations (postmarketing).

Metabolic-Nutritional

Hypoglycemia (12%); edema (6%).

Musculoskeletal

Arthralgia, back pain (5%).

Respiratory

Upper respiratory tract infection (16%); sinusitis (6%); pulmonary edema, pulmonary effusions (postmarketing).

Miscellaneous

Injury (8%); viral infection (5%); anaphylactic reaction, angioedema (postmarketing).

Precautions

Warnings

CHF

May occur or be exacerbated. Observe patients for signs and symptoms of heart failure after starting therapy or increasing the dose. Manage heart failure according to current standards of care. Consider discontinuation or dose reduction if signs or symptoms develop. Use of drug is not recommended in patients with symptomatic heart failure.

Lactic acidosis

Lactic acidosis is a rare but serious metabolic complication that can occur because of metformin accumulation during treatment with rosiglitazone/metformin. It is fatal in approximately 50% of cases.

Myocardial ischemia

Rosiglitazone is associated with an increased risk of myocardial ischemic events (eg, angina, MI). However, available data on the risk of myocardial ischemia are inconclusive.

Monitor

Monitor all patients, especially those receiving rosiglitazone concurrently with a sulfonylurea or insulin and those at risk of heart failure or with mild to moderate heart failure, for signs and symptoms relating to fluid retention, including heart failure. Because the risk of metformin accumulation and lactic acidosis increases with the degree of renal function impairment, assess renal function before starting therapy and at least annually thereafter. Discontinue rosiglitazone/metformin if there is evidence of renal function impairment. Measure fasting blood glucose and HbA 1c periodically to monitor therapeutic response. Initial and periodic monitoring of liver enzymes, hematologic parameters, and renal function is recommended.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

In general, elderly patients are not titrated to the max dose because of age-related decreases in renal function.

Renal Function

Decreased renal function results in decreased renal Cl and prolongation of the metformin half-life. Concomitant medications that affect renal function may result in hemodynamic changes or interfere with disposition of metformin (eg, cationic drugs); use with caution. Avoid metformin in patients whose serum creatinine levels exceed the ULN for their age.

Hepatic Function

Avoid metformin in patients with clinical or laboratory evidence of hepatic disease.

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 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.

Special Risk Patients

Do not titrate elderly, debilitated, and malnourished patients to the max dose. Use with caution in patients with edema; avoid use in patients with type 1 diabetes.

Bone fractures

Increased incidence of bone fractures has been noted in women taking rosiglitazone, but not men.

Change in clinical status

Promptly evaluate patients who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis. Evaluate serum electrolytes and ketones, blood glucose, and, if indicated, blood pH, lactate, pyruvate, and metformin concentrations.

Coadministration with insulin

The addition of rosiglitazone to insulin therapy increased the risk of CHF and myocardial ischemia. Coadministration is not recommended.

Edema

Rosiglitazone may cause fluid retention; use with caution in patients with edema or those who are at risk of heart failure.

Hematologic

Dose-related decreases in HgB and Hct have been reported in patients taking rosiglitazone.

Hypoglycemia

Risk may be increased when used in combination with other hypoglycemic agents, necessitating dose reduction of concomitant therapy.

Hypoxic states

Immediately discontinue therapy in any condition characterized by hypoxemia (eg, acute CHF, MI).

Iodinated contrast materials

Withhold metformin therapy at the time of or prior to parenteral contrast studies with iodinated materials. Reinstitute therapy 48 h after the study and after renal function has been determined to be healthy.

Lactic acidosis

Can occur as a result of metformin accumulation (eg, renal function impairment) or in pathophysiologic conditions associated with tissue hypoperfusion and hypoxia. The risk of lactic acidosis increases with the degree of renal function impairment and the age of the patient.

Macular edema

Has been reported in postmarketing experience in patients taking rosiglitazone.

Ovulation

Rosiglitazone therapy may result in ovulation in some premenopausal anovulatory women, increasing the risk of pregnancy.

Surgical procedures

Treatment should be temporarily suspended for any surgical procedure, except minor procedures not associated with restricted intake of food and fluids, and should not be restarted until oral intake has resumed and renal function has been evaluated as normal.

Type 1 diabetes

Not indicated for use in patients with type 1 diabetes.

Vitamin B 12 levels

Metformin may decrease vitamin B 12 levels.

Weight gain

Dose-related weight gain was seen with rosiglitazone.

Overdosage

Symptoms

Lactic acidosis.

Patient Information

  • Educate patient regarding diabetes and its management, including target ranges for blood sugar control. Instruct patient that medication is not a substitute for diet and exercise, and to continue to follow prescribed regimens.
  • Educate patient or caregiver regarding potential long-term complications of diabetes and the need for regular physical and eye examinations.
  • Advise patient to read patient information leaflet before starting therapy and with each refill.
  • Advise patient to take dose once or twice daily, as prescribed, and to take with food to decrease GI distress.
  • Advise patient that dose may be gradually increased every 2 wk until max benefit is obtained, but that it can take up to 2 to 3 mo for full benefit to be noted.
  • Advise patient not to stop taking or change the dose unless advised by health care provider.
  • Ensure that patient understands how to use home glucose monitor and has a plan for monitoring and recording blood sugar measurements (eg, log). Advise patient to take log to each visit with health care provider.
  • Educate patient regarding value of periodic HbA 1c testing to confirm level of glucose control.
  • Advise patient to discuss with health care provider a plan for managing each of the following situations: medication dosing during intercurrent conditions (eg, infection, sick days, stress, trauma, vomiting), accidental administration of too little or too much medication, missed dose, inadequate food intake or a skipped meal, travel across time zones, change in physical activity.
  • Advise patient to carry medical identification (eg, bracelet, card) of diabetes.
  • Caution patient to avoid excessive alcohol intake to reduce risk of metabolic acidosis.
  • Instruct patient to report any of the following to health care provider immediately: abdominal pain, anorexia, dark urine, general body discomfort, fatigue, muscle aches, nausea, rapid weight gain, unexplained drowsiness, unexplained rapid breathing or shortness of breath, vomiting, yellowing of the skin or eyes.
  • Review symptoms of hypoglycemia and hyperglycemia, and action plans to undertake in the event either occurs.
  • Instruct patient to notify health care provider if experiencing hypoglycemic episodes or if measured blood sugar is outside target range.
  • Caution premenopausal 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.

Copyright © 2009 Wolters Kluwer Health.

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