Rosiglitazone and metformin

Rosiglitazone and metformin combination is used to treat a type of diabetes mellitus called type 2 diabetes. It is used together with a proper diet and exercise to help control blood sugar levels.

Rosiglitazone helps your body use insulin better. Metformin reduces the absorption of sugar from the stomach, reduces the release of stored sugar from the liver, and helps your body use sugar better.

rosiglitazone and metformin is available only with your doctor's prescription.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Pale skin
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness

• Anxiety
• blurred vision
• chest pain or discomfort
• chills
• cold sweats
• coma
• confusion
• cool, pale skin
• depression
• dilated neck veins
• dizziness
• extreme fatigue
• fast heartbeat
• headache
• increased hunger
• irregular breathing
• irregular heartbeat
• nausea
• nightmares
• seizures
• shakiness
• slurred speech
• swelling of the face, fingers, feet, or lower legs
• weight gain

• Abdominal or stomach discomfort
• decreased appetite
• diarrhea
• fast, shallow breathing
• general feeling of discomfort
• muscle pain or cramping
• sleepiness

• Change in vision
• dark urine
• decreased urine output
• hives or welts, itching, or skin rash
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• pain or discomfort in the arms, jaw, back, or neck
• redness of the skin
• stomach pain
• sweating
• vomiting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Body aches or pain
• cough, fever, sneezing, or sore throat
• difficulty with breathing
• ear congestion
• loss of voice
• pain or tenderness around the eyes and cheekbones
• stuffy or runny nose

• Back pain
• cold or flu-like symptoms
• difficulty with moving
• pain in the joints

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time rosiglitazone and metformin is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take rosiglitazone and metformin or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to rosiglitazone and metformin. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

• Avandamet [DSC]

• Antidiabetic Agent, Biguanide
• Antidiabetic Agent, Thiazolidinedione

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

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Atazanavir: May increase the serum concentration of Rosiglitazone. Monitor therapy

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Cholestyramine Resin: May decrease the serum concentration of Rosiglitazone. Management: Administer rosiglitazone at least 2 hours prior to cholestyramine in order to minimize the likelihood of an interaction, and monitor patients closely for evidence of reduced rosiglitazone effectiveness. Consider therapy modification

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May decrease the metabolism of CYP2C8 Substrates. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

Gemfibrozil: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Limit pioglitazone maximum adult dose to 15 mg/day, and consider dose reduction of rosiglitazone, when used in combination with gemfibrozil. Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: May enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Ethiodized Oil. Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Monitor therapy

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy

Lumacaftor: May increase the serum concentration of CYP2C8 Substrates. Lumacaftor may decrease the serum concentration of CYP2C8 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pregabalin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

RifAMPin: May increase the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Consider alternatives to the concomitant use of rifampin with thiazolidinedione antidiabetic agents. Monitor patients receiving these combinations for decreased effects of the thiazolidinedione derivative. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Selexipag. Management: If initiating selexipag in a patient on a moderate CYP2C8 inhibitor, consider a less frequent dosing regimen (ie, once daily). If initiating a moderate CYP2C8 inhibitor in a patient on selexipag, consider a selexipag dose reduction. Consider therapy modification

Sulfonylureas: Antidiabetic Agents (Thiazolidinedione) may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Vasodilators (Organic Nitrates): May enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Concerns related to adverse effects:

• Edema: Dose-related edema may occur. Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Monitor for signs/symptoms of heart failure.

• Fractures: Increased incidence of bone fractures in females treated with rosiglitazone was observed during analysis of long-term trial; majority of fractures occurred in the upper arm, hand and foot (differing from the hip or spine fractures usually associated with postmenopausal osteoporosis). Consider risk of fracture prior to initiation and during use. According to the American Diabetes Association guidelines, thiazolidinediones should be avoided in patients with fracture risk factors (ADA 2016a).

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including rosiglitazone, may cause or exacerbate congestive heart failure; closely monitor for signs and symptoms of congestive heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases; if heart failure develops, treat accordingly and consider dose reduction or discontinuation. Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure. Rosiglitazone may be associated with an increased risk of angina and MI and a higher frequency of cardiovascular events has also been noted in patients with NYHA class I or II heart failure treated with rosiglitazone. Metformin should be used with caution in patients with heart failure requiring pharmacologic management, particularly in unstable or acute heart failure due to risk of lactic acidosis secondary to hypoperfusion. In a scientific statement from the American Heart Association, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Use with caution in patients at risk for cardiovascular events and monitor closely. Discontinue if any deterioration in cardiac status occurs.

• Hematologic effects: Rosiglitazone may decrease hemoglobin, hematocrit, and/or WBC count (slight); effects may be related to increased plasma volume and/or dose-related. Changes in hemoglobin and hematocrit generally occurred during the first 3 months after initiation of rosiglitazone therapy and after dose increases. Use rosiglitazone with caution in patients with anemia or depressed leukocyte counts (may reduce hemoglobin, hematocrit, and/or WBC). Metformin may impair vitamin B12 absorption; particularly in those with inadequate vitamin B12 or calcium intake/absorption; very rarely associated with anemia. Rapid reversal of vitamin B12 deficiency may be observed with discontinuation of therapy or supplementation. Monitor vitamin B12 serum concentrations periodically with long-term therapy.

• Hypoglycemia: Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished patients, and in patients with adrenal or pituitary insufficiency.

• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended.Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• Macular edema: Has been reported with thiazolidinedione use, including rosiglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. In addition to regular ophthalmic exams, diabetic patients with visual symptoms should receive prompt ophthalmic evaluation. Improvement in macular edema may occur with discontinuation of rosiglitazone therapy.

• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Hepatic impairment: Use metformin with caution in patients with hepatic impairment due to potential for lactic acidosis. Use rosiglitazone with caution in patients with elevated transaminases (AST or ALT); do not initiate in patients with active liver disease of ALT >2.5 times the upper limit of normal (ULN) at baseline; evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation. During therapy, if ALT >3 times ULN, reevaluate levels promptly and discontinue rosiglitazone if elevation persists or if jaundice occurs at any time during use. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.

• Ischemic heart disease: Do not initiate rosiglitazone in patients with stable ischemic heart disease due to an increased risk of cardiovascular complications (Fihn 2012).

• Renal impairment: Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy using estimated glomerular filtration rate (eGFR). Initiation of therapy is not recommended if eGFR is between 30 to 45 mL/minute/1.73 m2 and is contraindicated if eGFR <30 mL/minute/1.73 m2. Assess benefits/risks of continuing therapy in patients whose eGFR falls below 45 mL/minute/1.73 m2 during therapy. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution; risk of metformin associated lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: Temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease ([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

• Surgical procedures: Metformin therapy should be suspended for any surgical procedures (except minor procedures not associated with restricted intake of food and fluids). Restart only after normal oral intake resumed and normal renal function is verified.