(re PAG li nide & met FOR min)
Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM), as an adjunct to diet and exercise, in patients currently receiving or not adequately controlled on metformin and/or a meglitinide
Hypersensitivity to repaglinide, metformin, or any component of the formulation; renal impairment (serum creatinine ≥1.5 mg/dL [males] or ≥1.4 mg/dL [females] or abnormal creatinine clearance); acute or chronic metabolic acidosis (including diabetic ketoacidosis); concomitant administration of gemfibrozil
Note: The manufacturer recommends to temporarily discontinue metformin in patients undergoing radiologic studies in which intravascular iodinated contrast media are utilized.
Lactic acidosis is a rare but serious complication that can occur because of metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure (CHF).
The onset of lactic acidosis is often subtle and accompanied only by nonspecific symptoms, such as malaise, myalgia, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
If acidosis is suspected, discontinue repaglinide/metformin and hospitalize the patient immediately.
Type 2 diabetes mellitus: Oral: Note: Daily doses should be divided and given 2-3 times daily with meals (maximum single dose: 4 mg/dose [repaglinide], 1000 mg/dose [metformin]; maximum daily dose: 10 mg/day [repaglinide], 2500 mg/day [metformin])
Patients currently taking repaglinide and metformin: Initial doses should be based on (but not exceeding) the patient 's current doses of repaglinide and metformin; titrate as needed to the maximum daily dose to achieve targeted glycemic control
Patients inadequately controlled on metformin alone: Initial dose: Repaglinide 1 mg/metformin 500 mg twice daily with meals. Titrate slowly to reduce the risk of repaglinide-induced hypoglycemia.
Patients inadequately controlled on a meglitinide alone: Initial dose: Metformin 500 mg twice daily plus repaglinide at a dose similar to (but not exceeding) the patient 's current dose. Titrate slowly to reduce the risk of metformin-induced gastrointestinal adverse effects.
Refer to adult dosing.
Manufacturers labeling: Serum creatinine (SCr) ≥1.5 mg/dL (males) or ≥1.4 mg/dL (females) or abnormal CrCl (not defined): Use is contraindicated.
Alternate recommendations: Note: The United Kingdom National Institute for Health and Clinical Excellence (NICE) Guidelines recommends prescribing metformin with caution in those patients who are at risk of sudden deterioration in renal function and at risk of an estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73 m2 (NICE, 2008]). Some evidence suggests that use of metformin is unsafe when eGFR <30 mL/minute/1.73 m2 (calculated using MDRD) (Shaw, 2007). A review of the available data by members of the American Diabetes Association proposed the following recommendations based on eGFR (Lipska, 2011):
eGFR ≥60 mL/minute/1.73 m2: No contraindications, monitor renal function annually
eGFR ≥45 to <60 mL/minute/1.73 m2: Continue use; monitor renal function every 3 to 6 months
eGFR ≥30 to <45 mL/minute/1.73 m2: In patients currently receiving metformin, use with caution, consider dosage reduction (eg, 50% reduction or 50% of maximal dose), monitor renal function every 3 months. Do not initiate therapy in patients with eGFR <45 mL/minute/1.73 m2
eGFR <30 mL/minute/1.73 m2: Discontinue use
The manufacturer recommends to avoid metformin since liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with liver dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett, 2010; Zhang, 2014). Repaglinide should be used with caution in patients with hepatic impairment.
Administer 15-30 minutes before meals to avoid risk of hypoglycemia/GI upset; if a meal skipped or patient is unable to take anything by mouth, do not administer dose.
Should be taken 15-30 minutes before meals to prevent hypoglycemia and decrease the risk of GI upset; if the patient misses a meal or is unable to take anything by mouth, the fixed-dose repaglinide/metformin combination agent should not be administered. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy. Treatment may cause hypoglycemia; the patient should be able to recognize the signs and symptoms of hypoglycemia (palpitations, tachycardia, sweaty palms, diaphoresis, lightheadedness, etc). Monitor for signs and symptoms of vitamin B12 and/or folic acid deficiency; supplementation may be required.
Do not store above 25 ‚ °C (77 ‚ °F). Protect from moisture.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
PrandiMet ‚ ®:
1/500: Repaglinide 1 mg and metformin hydrochloride 500 mg
2/500: Repaglinide 2 mg and metformin hydrochloride 500 mg
Generic:
1/500: Repaglinide 1 mg and metformin hydrochloride 500 mg
2/500: Repaglinide 2 mg and metformin hydrochloride 500 mg
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
Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Atazanavir: May increase the serum concentration of Repaglinide. Management: Use of repaglinide or other narrow therapeutic index CYP2C8 substrates with atazanavir without concurrent ritonavir is not recommended. If repaglinide is used with ritonavir-boosted atazanavir, no significant interaction is expected. Avoid combination
Bosentan: May decrease the serum concentration of CYP3A4 Substrates. 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
Cimetidine: May increase the serum concentration of MetFORMIN. Consider therapy modification
Clopidogrel: May increase the serum concentration of Repaglinide. Management: Consider a repaglinide dose adjustment and monitor for increased repaglinide effects (eg, hypoglycemia) if combined with clopidogrel. Canadian labeling states that this combination is contraindicated. Consider therapy modification
CycloSPORINE (Systemic): May increase the serum concentration of Repaglinide. Monitor therapy
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
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
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 Repaglinide. 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
Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Gemfibrozil: May increase the serum concentration of Repaglinide. The addition of itraconazole may augment the effect of gemfibrozil on repaglinide. Avoid combination
Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy
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
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
Macrolide Antibiotics: May increase the serum concentration of Repaglinide. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. 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
Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. 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
Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Pegvisomant: 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 decrease the serum concentration of Repaglinide. Management: Consider alternatives to this combination. Dose timing may substantially affect this interaction; in clinical studies, the lowest magnitude of interaction was seen when repaglinide was given 1 h after rifampin (compared to 0, 12, or 24 h). 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
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Telaprevir: May increase the serum concentration of Repaglinide. Monitor therapy
Teriflunomide: May increase the serum concentration of Repaglinide. Monitor therapy
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy
Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy
Trimethoprim: May decrease the metabolism of Repaglinide. 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
Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy
Regular assessment of fasting blood glucose, postprandial blood glucose, and hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]); initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) and renal function should be performed at least annually. Evaluation of vitamin B12 and folate should be performed if anemia is present.
The following information reflects the frequency of adverse effects experienced by patients who received the repaglinide/metformin fixed-dose combination product. Also see individual agents.
>10%:
Central nervous system: Headache (22%)
Endocrine & metabolic: Hypoglycemia (33%)
Gastrointestinal: Diarrhea (19%), nausea (15%)
Respiratory: Upper respiratory tract infection (11%)
Concerns related to adverse effects:
- Cardiovascular mortality: Some studies suggest that sulfonylureas may be associated with increased cardiovascular events. Theoretically, repaglinide may also increase cardiovascular events, but there are no long-term studies assessing this concern; metformin does not appear to share this risk.
- Hypoglycemia: May cause hypoglycemia; appropriate patient selection, dosage, and patient education are important to avoid hypoglycemic episodes. Ethanol may increase risk of hypoglycemia; instruct patients to avoid ethanol.
- Lactic acidosis: [US Boxed Warning]: Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin that requires urgent care and hospitalization. The risk is increased in patients with acute congestive heart failure, dehydration, excessive alcohol intake, hepatic or renal impairment, or sepsis. Symptoms may be nonspecific (eg, abdominal distress, malaise, myalgia, respiratory distress, somnolence); low pH, increased anion gap and elevated blood lactate may be observed. Discontinue immediately if acidosis is suspected. 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.
Disease-related concerns:
- Adrenal/pituitary impairment: Use with caution in patients with adrenal and/or pituitary impairment; may be more susceptible to glucose-lowering effects.
- Diabetes mellitus (type 1): Not indicated for use in patients with insulin-dependent diabetes mellitus (IDDM; type 1).
- Heart failure: Use caution in patients with heart failure requiring pharmacologic management, particularly in patients with unstable or acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion.
- Hepatic impairment: Use with caution in patients with hepatic impairment due to potential for lactic acidosis.
- Renal impairment: Metformin is substantially excreted by the kidney; use with caution in patients with renal impairment (use is contraindicated in some patients). Monitor renal function; may assess more frequently in patients at increased risk of developing renal impairment (eg, elderly). 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 therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Concurrent drug therapy issues:
- Gemfibrozil: Concomitant use has been reported to result in prolonged, severe hypoglycemia; the addition of itraconazole may augment the effect of gemfibrozil on repaglinide. Concurrent use of gemfibrozil is contraindicated with the repaglinide/metformin fixed-dose combination product.
- NPH insulin: Repaglinide is not indicated for use in combination with NPH insulin; in two studies, reports of myocardial ischemia (6 events) in patients using repaglinide plus insulin have caused concern. Further evaluation is required to assess the safety of this combination.
Special populations:
- Elderly: Use with caution in the elderly; may be more susceptible to glucose-lowering effects. Metformin should not be initiated in patients ≥80 years of age unless normal renal function is confirmed.
- Malnourished patients: Use with caution in malnourished patients; may be more susceptible to glucose-lowering effects.
Other warnings/precautions:
- Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformins effect on lactate metabolism.
- Iodinated contrast: The FDA recommends temporary discontinuation of 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. 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). Temporary discontinuation of metformin should occur at the time of or prior to the procedure, withheld for 48 hours following the procedure, and then resumed only when normal renal function is confirmed.
- Surgical procedures: Therapy should be suspended for any surgical procedures (resume only after normal intake resumed and normal renal function is verified).
C
Animal reproduction studies have not been conducted with this combination. See individual agents.
Combination therapy; repaglinide and metformin act to improve glycemic control via two different mechanisms of action:
Repaglinide is a nonsulfonylurea hypoglycemic agent which stimulates insulin release by blocking ATP-dependent potassium channels, depolarizing the membrane and facilitating calcium entry through calcium channels; increased intracellular calcium stimulates insulin release from the pancreatic beta cells.
Metformin prevents hyperglycemia by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity via increased peripheral glucose uptake and utilization.
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, flatulence, nausea, vomiting, diarrhea, rhinitis, or rhinorrhea. Have patient report immediately to prescriber bruising, bleeding, angina, chills, pharyngitis, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), or signs of too much lactic acid in the blood (lactic acidosis; fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, or muscle pain or cramps) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.