the medication [30:<60 mL/minute), which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia or when renal function is unknown; excessive ethanol intake (acute or chronic); moderate and severe hepatic impairment; cases of cardiovascular collapse and disease states associated with hypoxemia such as cardiorespiratory insufficiency which are often associated with hyperlactacidemia; during stress conditions (eg, severe infection, trauma, surgery and postoperative recovery phase); severe dehydration; pregnancy; breast-feeding Dosing: Adult Diabetes mellitus, type 2: Oral: Extended release (ER) formulation: Note: Initial doses should be based on current daily dose of saxagliptin and metformin. Daily dose should generally be administered once daily. Maximum: Saxagliptin 5 mg/metformin 2,000 mg ER per day. Patients inadequately controlled on metformin alone: Initial: Saxagliptin 2.5 to 5 mg once daily plus current daily dose of metformin. Patients who require saxagliptin 2.5 mg and metformin> 1,000 mg/day should not be switched to the combination product. Patients inadequately controlled on saxagliptin 5 mg alone: Initial dose: Saxagliptin 5 mg/metformin 500 mg ER once daily. Patients who require saxagliptin 2.5 mg and are metformin-naïve or require metformin >1,000 mg/day should not be switched to the combination product. Concomitant use with strong CYP3A4/5 inhibitors: Maximum: Saxagliptin 2.5 mg/metformin 1,000 mg once daily Concomitant use with insulin or insulin secretagogues: Reduced dose of insulin or insulin secretagogues (eg, sulfonylureas) may be needed. Immediate release formulation [Canadian product]: Initial doses should be based on current dose of saxagliptin and metformin; daily dose should be divided into 2 equal doses given with meals. Maximum: Saxagliptin 5 mg/metformin 2,000 mg per day Patients inadequately controlled on metformin alone: Initial dose: Saxagliptin 2.5 mg twice daily plus current dose of metformin. Concomitant use with insulin: Reduced dose of insulin may be needed. Dosing: Geriatric Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor). Dosing: Renal Impairment eGFR >45 mL/minute/1.73 m 2 : No dosage adjustment necessary; monitor renal function at least annually. eGFR 30 to 45 mL/minute/1.73 m 2 : Use is not recommended for initiation of therapy; if eGFR falls to <45 mL/minute/1.73 m 2 during therapy, consider benefits/risks of continuing therapy and limit saxagliptin dose to 2.5 mg once daily. eGFR> <30 mL/minute/1.73 m 2 : Use is contraindicated. Dosing: Hepatic Impairment 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). Administration Oral: Administer extended release (ER) tablets once daily with the evening meal. Swallow whole; do not crush, cut, or chew ER tablets. Immediate release formulation [Canadian product] should be administered twice daily with meals (eg, breakfast and dinner). Storage Store at 20 C to 25 C (68 F to 77 F); excursions permitted between 15 C to 30 C (59 F to 86 F). Drug Interactions Abemaciclib: May increase the serum concentration of MetFORMIN. 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 Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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. 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 Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination CYP3A4 Inducers (Strong): May decrease the serum concentration of SAXagliptin. Monitor therapy CYP3A4 Inhibitors (Moderate): May increase the serum concentration of SAXagliptin. Monitor therapy CYP3A4 Inhibitors (Strong): May increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination 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 Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination Insulins: Dipeptidyl Peptidase-IV Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification 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; Diatrizoate Sodium; 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 decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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 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 Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification Sulfonylureas: Dipeptidyl Peptidase-IV Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients 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 Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy Adverse Reactions See individual agents. ALERT: U.S. Boxed Warning Lactic acidosis: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), 65 years, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information. If metformin-associated lactic acidosis is suspected, immediately discontinue therapy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. Warnings/Precautions Concerns related to adverse effects: Arthralgia: Severe and disabling arthralgia has been reported with DPP-IV inhibitor use; onset may occur within one day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-IV inhibitor therapy resumed. Bullous pemphigoid: DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions. Discontinue therapy if bullous pemphigoid is suspected and consider referral to a dermatologist. Hematologic: Dose-related decrease in lymphocyte count has been observed with saxagliptin; clinical significance is not known. Monitoring of lymphocyte counts may be warranted in patients with unusual or persistent infection. Hypersensitivity reactions: Rare hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative dermatologic reactions have been reported with saxagliptin use; discontinue if signs/symptoms of severe hypersensitivity reaction occur. Events have generally been noted within the first 3 months of therapy, and may occur with the initial dose. Use with caution if patient has experienced angioedema with other DPP-IV inhibitor use. 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 use in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function. Pancreatitis: Cases of acute pancreatitis have been reported with saxagliptin use. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis as it is not known if this population is at greater risk. Vitamin B 12 concentrations: Long-term metformin use is associated with vitamin B 12 deficiency; monitor vitamin B 12 serum concentrations periodically with long-term therapy. Monitoring of B 12 serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2017c). Disease-related concerns: Heart failure: Use caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable or acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion. Heart failure that may require hospitalization has been reported with saxagliptin in a multi-center, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history of, or at risk for, cardiovascular events; risk was increased in patients with preexisting heart failure or renal impairment and during the first 12 months of therapy (Scirica 2013; Scirica 2014). However, a population-based retrospective study in an ambulatory setting with relatively lower baseline cardiovascular risk factors failed to demonstrate increased risk in patients on saxagliptin compared to other agents (eg, sitagliptin, pioglitazone, sulfonylureas, insulin) (Toh 2016). Monitor for signs and symptoms of heart failure during therapy and consider discontinuation if condition develops. In a scientific statement from the American Heart Association, saxagliptin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Hepatic impairment: Avoid use in patients with hepatic impairment due to potential for lactic acidosis. Renal impairment: Metformin is substantially excreted by the kidney; use is contraindicated in patients with eGFR <30 mL/minute/1.73 m 2 . 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; the risk of metformin associated lactic acidosis is increased 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 m 2 ; 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 m 2 ; 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 m 2 ]) 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 should be withheld 24 hours before surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2017d). Monitoring Parameters Urine for glucose and ketones; plasma glucose; HbA 1c (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 2017a]); initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices, and lymphocyte counts if unusual or persistent infection); hepatic function; renal function (eGFR) should be performed prior to initiation of therapy and at least annually (more often in patients at risk of developing renal impairment; every 3 to 6 months if eGFR 45 to> <60 mL/minute/1.73 m 2 ; every 3 months if eGFR 30 to> <45 mL/minute/1.73 m 2 [Lipska 2011]); vitamin B 12 (periodically with long-term treatment); folate (if megaloblastic anemia is suspected); signs/symptoms of pancreatitis and/or heart failure Pregnancy Considerations Adverse events were not observed in animal reproduction studies conducted with this combination. Refer to individual monographs. Patient Education 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 nausea, vomiting, diarrhea, flatulence, loss of strength and energy, headache, common cold symptoms, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), angina, chills, pharyngitis, skin blisters, skin breakdown, persistent joint pain, or severe joint pain (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 health care 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. Next Interactions Print this page Add to My Med List More about metformin/saxagliptin Side Effects During Pregnancy Dosage Information Drug Interactions Support Group En Español 14 Reviews Add your own review/rating Drug class: antidiabetic combinations Consumer resources Metformin and saxagliptin Saxagliptin and Metformin Saxagliptin and metformin (Advanced Reading) Professional resources Other brands: Kombiglyze XR Related treatment guides Diabetes, Type 2> ]} Drug Status Rx Availability Prescription only B Pregnancy Category No proven risk in humans N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Metformin / saxagliptin Rating 14 User Reviews 5.9 /10 14 User Reviews 5.9 Rate it! Drug Class Antidiabetic combinations Related Drugs antidiabetic combinations Janumet , Kombiglyze XR , Jentadueto , Invokamet , Glucovance , ActoPlus Met Diabetes, Type 2 metformin , insulin aspart , glipizide , glimepiride , Januvia , pioglitazone , Victoza , Actos , Tradjenta , Glucophage , glyburide , Janumet , Invokana , Amaryl , Welchol , Onglyza , sitagliptin , Trulicity , Jardiance , Lantus , Farxiga , Levemir , Tresiba , Glucotrol , Bydureon , More...} } is consider
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