• Hypotension: Empagliflozin may cause symptomatic hypotension due to intravascular volume depletion, especially in patients with renal impairment (eGFR <60 mL/minute/1.73 m2), elderly patients, patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or those with low systolic BP. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy ≥3 days prior to surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• 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, myalgia, 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 of age; having a radiologic study with contrast, surgery, and other procedures; hypoxic states (eg, acute heart failure [HF]); 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.
• Lower limb amputation: There are conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Khouri 2018; Inzucchi 2018). Consider alternatives to SGLT2 inhibitors in patients at risk for lower limb amputation, including neuropathy (loss of protective sensation), foot deformity, vascular disease, and history of previous foot ulceration. Patients taking any SGLT2 inhibitor should be monitored frequently for signs and symptoms of foot ulceration. Discontinue empagliflozin therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs (FDA Drug Safety Communication 2017).
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving empagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
• Pancreatitis: Cases of acute pancreatitis, including fatalities, have been reported with linagliptin 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.
• Renal effects: Acute kidney injury (AKI) has been reported with empagliflozin. Prior to initiation, consider risk factors for AKI (eg, hypovolemia, chronic renal insufficiency, HF, use of concomitant medications [eg, diuretics, ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if AKI occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR that tended to stabilize after ~4 weeks (Wanner 2016). Assess renal function prior to initiation and periodically during treatment.
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis requiring hospitalization, have been reported with empagliflozin; treatment with SGLT2 inhibitors, including empagliflozin, increases the risk for urinary tract infection (UTI); monitor for signs and symptoms of UTI and treat as needed.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and, in particular, those with peripheral neuropathy or anemia (ADA 2020).
Disease-related concerns:
• Heart failure: Metformin may be used in patients with stable HF; avoid use in unstable or hospitalized patients with HF (ADA 2020). The risk of lactic acidosis may be increased secondary to hypoperfusion. Use of metformin in patients with HF may be associated with reduced mortality and reduction in hospital readmission for HF (Crowley 2017; Eurich 2013). In cardiovascular outcome trials of patients with type 2 diabetes and atherosclerotic cardiovascular disease, treatment with other DPP-4 inhibitors has been associated with HF. However, in a randomized, double-blind, placebo-controlled trial of linagliptin in patients with type 2 diabetes mellitus and high cardiovascular and renal risks, the rate of hospitalization for HF did not differ from placebo, including in patients with preexisting HF. Median follow-up was 2.2 years (McGuire 2018; Rosenstock 2018). The American Diabetes Association suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with HF (ADA 2020).
• Hepatic impairment: The manufacturer recommends to generally avoid metformin use in patients with hepatic impairment due to potential for lactic acidosis. However, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, may be associated with a survival benefit in carefully selected patients (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy and periodically thereafter using eGFR; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. According to the manufacturer, this combination product should not be initiated or continued if eGFR is <45 mL/minute/1.73m2; use is contraindicated in patients with an eGFR <30 mL/minute/1.73 m2 or maintained on dialysis. 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. Glycemic efficacy of empagliflozin may be decreased in renal impairment. In the EMPA-REG OUTCOME trial, empagliflozin reduced the occurrence of incident or worsening nephropathy (a secondary end point) in diabetic patients with an eGFR ≥30 mL/minute/1.73 m2 and high cardiovascular risk receiving standard care. Post hoc analysis suggested that the renal benefits may persist in the subset of patients with baseline renal impairment (eGFR 30 to <60 mL/minute/1.73 m2) (Wanner 2016). An additional post hoc analysis showed consistent cardiovascular mortality benefits across subgroups with eGFR 30 to <45 mL/minute/1.73 m2, 45 to <60 mL/minute/1.73 m2, and ≥60 mL/minute/1.73 m2 (Wanner 2018).
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.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2020).
Dosage form specific issues:
• ER tablet: Incompletely dissolved tablets may appear in the stool. Assess glycemic control if patient observes tablets in the stool.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin’s effect on lactate metabolism.
• Iodinated contrast: According to the manufacturer, it is recommended to temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with a history of hepatic disease, alcoholism, HF, or in patients who will receive intraarterial 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 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 4 or 5 [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2017).
• Patient education: Diabetes self-management education is essential to maximize the effectiveness of therapy.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (eg, fever, trauma, infection, surgery).
• Surgical procedures: Consider temporary discontinuation of empagliflozin-containing products 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Monitoring Parameters
HbA1c (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 2020]); plasma glucose, hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices); renal function (baseline then at least annually or when clinically indicated; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m2; every 3 months if eGFR 30 to <45 mL/minute/1.73 m2 [Lipska 2011]); volume status (eg, BP, hematocrit, electrolytes); hematologic parameters (annually); vitamin B12 serum concentrations every 2 to 3 years; folate (if megaloblastic anemia is suspected); BP; signs and symptoms of genital mycotic infections and urinary tract infection; lower limb and feet (sores, ulcers, infection); if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).
Pregnancy Considerations
Due to adverse effects on renal development observed in animal studies following use of empagliflozin, the manufacturer does not recommend use of this combination product during the second and third trimesters of pregnancy.
Ovulation rates may increase in some anovulatory females following use of metformin.
Refer to individual monographs for additional information.
Further information
Medical Disclaimer
The content of Holevn is solely for the purpose of providing information about Thuốc Empagliflozin, Linagliptin, and Metformin and is not intended to be a substitute for professional medical advice, diagnosis or treatment. Please contact your nearest doctor or clinic, hospital for advice. We do not accept liability if the patient arbitrarily uses the drug without following a doctor’s prescription.
Reference from: https://www.drugs.com/ppa/empagliflozin-linagliptin-and-metformin.html
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
Test Interactions
Empagliflozin will cause a positive test for glucosuria. Empagliflozin may interfere with 1,5-anhydroglucitol assay; use alternative methods to monitor glycemic control.
Adverse Reactions
Also see individual agents.
1% to 10%:
Gastrointestinal: Diarrhea (2% to 7%), constipation (5% to 6%), gastroenteritis (3% to 6%)
Genitourinary: Urinary tract infection (10%)
Nervous system: Headache (5%)
Respiratory: Upper respiratory tract infection (8% to 10%), nasopharyngitis (6% to 8%)
<1%: Hypoglycemia
Postmarketing: Lactic acidosis
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 of age, 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 empagliflozin/linagliptin/metformin 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 dipeptidyl peptidase 4 (DPP-4) inhibitor use; onset may occur within 1 day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy is resumed.
• Bone fractures: An increased incidence of bone fractures has been observed with other sodium-glucose transport protein 2 (SGLT2) inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (Ruanpeng 2017; Tang 2016).
• 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.
• Genital mycotic infections: Empagliflozin may increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections are at greater risk.
• Hypersensitivity reactions: Discontinue if signs/symptoms of severe hypersensitivity reaction occur. Patients may experience hypersensitivity reactions (eg, angioedema, urticaria), with some being severe, due to empagliflozin. Hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative dermatologic reactions, have been reported with linagliptin use. 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-4 inhibitor use.
• Hypotension: Empagliflozin may cause symptomatic hypotension due to intravascular volume depletion, especially in patients with renal impairment (eGFR <60 mL/minute/1.73 m2), elderly patients, patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or those with low systolic BP. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy ≥3 days prior to surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• 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, myalgia, 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 of age; having a radiologic study with contrast, surgery, and other procedures; hypoxic states (eg, acute heart failure [HF]); 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.
• Lower limb amputation: There are conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Khouri 2018; Inzucchi 2018). Consider alternatives to SGLT2 inhibitors in patients at risk for lower limb amputation, including neuropathy (loss of protective sensation), foot deformity, vascular disease, and history of previous foot ulceration. Patients taking any SGLT2 inhibitor should be monitored frequently for signs and symptoms of foot ulceration. Discontinue empagliflozin therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs (FDA Drug Safety Communication 2017).
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving empagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
• Pancreatitis: Cases of acute pancreatitis, including fatalities, have been reported with linagliptin 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.
• Renal effects: Acute kidney injury (AKI) has been reported with empagliflozin. Prior to initiation, consider risk factors for AKI (eg, hypovolemia, chronic renal insufficiency, HF, use of concomitant medications [eg, diuretics, ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if AKI occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR that tended to stabilize after ~4 weeks (Wanner 2016). Assess renal function prior to initiation and periodically during treatment.
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis requiring hospitalization, have been reported with empagliflozin; treatment with SGLT2 inhibitors, including empagliflozin, increases the risk for urinary tract infection (UTI); monitor for signs and symptoms of UTI and treat as needed.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and, in particular, those with peripheral neuropathy or anemia (ADA 2020).
Disease-related concerns:
• Heart failure: Metformin may be used in patients with stable HF; avoid use in unstable or hospitalized patients with HF (ADA 2020). The risk of lactic acidosis may be increased secondary to hypoperfusion. Use of metformin in patients with HF may be associated with reduced mortality and reduction in hospital readmission for HF (Crowley 2017; Eurich 2013). In cardiovascular outcome trials of patients with type 2 diabetes and atherosclerotic cardiovascular disease, treatment with other DPP-4 inhibitors has been associated with HF. However, in a randomized, double-blind, placebo-controlled trial of linagliptin in patients with type 2 diabetes mellitus and high cardiovascular and renal risks, the rate of hospitalization for HF did not differ from placebo, including in patients with preexisting HF. Median follow-up was 2.2 years (McGuire 2018; Rosenstock 2018). The American Diabetes Association suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with HF (ADA 2020).
• Hepatic impairment: The manufacturer recommends to generally avoid metformin use in patients with hepatic impairment due to potential for lactic acidosis. However, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, may be associated with a survival benefit in carefully selected patients (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy and periodically thereafter using eGFR; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. According to the manufacturer, this combination product should not be initiated or continued if eGFR is <45 mL/minute/1.73m2; use is contraindicated in patients with an eGFR <30 mL/minute/1.73 m2 or maintained on dialysis. 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. Glycemic efficacy of empagliflozin may be decreased in renal impairment. In the EMPA-REG OUTCOME trial, empagliflozin reduced the occurrence of incident or worsening nephropathy (a secondary end point) in diabetic patients with an eGFR ≥30 mL/minute/1.73 m2 and high cardiovascular risk receiving standard care. Post hoc analysis suggested that the renal benefits may persist in the subset of patients with baseline renal impairment (eGFR 30 to <60 mL/minute/1.73 m2) (Wanner 2016). An additional post hoc analysis showed consistent cardiovascular mortality benefits across subgroups with eGFR 30 to <45 mL/minute/1.73 m2, 45 to <60 mL/minute/1.73 m2, and ≥60 mL/minute/1.73 m2 (Wanner 2018).
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.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2020).
Dosage form specific issues:
• ER tablet: Incompletely dissolved tablets may appear in the stool. Assess glycemic control if patient observes tablets in the stool.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin’s effect on lactate metabolism.
• Iodinated contrast: According to the manufacturer, it is recommended to temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with a history of hepatic disease, alcoholism, HF, or in patients who will receive intraarterial 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 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 4 or 5 [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2017).
• Patient education: Diabetes self-management education is essential to maximize the effectiveness of therapy.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (eg, fever, trauma, infection, surgery).
• Surgical procedures: Consider temporary discontinuation of empagliflozin-containing products 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Monitoring Parameters
HbA1c (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 2020]); plasma glucose, hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices); renal function (baseline then at least annually or when clinically indicated; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m2; every 3 months if eGFR 30 to <45 mL/minute/1.73 m2 [Lipska 2011]); volume status (eg, BP, hematocrit, electrolytes); hematologic parameters (annually); vitamin B12 serum concentrations every 2 to 3 years; folate (if megaloblastic anemia is suspected); BP; signs and symptoms of genital mycotic infections and urinary tract infection; lower limb and feet (sores, ulcers, infection); if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).
Pregnancy Considerations
Due to adverse effects on renal development observed in animal studies following use of empagliflozin, the manufacturer does not recommend use of this combination product during the second and third trimesters of pregnancy.
Ovulation rates may increase in some anovulatory females following use of metformin.
Refer to individual monographs for additional information.
Further information
Medical Disclaimer
The content of Holevn is solely for the purpose of providing information about Thuốc Empagliflozin, Linagliptin, and Metformin and is not intended to be a substitute for professional medical advice, diagnosis or treatment. Please contact your nearest doctor or clinic, hospital for advice. We do not accept liability if the patient arbitrarily uses the drug without following a doctor’s prescription.
Reference from: https://www.drugs.com/ppa/empagliflozin-linagliptin-and-metformin.html
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
Test Interactions
Empagliflozin will cause a positive test for glucosuria. Empagliflozin may interfere with 1,5-anhydroglucitol assay; use alternative methods to monitor glycemic control.
Adverse Reactions
Also see individual agents.
1% to 10%:
Gastrointestinal: Diarrhea (2% to 7%), constipation (5% to 6%), gastroenteritis (3% to 6%)
Genitourinary: Urinary tract infection (10%)
Nervous system: Headache (5%)
Respiratory: Upper respiratory tract infection (8% to 10%), nasopharyngitis (6% to 8%)
<1%: Hypoglycemia
Postmarketing: Lactic acidosis
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 of age, 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 empagliflozin/linagliptin/metformin 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 dipeptidyl peptidase 4 (DPP-4) inhibitor use; onset may occur within 1 day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy is resumed.
• Bone fractures: An increased incidence of bone fractures has been observed with other sodium-glucose transport protein 2 (SGLT2) inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (Ruanpeng 2017; Tang 2016).
• 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.
• Genital mycotic infections: Empagliflozin may increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections are at greater risk.
• Hypersensitivity reactions: Discontinue if signs/symptoms of severe hypersensitivity reaction occur. Patients may experience hypersensitivity reactions (eg, angioedema, urticaria), with some being severe, due to empagliflozin. Hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative dermatologic reactions, have been reported with linagliptin use. 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-4 inhibitor use.
• Hypotension: Empagliflozin may cause symptomatic hypotension due to intravascular volume depletion, especially in patients with renal impairment (eGFR <60 mL/minute/1.73 m2), elderly patients, patients on other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or those with low systolic BP. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor for signs and symptoms of hypotension after initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy ≥3 days prior to surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis; discontinue therapy and treat promptly if ketoacidosis is suspected.
• 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, myalgia, 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 of age; having a radiologic study with contrast, surgery, and other procedures; hypoxic states (eg, acute heart failure [HF]); 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.
• Lower limb amputation: There are conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Khouri 2018; Inzucchi 2018). Consider alternatives to SGLT2 inhibitors in patients at risk for lower limb amputation, including neuropathy (loss of protective sensation), foot deformity, vascular disease, and history of previous foot ulceration. Patients taking any SGLT2 inhibitor should be monitored frequently for signs and symptoms of foot ulceration. Discontinue empagliflozin therapy if any of the following occur: signs and symptoms of new infection (including osteomyelitis), new pain or tenderness, or sores/ulcers involving the lower limbs (FDA Drug Safety Communication 2017).
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving empagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis. Discontinue in patients who develop necrotizing fasciitis and initiate treatment immediately.
• Pancreatitis: Cases of acute pancreatitis, including fatalities, have been reported with linagliptin 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.
• Renal effects: Acute kidney injury (AKI) has been reported with empagliflozin. Prior to initiation, consider risk factors for AKI (eg, hypovolemia, chronic renal insufficiency, HF, use of concomitant medications [eg, diuretics, ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs]). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if AKI occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR that tended to stabilize after ~4 weeks (Wanner 2016). Assess renal function prior to initiation and periodically during treatment.
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis requiring hospitalization, have been reported with empagliflozin; treatment with SGLT2 inhibitors, including empagliflozin, increases the risk for urinary tract infection (UTI); monitor for signs and symptoms of UTI and treat as needed.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and, in particular, those with peripheral neuropathy or anemia (ADA 2020).
Disease-related concerns:
• Heart failure: Metformin may be used in patients with stable HF; avoid use in unstable or hospitalized patients with HF (ADA 2020). The risk of lactic acidosis may be increased secondary to hypoperfusion. Use of metformin in patients with HF may be associated with reduced mortality and reduction in hospital readmission for HF (Crowley 2017; Eurich 2013). In cardiovascular outcome trials of patients with type 2 diabetes and atherosclerotic cardiovascular disease, treatment with other DPP-4 inhibitors has been associated with HF. However, in a randomized, double-blind, placebo-controlled trial of linagliptin in patients with type 2 diabetes mellitus and high cardiovascular and renal risks, the rate of hospitalization for HF did not differ from placebo, including in patients with preexisting HF. Median follow-up was 2.2 years (McGuire 2018; Rosenstock 2018). The American Diabetes Association suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with HF (ADA 2020).
• Hepatic impairment: The manufacturer recommends to generally avoid metformin use in patients with hepatic impairment due to potential for lactic acidosis. However, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, may be associated with a survival benefit in carefully selected patients (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy and periodically thereafter using eGFR; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. According to the manufacturer, this combination product should not be initiated or continued if eGFR is <45 mL/minute/1.73m2; use is contraindicated in patients with an eGFR <30 mL/minute/1.73 m2 or maintained on dialysis. 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. Glycemic efficacy of empagliflozin may be decreased in renal impairment. In the EMPA-REG OUTCOME trial, empagliflozin reduced the occurrence of incident or worsening nephropathy (a secondary end point) in diabetic patients with an eGFR ≥30 mL/minute/1.73 m2 and high cardiovascular risk receiving standard care. Post hoc analysis suggested that the renal benefits may persist in the subset of patients with baseline renal impairment (eGFR 30 to <60 mL/minute/1.73 m2) (Wanner 2016). An additional post hoc analysis showed consistent cardiovascular mortality benefits across subgroups with eGFR 30 to <45 mL/minute/1.73 m2, 45 to <60 mL/minute/1.73 m2, and ≥60 mL/minute/1.73 m2 (Wanner 2018).
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.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for hospitalized patients (ADA 2020).
Dosage form specific issues:
• ER tablet: Incompletely dissolved tablets may appear in the stool. Assess glycemic control if patient observes tablets in the stool.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin’s effect on lactate metabolism.
• Iodinated contrast: According to the manufacturer, it is recommended to temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with a history of hepatic disease, alcoholism, HF, or in patients who will receive intraarterial 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 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 4 or 5 [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2017).
• Patient education: Diabetes self-management education is essential to maximize the effectiveness of therapy.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (eg, fever, trauma, infection, surgery).
• Surgical procedures: Consider temporary discontinuation of empagliflozin-containing products 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Monitoring Parameters
HbA1c (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 2020]); plasma glucose, hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices); renal function (baseline then at least annually or when clinically indicated; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m2; every 3 months if eGFR 30 to <45 mL/minute/1.73 m2 [Lipska 2011]); volume status (eg, BP, hematocrit, electrolytes); hematologic parameters (annually); vitamin B12 serum concentrations every 2 to 3 years; folate (if megaloblastic anemia is suspected); BP; signs and symptoms of genital mycotic infections and urinary tract infection; lower limb and feet (sores, ulcers, infection); if signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]).
Pregnancy Considerations
Due to adverse effects on renal development observed in animal studies following use of empagliflozin, the manufacturer does not recommend use of this combination product during the second and third trimesters of pregnancy.
Ovulation rates may increase in some anovulatory females following use of metformin.
Refer to individual monographs for additional information.
Further information
Medical Disclaimer
The content of Holevn is solely for the purpose of providing information about Thuốc Empagliflozin, Linagliptin, and Metformin and is not intended to be a substitute for professional medical advice, diagnosis or treatment. Please contact your nearest doctor or clinic, hospital for advice. We do not accept liability if the patient arbitrarily uses the drug without following a doctor’s prescription.
Reference from: https://www.drugs.com/ppa/empagliflozin-linagliptin-and-metformin.html
