METFORMIN Drug Interactions: What You Need to Know

INTERACTIONS Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets.

Table

2: Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ]. Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine.

Alcohol Clinical

Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.

Insulin

Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.

Drugs Affecting Glycemic Control Clinical

Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

• Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring ( 7 )
• Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use ( 7 )
• Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake ( 7 )

Drug Interactions In Vivo

Assessment of Drug Interactions Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without coadministered drug)

No

Effect =

1.00 AUC AUC = AUC inf C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin

0.91 Ratio of arithmetic means

0.93 Furosemide 40 mg 850 mg metformin 1.09

1.22 Nifedipine 10 mg 850 mg metformin 1.16

1.21 Propranolol 40 mg 850 mg metformin 0.90

0.94 Ibuprofen 400 mg 850 mg metformin 1.05

1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions (5.1) and Drug Interactions (7) . ]

Cimetidine

400 mg 850 mg metformin 1.40

1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [ See Warnings and Precautions (5.1) and Drug Interactions (7) .]

Topiramate

5 mg At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 5 mg metformin 1.25

1.17 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without coadministered drug)

No

Effect =

1.00 AUC AUC = AUC inf unless otherwise noted C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide

0.78 Ratio of arithmetic means, p-value of difference < 0.05

0.63 Furosemide 40 mg 850 mg furosemide 0.87

0.69 Nifedipine 10 mg 850 mg nifedipine

1.10 AUC 0-24hr reported

1.08 Propranolol 40 mg 850 mg propranolol 1.01

1.02 Ibuprofen 400 mg 850 mg ibuprofen

0.97 Ratio of arithmetic means

1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01

Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with:

• Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation [see Boxed Warning].
• Severe renal impairment (eGFR below 30 mL/min) [see Warnings and Precautions (5.2)].
• A history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in pioglitazone and metformin hydrochloride tablets.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2)]. Pioglitazone and metformin hydrochloride tablets is contraindicated in patients with:
• Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation [see Boxed Warning].
• Severe renal impairment (eGFR below 30 mL/min) [see Warnings and Precautions ( 5.2 )].
• A history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in pioglitazone and metformin hydrochloride tablets.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions ( 5.2 )].

AND PRECAUTIONS

• Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR. (5.2)
• Heart Failure: Consider the risks and benefits of KOMBIGLYZE XR in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.3 )
• Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.4 )
• Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues: Consider a lower dosage of insulin or insulin secretagogue when used in combination with KOMBIGLYZE XR. ( 5.5 )
• Hypersensitivity-Related Events: There have been post-marketing reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions in patients treated with saxagliptin. If hypersensitivity reactions occur, discontinue KOMBIGLYZE XR, treat promptly, and monitor until signs and symptoms resolve. ( 5.6 )
• Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.7 )
• Bullous Pemphigoid : There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue KOMBIGLYZE XR ( 5.8 ).

5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of KOMBIGLYZE XR. In KOMBIGLYZE XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue KOMBIGLYZE XR and report these symptoms to their health care provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The post-marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [ see Clinical Pharmacology (12.3) ]:

• Before initiating KOMBIGLYZE XR, obtain an estimated glomerular filtration rate (eGFR).
• KOMBIGLYZE XR is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [ see Contraindications (4) ].
• Initiation of KOMBIGLYZE XR is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m 2 .
• Obtain an eGFR at least annually in all patients taking KOMBIGLYZE XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking KOMBIGLYZE XR whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit and risk of continuing therapy.

Drug

Interactions : The concomitant use of KOMBIGLYZE XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [ see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients.

Age

65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [ see Use in Specific Populations (8.5) ].

Radiological

Studies with Contrast : Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop KOMBIGLYZE XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart KOMBIGLYZE XR if renal function is stable. Surgery and Other Procedures : Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. KOMBIGLYZE XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic

States : Several of the post-marketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue KOMBIGLYZE XR.

Excessive Alcohol

Intake : Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.

Hepatic

Impairment : Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of KOMBIGLYZE XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 Pancreatitis There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin. In a cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to 9 of 8173 (0.1%) receiving placebo. Pre-existing risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo. After initiation of KOMBIGLYZE XR, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using KOMBIGLYZE XR.

5.3 Heart Failure In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Patients with a prior history of heart failure and patients with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of KOMBIGLYZE XR prior to initiating treatment in patients at a higher risk for heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure, and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KOMBIGLYZE XR.

5.4 Vitamin B 12 Concentrations In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on KOMBIGLYZE XR and manage any abnormalities [ see Adverse Reactions (6.1) ].

5.5 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Saxagliptin When saxagliptin was used in combination with insulin or an insulin secretagogue, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with insulin or an insulin secretagogue [ see Adverse Reactions (6.1) ]. Therefore, a lower dosage of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with KOMBIGLYZE XR. Metformin HCl Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.6 Hypersensitivity Reactions There have been post-marketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE XR, assess for other potential causes for the event, and institute alternative treatment for diabetes [ see Adverse Reactions (6.2) ]. Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with KOMBIGLYZE XR.

5.7 Severe and Disabling Arthralgia There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.8 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP 4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP 4 inhibitor. Tell patients to report development of blisters or erosions while receiving KOMBIGLYZE XR. If bullous pemphigoid is suspected, KOMBIGLYZE XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of KOMBIGLYZE XR. In KOMBIGLYZE XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue KOMBIGLYZE XR and report these symptoms to their health care provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The post-marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [ see Clinical Pharmacology (12.3) ]:

• Before initiating KOMBIGLYZE XR, obtain an estimated glomerular filtration rate (eGFR).
• KOMBIGLYZE XR is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [ see Contraindications (4) ].
• Initiation of KOMBIGLYZE XR is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m 2 .
• Obtain an eGFR at least annually in all patients taking KOMBIGLYZE XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking KOMBIGLYZE XR whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit and risk of continuing therapy.

Drug

Interactions : The concomitant use of KOMBIGLYZE XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [ see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients.

Age

65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [ see Use in Specific Populations (8.5) ].

Radiological

Studies with Contrast : Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop KOMBIGLYZE XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart KOMBIGLYZE XR if renal function is stable. Surgery and Other Procedures : Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. KOMBIGLYZE XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic

States : Several of the post-marketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue KOMBIGLYZE XR.

Excessive Alcohol

Intake : Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.

Hepatic

Impairment : Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of KOMBIGLYZE XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 Pancreatitis There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin. In a cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to 9 of 8173 (0.1%) receiving placebo. Pre-existing risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo. After initiation of KOMBIGLYZE XR, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using KOMBIGLYZE XR.

5.4 Vitamin B 12 Concentrations In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on KOMBIGLYZE XR and manage any abnormalities [ see Adverse Reactions (6.1) ].

5.5 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Saxagliptin When saxagliptin was used in combination with insulin or an insulin secretagogue, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with insulin or an insulin secretagogue [ see Adverse Reactions (6.1) ]. Therefore, a lower dosage of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with KOMBIGLYZE XR. Metformin HCl Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.6 Hypersensitivity Reactions There have been post-marketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE XR, assess for other potential causes for the event, and institute alternative treatment for diabetes [ see Adverse Reactions (6.2) ]. Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with KOMBIGLYZE XR.

5.7 Severe and Disabling Arthralgia There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.8 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP 4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP 4 inhibitor. Tell patients to report development of blisters or erosions while receiving KOMBIGLYZE XR. If bullous pemphigoid is suspected, KOMBIGLYZE XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.