`
`
`• Hypersensitivity to metformin hydrochloride. (4)
`
`
`
`• Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
`
`
`• History of a serious hypersensitivity
`(e.g., anaphylaxis,
`reaction
`
`
`angioedema, exfoliative skin conditions) to KOMBIGLYZE XR or
`
`saxagliptin. (4)
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS ---------------------­
`• Lactic Acidosis: See boxed warning. (5.1)
`
`
`
`• Pancreatitis:
`
`
`
`
`If pancreatitis
`suspected, promptly discontinue
`is
`
`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 B12 Deficiency: Metformin may lower vitamin B12 levels. Measure
`
`
`
`
`
`
`
`
`
`hematological parameters annually. (5.4, 6.1)
`• Hypoglycemia: In the saxagliptin add-on to sulfonylurea, add-on to insulin,
`
`
`
`
`
`
`
`
`and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia
`
`
`was reported more commonly in patients treated with saxagliptin compared
`
`
`to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or
`
`insulin, a lower dose of the insulin secretagogue or insulin may be required
`
`
`to minimize the risk of hypoglycemia. (5.6, 6.1)
`
`• Hypersensitivity-Related Events (e.g., urticaria, facial edema): More
`
`
`
`
`
`common in patients treated with saxagliptin than in patients treated with
`
`
`placebo; and post-marketing reports of serious hypersensitivity reactions,
`
`
`such as anaphylaxis, angioedema, and exfoliative skin conditions in
`
`patients treated with saxagliptin. Promptly discontinue KOMBIGLYZE
`
`
`
`XR, assess for other potential causes, institute appropriate monitoring and
`
`treatment, and initiate alternative treatment for diabetes. (5.7, 6.1, 6.2)
`• 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. (5.8)
`• 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 (5.9).
`
`• Macrovascular Outcomes: There have been no clinical studies establishing
`
`
`
`
`
`
`
`
`conclusive evidence of macrovascular risk reduction with KOMBIGLYZE
`
`
`XR or any other antidiabetic drug. (5.10)
`
`
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`• Adverse reactions reported in >5% of patients treated with metformin
`
`
`
`
`
`extended-release and more commonly than in patients treated with placebo
`
`
`are: diarrhea and nausea/vomiting. (6.1)
`
`
`
`
`
`
`
`
`
`
`
`
`• Adverse reactions reported in ≥5% of patients treated with saxagliptin and
`
`
`
`more commonly than in patients treated with placebo are: upper respiratory
`
`
`
`tract infection, urinary tract infection, and headache. (6.1)
`
`
`
`
`
`
`
`
`
`
`• Adverse reactions reported in ≥5% of treatment-naive patients treated with
`
`
`
`
`
`coadministered saxagliptin and metformin and more commonly than in
`patients treated with metformin alone are: headache and nasopharyngitis.
`
`(6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`------------------------------ DRUG INTERACTIONS ----------------------------­
`
`
`
`• Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole)
`
`
`
`
`significantly increases saxagliptin concentrations. Limit
`KOMBIGLYZE XR dose to 2.5 mg/1000 mg once daily. (2.2, 7.1)
`
`
`
`• Carbonic anhydrase inhibitors may increase the risk of lactic acidosis.
`
`
`
`
`
`
`
`
`
`Consider more frequent monitoring. (7.2)
`
`• 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. (7.3)
`
`
`• Alcohol can potentiate the effect of metformin on lactate metabolism. Warn
`
`
`
`patients against excessive alcohol intake. (7.4)
`
`----------------------- USE IN SPECIFIC POPULATIONS ---------------------­
`
`
`
`• No adequate and well-controlled studies in pregnant women. (8.1)
`
`
`
`• Geriatric Use: Assess renal function more frequently. (8.5)
`
`
`
`
`• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` WARNING: LACTIC ACIDOSIS
`
`
`
`
` See full prescribing information for complete boxed warning.
`
` Post-marketing cases of metformin-associated lactic acidosis have
`
` in death, hypothermia, hypotension, and resistant
`
`resulted
` included malaise, myalgias,
`
`bradyarrhythmias. Symptoms
`
` respiratory distress, somnolence, and abdominal pain. Laboratory
`
` abnormalities included elevated blood lactate levels, anion gap
`
`
`
`
` acidosis, increased lactate/pyruvate ratio; and metformin plasma
`
`
`
`
`
`
`
` levels generally >5 mcg/mL. (5.1)
`
`
`
` Risk factors include renal impairment, concomitant use of certain
`
`
` drugs, age >65 years old, radiological studies with contrast, surgery
`
`
`
`
`
`
`
` and other procedures, hypoxic states, 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. (5.1)
`
`
`If lactic acidosis is suspected, discontinue KOMBIGLYZE XR and
`
` institute general supportive measures in a hospital setting. Prompt
`
`
`
`
`
` hemodialysis is recommended. (5.1)
` ----------------------------- RECENT MAJOR CHANGES ----------------------­
`
`
`
`
`
`
`
`
`
` 1/2017
` Boxed Warning
` Dosing and Administration (2.3, 2.4)
`
`
`
` 1/2017
`
` Contraindications (4)
`
`
`
` 1/2017
`
`
`
`
`
` Warnings and Precautions (5.1, 5.9)
`
`
`
` 1/2017
`
`
`
` Warnings and Precautions (5.2, 5.3)
`
`
`
` 4/2016
`
`--------------------------- INDICATIONS AND USAGE -------------------------­
`
`
`
`
`KOMBIGLYZE XR is a combination of saxagliptin, a dipeptidyl peptidase-4
`
`
`
`(DPP4) inhibitor, and metformin, a biguanide, indicated as an adjunct to diet
`
`
`
`
`
`and exercise to improve glycemic control in adults with type 2 diabetes
`
`
`mellitus when treatment with both saxagliptin and metformin is appropriate.
`
`
`
`
`
`(1, 14)
`
`Limitations of Use:
`
`• Not used for the treatment of type 1 diabetes mellitus or diabetic
`
`ketoacidosis. (1.1)
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`• Administer once daily with the evening meal. (2.1)
`
`
`• Individualize the starting dose based on the patient’s current regimen then
`
`
`
`
`adjust the dosage based on effectiveness and tolerability. (2.1)
`
`
`
`• Do not exceed a daily dosage of 5 mg saxagliptin/2000 mg metformin HCl
`
`
`
`
`
`
`
`extended-release. (2.1)
`
`• Swallow whole. Never crush, cut, or chew. (2.1)
`
`
`
`
`• Limit the saxagliptin dosage to 2.5 mg daily for patients also taking strong
`
`
`
`
`
`
`
`
`
`
`
`
`cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). (2.2, 7.1)
`
`
`• Assess renal function prior to initiation of KOMBIGLYZE XR and
`
`
`
`periodically thereafter. (2.3)
`
`o Do not use in patients with eGFR below 30 mL/min/1.73 m2 .
`
`
`
`
`o
`
`
`
`
`Initiation is not recommended in patients with eGFR between
`30 - 45 mL/min/1.73 m2 .
`
`
`
`o Assess risk/benefit of continuing if eGFR falls below
`
`
`
`
`45 mL/min/1.73 m2 .
`
`
`
`
`o
`
`
`
`
`
`
`
`
`
`
`
`Limit the saxagliptin component to 2.5 mg daily if eGFR is less than
`45 mL/min/1.73 m2 .
`
`o Discontinue if eGFR falls below 30 mL/min/1.73 m2 .
`
`
`
`
`
`
`• KOMBIGLYZE XR may need to be discontinued at time of, or prior to,
`
`
`
`iodinated contrast imaging procedures. (2.4)
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`Tablets:
`
`
`
`
`
`• 5 mg saxagliptin/500 mg metformin HCl extended-release (3)
`
`
`
`• 5 mg saxagliptin/1000 mg metformin HCl extended-release (3)
`
`
`• 2.5 mg saxagliptin/1000 mg metformin HCl extended-release (3)
`
`
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2). (4)
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
` KOMBIGLYZE XR safely and effectively. See full prescribing
`
`
` information for KOMBIGLYZE XR.
`
`
`
`KOMBIGLYZE® XR (saxagliptin and metformin hydrochloride
`
`
`
`
`
`extended-release) tablets, for oral use
`
`Initial U.S. Approval: 2010
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`
`
`Revised: 1/2017
`
`
`
`
`Reference ID: 4043164
`
`
`
` 1
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
`
`1 INDICATIONS AND USAGE
`
`1.1 Limitation of Use
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`
`
`2.2 Dosage Adjustments with Concomitant Use of Strong CYP3A4/5
`
`
`
`
`Inhibitors
`
`
`2.3 Recommendations for Dosing and Administration in Renal Impairment
`
`
`
`
`
`2.4 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Lactic Acidosis
`
`
`5.2 Pancreatitis
`
`
`5.3 Heart Failure
`
`
`5.4 Vitamin B12 Concentrations
`
`5.5 Change in Clinical Status of Patients with Previously Controlled Type 2
`
`
`
`
`
`Diabetes
`
`
`5.6 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`
`
`
`
`5.7 Hypersensitivity Reactions
`
`
`5.8 Severe and Disabling Arthralgia
`
`
`5.9 Bullous Pemphigoid
`
`
`
`5.10 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`7.1 Strong Inhibitors of CYP3A4/5 Enzymes
`
`
`
`
`
`7.2 Carbonic Anhydrase Inhibitors
`
`
`
`
`7.3 Drugs that Reduce Metformin Clearance
`
`
`
`
`7.4 Alcohol
`
`
`7.5 Insulin Secretagogues or Insulin
`
`
`
`7.6 Use with Other Drugs
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`14.1 Glycemic Efficacy Trials
`
`
`14.2 Cardiovascular Safety Trial
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`
`
`
`
`
`Reference ID: 4043164
`
`
`
` 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
` WARNING: LACTIC ACIDOSIS
`
`
`
`
`
`
`
`
`
`
` • Post-marketing 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/Liter), anion gap acidosis (without evidence of ketonuria
`
` or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5
`
`
`
` mcg/mL [see Warnings and Precautions (5.1)].
` • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of
`
`
`
`
`
`
` certain drugs (e.g.,carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater,
` having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., 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 [see Dosage and Administration (2.2),
`
`
`
` Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific
`
`
` Populations (8.6, 8.7)].
`
` • If metformin-associated lactic acidosis is suspected, immediately discontinue KOMBIGLYZE XR
` and institute general supportive measures in a hospital setting. Prompt hemodialysis is
`
`
`
` recommended [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
` KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`
`
`
`
` with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate [see
`
`
` Clinical Studies (14)].
`
` 1.1 Limitation of Use
`
` KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`
`
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
` 2.1 Recommended Dosage
`
`
`
`
`
` The dosage of KOMBIGLYZE XR should be individualized on the basis of the patient’s current regimen,
` effectiveness, and tolerability. KOMBIGLYZE XR should generally be administered once daily with the
`
` evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with
`
`
`
`
`
`
` metformin. The following dosage forms are available:
`
`
`
` KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/500 mg
`
`•
`
` KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 5 mg/1000 mg
`
`
`
`•
` KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets 2.5 mg/1000 mg
`
`
`
`•
`
`3
`
`
`
`
`
`Reference ID: 4043164
`
`

`

`
`
`
`The recommended starting dose of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who
`
`are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once
`
`daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin.
`
`
`
`
`
`In patients treated with metformin, the dosage of KOMBIGLYZE XR should provide metformin at the
`
`
`dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from
`
`
`metformin immediate-release to metformin extended-release, glycemic control should be closely
`
`monitored and dosage adjustments made accordingly.
`
`
`
`Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be treated with
`
`KOMBIGLYZE XR 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are either metformin
`naive or who require a dose of metformin higher than 1000 mg should use the individual components.
`
`
`
`
`
`
`The maximum daily recommended dosage is 5 mg for saxagliptin and 2000 mg for metformin extended-
`
`
`release.
`
`
`No studies have been performed specifically examining the safety and efficacy of KOMBIGLYZE XR in
`
`
`
`patients previously treated with other antihyperglycemic medications and switched to KOMBIGLYZE
`
`
`
`XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring
`
`
`as changes in glycemic control can occur.
`
`
`Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or
`
`
`
`chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the feces as a
`
`
`soft, hydrated mass that may resemble the original tablet.
`
`
`
`
` 2.2 Dosage Adjustments with Concomitant Use of Strong CYP3A4/5 Inhibitors
` The maximum recommended dosage of saxagliptin is 2.5 mg once daily when coadministered with strong
`
`
`
`
`
` cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir,
` itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the
`
`
`
` KOMBIGLYZE XR dosage to 2.5 mg/1000 mg once daily [see Dosage and Administration (2.1), Drug
`
`
` Interactions (7.1), and Clinical Pharmacology (12.3)].
`
`
`
` 2.3 Recommendations for Dosing and Administration in Renal Impairment
`
`
` Assess renal function prior to initiation of KOMBIGLYZE XR and periodically thereafter.
`
`
`
`KOMBIGLYZE XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR)
`
`
`
`
`
`
` below 30 mL/minute/1.73 m2 .
`
`
`
` Initiation of KOMBIGLYZE XR in patients with an eGFR between 30 – 45 mL/minute/1.73 m2 is not
`
`recommended.
`
`
`
`
`
`
`
`
`In patients taking KOMBIGLYZE XR whose eGFR later falls below 45 mL/minute/1.73 m2, assess the
`benefit risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily.
`
`
`
`4
`
`
`
`Reference ID: 4043164
`
`

`

`
`
`Discontinue KOMBIGLYZE XR if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see
`
`
`
`Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
`
` 2.4 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`
` Discontinue 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 m2; a history of liver disease, alcoholism or heart
`
`
`failure; or in any patient who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR
`
`
`
`
`48 hours after the imaging procedure; restart KOMBIGLYZE XR if renal function is stable [see Warnings
`
`
`
`
`
`
`
`
`and Precautions (5.1)].
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/500 mg tablets are
`
`•
` light brown to brown, biconvex, capsule-shaped, film-coated tablets with “5/500” printed on one side and
`
`
`
` “4221” printed on the reverse side, in blue ink.
` KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 5 mg/1000 mg tablets are
`
`
`
`•
`
` pink, biconvex, capsule-shaped, film-coated tablets with “5/1000” printed on one side and “4223” printed
`
`
` on the reverse side, in blue ink.
` KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) 2.5 mg/1000 mg tablets
`
`
`
`•
`
`
` are pale yellow to light yellow, biconvex, capsule-shaped, film-coated tablets with “2.5/1000” printed on
` one side and “4222” printed on the reverse side, in blue ink.
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` KOMBIGLYZE XR is contraindicated in patients with:
`
`
`
` • Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
`
`• Hypersensitivity to metformin hydrochloride.
`
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be
`
`
`treated with insulin.
`
`• History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin, such as
`
`
`
`anaphylaxis, angioedema, or exfoliative skin conditions [see Warnings and Precautions (5.7) and
`
`
`Adverse Reactions (6.2)].
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Lactic Acidosis
`
`
`
`
` There have been post-marketing 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.
`
`
`
`
`Reference ID: 4043164
`
`5
`
`
`
`

`

`
`
`
`
`
`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
`
`
`
`hydrochloride 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 healthcare 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 m2
`
`
`
` [see Contraindications (4)].
`
`Initiation of KOMBIGLYZE XR is not recommended in patients with eGFR between 30 and
`
` 45 mL/minute/1.73 m2 .
`
`
`• 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 m2 ,
`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
`
`
`
`
`Reference ID: 4043164
`
`6
`
`
`
`

`

`
`
`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 m2; 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.
`
`
`
`
`Reference ID: 4043164
`
`7
`
`
`
`

`

`
`
` 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). Subjects with a prior history of heart failure and subjects 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 B12 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, is, however, very rarely associated with anemia and appears to be rapidly reversible with
`
`discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on
`
`
`
` an annual basis is advised in patients on KOMBIGLYZE XR and any apparent abnormalities should be
`
`
` appropriately investigated and managed [see Adverse Reactions (6.1)].
`
`
`
`
`
` Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be
`
`
`
`
`
`predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12
`
`
` measurements at 2- to 3-year intervals may be useful.
`
`
`
` 5.5 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes
`
`
`
`
`
` A patient with type 2 diabetes previously well-controlled on KOMBIGLYZE XR who develops laboratory
`
` abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly
`
`
`
` for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones,
`
`
` blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either
`
`
`
`
` form occurs, KOMBIGLYZE XR must be stopped immediately and other appropriate corrective measures
`
`
`
`
` initiated.
`
`
`
` 5.6 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`
` Saxagliptin
`
` When saxagliptin was used in combination with a sulfonylurea or with insulin, medications known to
`
`
`
` cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in
` combination with a sulfonylurea or with insulin [see Adverse Reactions (6.1)]. Therefore, a lower dose of
`
`
`
`
`
`
`
`
`Reference ID: 4043164
`
`
`8
`
`
`

`

`
`
`
`
`the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in
`
`combination with KOMBIGLYZE XR [see Dosage and Administration (2.3)].
`
`
`
`
`Metformin hydrochloride
`
`
`
`
`
`
`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.
`
` 5.7 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.
`
`
`
`
`
`
`
` 5.8 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.
`
` 5.9 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.
`
`
`
`
`
` 5.10 Macrovascular Outcomes
` There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`KOMBIGLYZE XR or any other antidiabetic drug.
`
`
`
`
`
`
`Reference ID: 4043164
`
`9
`
`
`

`

`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
` The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`
`
`
`
`
`
` • Pancreatitis [see Warnings and Precautions (5.2)]
`
`
`
`
`
` • Hear