Indication and Important Limitations of Use for KOMBIGLYZE XR (saxagliptin and metformin HCI extended-release) tablets
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.
KOMBIGLYZE XR should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
KOMBIGLYZE XR has not been studied in patients with a history of pancreatitis.
Lactic acidosis is a rare, but serious, complication that can occur due
to metformin accumulation. The risk increases with conditions such as sepsis, dehydration,
excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.
The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as
malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
Contraindications
- Renal impairment (eg, serum creatinine
levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or abnormal creatinine clearance)
- Hypersensitivity to metformin hydrochloride
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis
- History of a serious hypersensitivity reaction to KOMBIGLYZE XR or saxagliptin (eg, anaphylaxis, angioedema, or exfoliative skin conditions)
Warnings and Precautions
- The reported incidence of lactic acidosis in patients receiving metformin
is very low (approximately 0.03 cases/1000 patient-years). When it occurs, it is
fatal in approximately 50% of cases. Reported cases of lactic acidosis have occurred
primarily in diabetic patients with significant renal insufficiency.
- Patients with congestive heart failure requiring pharmacologic management, in
particular those with unstable or acute congestive heart failure who are at risk
of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis.
- Lactic acidosis risk increases with the degree of renal dysfunction and patient age.
The risk may be significantly decreased by use of minimum effective dose of metformin and
regular monitoring of renal function. Careful renal monitoring is particularly important in
the elderly. KOMBIGLYZE XR should not be initiated in patients ≥80 years of age unless
measurement of creatinine clearance demonstrates that renal function is not reduced.
- Withhold KOMBIGLYZE XR in the presence of any condition associated with hypoxemia,
dehydration, or sepsis.
- There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. After initiating KOMBIGLYZE XR, observe patients carefully 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 of developing pancreatitis while using KOMBIGLYZE XR.
- Before initiation of KOMBIGLYZE XR, and at least annually thereafter, renal function
should be assessed and verified as normal.
- KOMBIGLYZE XR is not recommended in patients with hepatic impairment.
- Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
- Warn patients against excessive alcohol intake.
- KOMBIGLYZE XR should be suspended for any surgical procedure (except minor procedures
not associated with restricted intake of food and fluids), and should not be restarted until
patient's oral intake has resumed and renal function is normal.
- Use of saxagliptin or metformin with medications known to cause hypoglycemia
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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. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with KOMBIGLYZE XR. |
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Metformin: 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, during concomitant use with other glucose-lowering
agents (such as sulfonylureas or insulin), or with use of ethanol. Elderly, debilitated, or
malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication
are particularly susceptible to hypoglycemic effects. |
- Intravascular contrast studies with iodinated materials can lead to acute alteration of renal
function and have been associated with lactic acidosis in patients receiving metformin. KOMBIGLYZE XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for
48 hours after the procedure and reinstituted only after renal function is normal.
- There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin, including 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. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be predisposed to angioedema with KOMBIGLYZE XR.
- There have been no clinical studies establishing conclusive evidence
of macrovascular risk
reduction with KOMBIGLYZE XR or any other
anti-diabetic drug.
Adverse Reactions
- Adverse reactions reported in >5% of patients treated with metformin extended-release and
more commonly than in patients treated with placebo were: diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%).
- Adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly
than in patients treated with placebo were: upper respiratory tract infection (7.7% vs 7.6%),
urinary tract infection (6.8% vs 6.1%), and headache (6.5% vs 5.9%).
- Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered
saxagliptin and metformin immediate-release (IR) and more commonly than in patients treated
with metformin IR alone were: headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).
- Confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin 5 mg compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively). Among the patients using insulin with metformin, the incidence of confirmed hypoglycemia was 4.8% with saxagliptin vs 1.9% with placebo.
Drug Interactions
Because ketoconazole, a strong CYP3A4/5 inhibitor,
increased saxagliptin exposure, limit KOMBIGLYZE XR to 2.5 mg/1000 mg once daily when
coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).
Use in Specific Populations
- Pregnant and Nursing Women: There are no adequate and well-controlled
studies in pregnant women. KOMBIGLYZE XR should be used during pregnancy only if clearly needed.
It is not known whether saxagliptin or metformin are secreted in human milk. Because many
drugs are secreted in human milk, caution should be exercised when KOMBIGLYZE XR is administered to a nursing woman.
- Pediatric Patients: Safety and effectiveness of KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) in pediatric patients have not been established.
Indication and Important Limitations of Use for ONGLYZA (saxagliptin)
ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.
ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
ONGLYZA has not been studied in patients with a history of pancreatitis.
Contraindications
- History of a serious hypersensitivity reaction to ONGLYZA (eg, anaphylaxis, angioedema, or exfoliative skin conditions)
Warnings and Precautions
- Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. After initiating ONGLYZA, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue ONGLYZA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while using ONGLYZA.
- Use with Medications Known to Cause Hypoglycemia: When ONGLYZA 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. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA.
- Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for other potential causes for the event, and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be predisposed to angioedema with ONGLYZA.
- Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug.
Most Common Adverse Reactions
- Most common adverse reactions (regardless of investigator assessment of causality)
reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients
treated with control were upper respiratory tract infection (7.7%, 7.6%),
headache (7.5%, 5.2%), nasopharyngitis (6.9%, 4.0%) and urinary tract infection (6.8%, 6.1%).
- When used as add-on combination therapy with a thiazolidinedione, the incidence of peripheral edema for ONGLYZA 2.5 mg, 5 mg, and placebo was 3.1%, 8.1% and 4.3%, respectively.
- Confirmed hypoglycemia was reported more commonly in patients treated with ONGLYZA 2.5 mg and ONGLYZA 5 mg compared to placebo in the add-on to glyburide trial (2.4%, 0.8% and 0.7%, respectively) and with ONGLYZA 5 mg compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively).
Drug Interactions
Because ketoconazole, a strong CYP3A4/5 inhibitor,
increased saxagliptin exposure, the dose of ONGLYZA should be limited to 2.5 mg when
coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin,
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
and telithromycin).
Use in Specific Populations
- Patients with Renal Impairment: The dose of ONGLYZA is
2.5 mg once daily for
patients with moderate or severe renal impairment, or with end-stage renal disease requiring
hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). ONGLYZA should be administered following
hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis.
Assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter.
- Pregnant and Nursing Women: There are no adequate and well-controlled studies in
pregnant women. ONGLYZA, like other antidiabetic medications, should be used during pregnancy only
if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many
drugs are secreted in human milk, caution should be exercised when ONGLYZA is
administered to a nursing woman.
- Pediatric Patients: Safety and effectiveness of ONGLYZA in pediatric patients have not been established.
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