QTERNMET XR(dapagliflozin, saxagliptin, and metforminhydrochloride)extended-release tablets(六)
tic 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 increasedlactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptakeof lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially inpatients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be institutedpromptly in a hospital setting, along with immediate discontinuation of QTERNMET XR.
In QTERNMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompthemodialysis is recommended to correct the acidosis and remove accumulated metformin (metforminhydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamicconditions). 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 occurinstruct them to discontinue QTERNMET 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 providedbelow:
Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred inpatients with significant renal impairment. The risk of metformin accumulation and metformin-associatedlactic acidosis increases with the severity of renal impairment because metformin is substantially excretedby the kidney. Clinical recommendations [see DOSAGE AND ADMINISTRATION (2.2) and CLINICALPHARMACOLOGY (12.3)] based upon the patient’s renal function include:
•Before initiating QTERNMET XR, obtain an estimated glomerular filtration rate (eGFR).
•Obtain an eGFR at least annually in all patients taking QTERNMET XR. In patients at increased riskfor the development of renal impairment (e.g., the elderly), renal function should be assessed morefrequently.
•QTERNMET XR is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m2 [seeCONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.6)].
Drug Interactions: The concomitant use of QTERNMET XR with specific drugs may increase the risk ofmetformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamicchange, interfere with acid-base balance, or increase metformin accumulation (e.g., cationic drugs) [seeDRUG 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 agebecause elderly patients have a greater likelihood of having hepatic, renal or cardiac impairment thanyounger patients. Assess renal function more frequently in elderly patients [see USE IN SPECIFICOPULATIONS (8.5)].
Radiological Studies with Contrast: Administration of intravascular iodin |
