Dosage & Administration
The maximum recommended dosage of KOMBIGLYZE XR is 2.5 mg of saxagliptin and 1,000 mg of metformin HCl given orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [
Individualize the starting dosage of KOMBIGLYZE XR based on the patient’s current regimen and the available strengths of KOMBIGLYZE XR [
Administer KOMBIGLYZE XR once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin HCl [
The recommended starting dosage of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin HCl is one KOMBIGLYZE XR tablet containing 5 mg saxagliptin and 500 mg metformin HCl extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin HCl.
In patients treated with metformin HCl, the recommended starting dosage of KOMBIGLYZE XR should provide metformin HCl at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin HCl immediate-release to KOMBIGLYZE XR, closely monitor glycemic control and adjust the dosage accordingly.
Patients who need 2.5 mg saxagliptin in combination with metformin HCl extended-release may be treated with KOMBIGLYZE XR 2.5 mg/1,000 mg. Patients who need 2.5 mg saxagliptin who are either metformin HCl naive or who require a dose of metformin HCl higher than 1,000 mg should use the individual components.
Gradually titrate the dosage of KOMBIGLYZE XR, as needed, after assessing therapeutic response and tolerability, up to a maximum recommended dosage of KOMBIGLYZE XR (5 mg for saxagliptin and 2,000 mg for metformin HCl extended-release orally once daily).
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.
If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
Bioequivalence and food effect of KOMBIGLYZE XR was characterized under low calorie diet. The low calorie diet consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5% fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy subjects demonstrated that KOMBIGLYZE XR combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA) and metformin HCl extended-release as individual tablets under fed conditions.
Saxagliptin
The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmaxand AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmaxvalues were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmaxfor both saxagliptin and its active metabolite was less than 25%.
No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.
Metformin extended-release Cmaxis achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmaxare less than dose proportional for metformin extended-release within the range of 500 to 2,000 mg. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to the same dose of metformin immediate-release tablets, however, the extent of absorption (as measured by AUC) is similar between extended-release tablets and immediate-release tablets.
The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite.
Following a single oral dose of metformin extended-release, Cmaxis achieved with a median value of 7 hours and a range of 4 to 8 hours.
Administration with a high-fat meal resulted in an increase in Tmaxof saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as KOMBIGLYZE XR combination tablets.
Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on Cmaxand Tmaxof metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release. Food has no significant effect on the pharmacokinetics of metformin when administered as KOMBIGLYZE XR combination tablets.
The
Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmaxand geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmaxis increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.
Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.
No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 White subjects with 105 subjects of other races (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Black or African American (n=51), and Hispanic or Latino ethnicity (n=24).
A single-dose, open-label trial was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmaxof saxagliptin or its metabolite. In subjects with moderate renal impairment with eGFR 30 to less than 45 mL/min/1.73 m2, severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function.
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
No dosage adjustment is recommended based on body mass index (BMI) which was not identified as a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.
Specific pharmacokinetic drug interaction studies with KOMBIGLYZE XR have not been performed, although such studies have been conducted with the individual saxagliptin and metformin components.
In
Coadministered Drug | Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. | Dosage of Saxagliptin | Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. | Cmax | ||||
No dosing adjustments required for the following: | |||||
Metformin | 1,000 mg | 100 mg | saxagliptin | 0.98 | 0.79 |
Glyburide | 5 mg | 10 mg | saxagliptin | 0.98 | 1.08 |
PioglitazoneResults exclude one patient. | 45 mg QD for 10 days | 10 mg QD for 5 days | saxagliptin | 1.11 | 1.11 |
Digoxin | 0.25 mg q6h first day followed by q12h second day followed by QD for | 10 mg QD for 7 days | saxagliptin | 1.05 | 0.99 |
Dapagliflozin | 10 mg single dose | 5 mg single dose | saxagliptin 5-hydroxy saxagliptin | ↓1% ↑9% | ↓7% ↑6% |
Simvastatin | 40 mg QD for 8 days | 10 mg QD for 4 days | saxagliptin | 1.12 | 1.21 |
Diltiazem | 360 mg LA QD for 9 days | 10 mg | saxagliptin | 2.09 | 1.63 |
RifampinThe plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin. | 600 mg QD for 6 days | 5 mg | saxagliptin | 0.24 | 0.47 |
Omeprazole | 40 mg QD for 5 days | 10 mg | saxagliptin | 1.13 | 0.98 |
Aluminum hydroxide + magnesium hydroxide + simethicone | aluminum hydroxide: | 10 mg | saxagliptin | 0.97 | 0.74 |
Famotidine | 40 mg | 10 mg | saxagliptin | 1.03 | 1.14 |
Limit KOMBIGLYZE XR dose to 2.5 mg/1,000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [ see Drug Interactions (7.1)and Dosage and Administration (2.2) ]: | |||||
Ketoconazole | 200 mg BID for 9 days | 100 mg | saxagliptin | 2.45 | 1.62 |
Ketoconazole | 200 mg BID for 7 days | 20 mg | saxagliptin | 3.67 | 2.44 |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.
Coadministered Drug | Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. | Dosage of Saxagliptin | Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. | Cmax | ||||
No dosing adjustments required for the following: | |||||
Metformin | 1000 mg | 100 mg | metformin | 1.20 | 1.09 |
Glyburide | 5 mg | 10 mg | glyburide | 1.06 | 1.16 |
PioglitazoneResults include all patients. | 45 mg QD for 10 days | 10 mg QD for 5 days | pioglitazone | 1.08 | 1.14 |
Digoxin | 0.25 mg q6h first day followed by q12h second day followed by QD for | 10 mg QD for 7 days | digoxin | 1.06 | 1.09 |
Simvastatin | 40 mg QD for 8 days | 10 mg QD for 4 days | simvastatin | 1.04 | 0.88 |
Diltiazem | 360 mg LA QD for 9 days | 10 mg | diltiazem | 1.10 | 1.16 |
Ketoconazole | 200 mg BID for 9 days | 100 mg | ketoconazole | 0.87 | 0.84 |
Ethinyl estradiol and norgestimate | ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days | 5 mg QD for 21 days | ethinyl estradiol | 1.07 | 0.98 |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.
Coadministered Drug | Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. | Dose of Metformin | Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF). | Cmax | ||||
No dosing adjustments required for the following: | |||||
Glyburide | 5 mg | 850 mg | metformin | 0.91Ratio 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 |
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7.3) ]. | |||||
Cimetidine | 400 mg | 850 mg | metformin | 1.40 | 1.61 |
Coadministered Drug | Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. | Dose of Metformin | Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF) unless otherwise noted. | Cmax | ||||
No dosing adjustments required for the following: | |||||
Glyburide | 5 mg | 850 mg | glyburide | 0.78Ratio 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 | 1.10AUC(0-24 hr) reported. | 1.08 |
Propranolol | 40 mg | 850 mg | propranolol | 1.01 | 1.02 |
Ibuprofen | 400 mg | 850 mg | ibuprofen | 0.97Ratio of arithmetic means. | 1.01 |
Cimetidine | 400 mg | 850 mg | cimetidine | 0.95 | 1.01 |
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Kombiglyze XR Prescribing Information
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 [
• 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[seeContraindications (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.
Assess renal function prior to initiation of KOMBIGLYZE XR and then as clinically indicated [
The recommended dosage of KOMBIGLYZE XR in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/minute/1.73 m2 is the same as the recommended dosage in patients with normal renal function [
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.
Initiation of KOMBIGLYZE XR in patients with an eGFR between 30 – 45 mL/minute/1.73 m2 is not recommended.
KOMBIGLYZE XR is contraindicated in patients with an eGFR below 30 mL/minute/1.73 m2.
Discontinue KOMBIGLYZE XR if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [
KOMBIGLYZE XR is contraindicated in patients with:
• Severe renal impairment (eGFR below 30 mL/min/1.73 m2).• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.• A history of a serious hypersensitivity reaction to saxagliptin, metformin HCl, or any of the ingredients in KOMBLIGLYZE XR. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported [see Warnings and Precautions (5.6)and Adverse Reactions (6.2)].
• Severe renal impairment (eGFR below 30 mL/min/1.73 m2). (4)• Metabolic acidosis, including diabetic ketoacidosis. (4)• History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin, metformin HCl, or any of the ingredients in KOMBIGLYZE XR. (4)
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 [
• 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[seeContraindications (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.
• Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with KOMBIGLYZE XR significantly increases saxagliptin concentrations. Limit KOMBIGLYZE XR dosage to 2.5 mg/1,000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor.• Carbonic anhydrase inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring. (7.2)• Drugs that reduce metformin clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use. (7.3)• See full prescribing information for additional drug interactions.
Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of KOMBIGLYZE XR should be limited to 2.5 mg of saxagliptin when coadministered with a strong CYP3A4/5 inhibitor [
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with KOMBIGLYZE XR may increase the risk for lactic acidosis.
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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.
Insulin and insulin secretagogues are known to cause hypoglycemia. Concomitant use of KOMBIGLYZE XR with insulin or an insulin secretagogue may require lower dosages of insulin or the insulin secretagogue to reduce the risk of hypoglycemia [
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving KOMBIGLYZE XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving KOMBIGLYZE XR, observe the patient closely for hypoglycemia.
In a 12-week randomized placebo-controlled trial, saxagliptin 2.5 mg was administered to 85 patients with moderate (n=48) or severe (n=18) renal impairment or end-stage renal disease (ESRD) (n=19) [
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. KOMBIGLYZE XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2[
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. KOMBIGLYZE XR is not recommended in patients with hepatic impairment [
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 [
• 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[seeContraindications (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.
KOMBIGLYZE XR is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
The maximum recommended dosage of KOMBIGLYZE XR is 2.5 mg of saxagliptin and 1,000 mg of metformin HCl given orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [
Individualize the starting dosage of KOMBIGLYZE XR based on the patient’s current regimen and the available strengths of KOMBIGLYZE XR [
Administer KOMBIGLYZE XR once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin HCl [
The recommended starting dosage of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin HCl is one KOMBIGLYZE XR tablet containing 5 mg saxagliptin and 500 mg metformin HCl extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin HCl.
In patients treated with metformin HCl, the recommended starting dosage of KOMBIGLYZE XR should provide metformin HCl at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin HCl immediate-release to KOMBIGLYZE XR, closely monitor glycemic control and adjust the dosage accordingly.
Patients who need 2.5 mg saxagliptin in combination with metformin HCl extended-release may be treated with KOMBIGLYZE XR 2.5 mg/1,000 mg. Patients who need 2.5 mg saxagliptin who are either metformin HCl naive or who require a dose of metformin HCl higher than 1,000 mg should use the individual components.
Gradually titrate the dosage of KOMBIGLYZE XR, as needed, after assessing therapeutic response and tolerability, up to a maximum recommended dosage of KOMBIGLYZE XR (5 mg for saxagliptin and 2,000 mg for metformin HCl extended-release orally once daily).
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.
If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
Bioequivalence and food effect of KOMBIGLYZE XR was characterized under low calorie diet. The low calorie diet consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5% fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy subjects demonstrated that KOMBIGLYZE XR combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA) and metformin HCl extended-release as individual tablets under fed conditions.
Saxagliptin
The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmaxand AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmaxvalues were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmaxfor both saxagliptin and its active metabolite was less than 25%.
No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.
Metformin extended-release Cmaxis achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmaxare less than dose proportional for metformin extended-release within the range of 500 to 2,000 mg. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to the same dose of metformin immediate-release tablets, however, the extent of absorption (as measured by AUC) is similar between extended-release tablets and immediate-release tablets.
The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite.
Following a single oral dose of metformin extended-release, Cmaxis achieved with a median value of 7 hours and a range of 4 to 8 hours.
Administration with a high-fat meal resulted in an increase in Tmaxof saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as KOMBIGLYZE XR combination tablets.
Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on Cmaxand Tmaxof metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release. Food has no significant effect on the pharmacokinetics of metformin when administered as KOMBIGLYZE XR combination tablets.
The
Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmaxand geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmaxis increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.
Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.
No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 White subjects with 105 subjects of other races (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Black or African American (n=51), and Hispanic or Latino ethnicity (n=24).
A single-dose, open-label trial was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmaxof saxagliptin or its metabolite. In subjects with moderate renal impairment with eGFR 30 to less than 45 mL/min/1.73 m2, severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function.
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
No dosage adjustment is recommended based on body mass index (BMI) which was not identified as a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.
Specific pharmacokinetic drug interaction studies with KOMBIGLYZE XR have not been performed, although such studies have been conducted with the individual saxagliptin and metformin components.
In
Coadministered Drug | Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. | Dosage of Saxagliptin | Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. | Cmax | ||||
No dosing adjustments required for the following: | |||||
Metformin | 1,000 mg | 100 mg | saxagliptin | 0.98 | 0.79 |
Glyburide | 5 mg | 10 mg | saxagliptin | 0.98 | 1.08 |
PioglitazoneResults exclude one patient. | 45 mg QD for 10 days | 10 mg QD for 5 days | saxagliptin | 1.11 | 1.11 |
Digoxin | 0.25 mg q6h first day followed by q12h second day followed by QD for | 10 mg QD for 7 days | saxagliptin | 1.05 | 0.99 |
Dapagliflozin | 10 mg single dose | 5 mg single dose | saxagliptin 5-hydroxy saxagliptin | ↓1% ↑9% | ↓7% ↑6% |
Simvastatin | 40 mg QD for 8 days | 10 mg QD for 4 days | saxagliptin | 1.12 | 1.21 |
Diltiazem | 360 mg LA QD for 9 days | 10 mg | saxagliptin | 2.09 | 1.63 |
RifampinThe plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin. | 600 mg QD for 6 days | 5 mg | saxagliptin | 0.24 | 0.47 |
Omeprazole | 40 mg QD for 5 days | 10 mg | saxagliptin | 1.13 | 0.98 |
Aluminum hydroxide + magnesium hydroxide + simethicone | aluminum hydroxide: | 10 mg | saxagliptin | 0.97 | 0.74 |
Famotidine | 40 mg | 10 mg | saxagliptin | 1.03 | 1.14 |
Limit KOMBIGLYZE XR dose to 2.5 mg/1,000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [ see Drug Interactions (7.1)and Dosage and Administration (2.2) ]: | |||||
Ketoconazole | 200 mg BID for 9 days | 100 mg | saxagliptin | 2.45 | 1.62 |
Ketoconazole | 200 mg BID for 7 days | 20 mg | saxagliptin | 3.67 | 2.44 |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.
Coadministered Drug | Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. | Dosage of Saxagliptin | Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. | Cmax | ||||
No dosing adjustments required for the following: | |||||
Metformin | 1000 mg | 100 mg | metformin | 1.20 | 1.09 |
Glyburide | 5 mg | 10 mg | glyburide | 1.06 | 1.16 |
PioglitazoneResults include all patients. | 45 mg QD for 10 days | 10 mg QD for 5 days | pioglitazone | 1.08 | 1.14 |
Digoxin | 0.25 mg q6h first day followed by q12h second day followed by QD for | 10 mg QD for 7 days | digoxin | 1.06 | 1.09 |
Simvastatin | 40 mg QD for 8 days | 10 mg QD for 4 days | simvastatin | 1.04 | 0.88 |
Diltiazem | 360 mg LA QD for 9 days | 10 mg | diltiazem | 1.10 | 1.16 |
Ketoconazole | 200 mg BID for 9 days | 100 mg | ketoconazole | 0.87 | 0.84 |
Ethinyl estradiol and norgestimate | ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days | 5 mg QD for 21 days | ethinyl estradiol | 1.07 | 0.98 |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.
Coadministered Drug | Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. | Dose of Metformin | Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF). | Cmax | ||||
No dosing adjustments required for the following: | |||||
Glyburide | 5 mg | 850 mg | metformin | 0.91Ratio 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 |
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7.3) ]. | |||||
Cimetidine | 400 mg | 850 mg | metformin | 1.40 | 1.61 |
Coadministered Drug | Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. | Dose of Metformin | Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 | ||
|---|---|---|---|---|---|
AUC AUC = AUC(INF) unless otherwise noted. | Cmax | ||||
No dosing adjustments required for the following: | |||||
Glyburide | 5 mg | 850 mg | glyburide | 0.78Ratio 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 | 1.10AUC(0-24 hr) reported. | 1.08 |
Propranolol | 40 mg | 850 mg | propranolol | 1.01 | 1.02 |
Ibuprofen | 400 mg | 850 mg | ibuprofen | 0.97Ratio of arithmetic means. | 1.01 |
Cimetidine | 400 mg | 850 mg | cimetidine | 0.95 | 1.01 |
Extended-Release Tablets:
• 5 mg of saxagliptin and 500 mg of metformin HCl: 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.• 5 mg of saxagliptin and 1,000 mg of metformin HCl: pink, biconvex, capsule-shaped, film-coated tablets with “5/1000” printed on one side and “4223” printed on the reverse side, in blue ink.• 2.5 mg of saxagliptin and 1,000 mg of metformin HCl: 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.
• Geriatric Use: Assess renal function more frequently.8.5 Geriatric UseKOMBIGLYZE XRElderly patients are more likely to have decreased renal function. Assess renal function more frequently in the elderly [
see Warnings and Precautions (5.1)and Clinical Pharmacology (12.3)].SaxagliptinIn the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin, a total of 4751 (42.0%) of the 11301 patients randomized to saxagliptin were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients.
Metformin HCIControlled clinical trials of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [
see Warnings and Precautions (5.1)].• Hepatic Impairment: Avoid use in patients with hepatic impairment.8.7 Hepatic ImpairmentUse of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. KOMBIGLYZE XR is not recommended in patients with hepatic impairment [
see Warnings and Precautions (5.1)].
KOMBIGLYZE XR is contraindicated in patients with:
• Severe renal impairment (eGFR below 30 mL/min/1.73 m2).• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.• A history of a serious hypersensitivity reaction to saxagliptin, metformin HCl, or any of the ingredients in KOMBLIGLYZE XR. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported [see].and5.6 Hypersensitivity ReactionsThere 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 [
seeAdverse 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.
6.2 Postmarketing ExperienceAdditional adverse reactions have been identified during post-approval use of KOMBIGLYZE XR, saxagliptin, or metformin HCl. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Saxagliptin• Gastrointestinal Disorders: Pancreatitis• Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions• Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, Severe and disabling arthralgia• Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid
Metformin HCl• Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury