Products3
Detailed information about drug products covered under this FDA approval, including NDC codes, dosage forms, ingredients, and administration routes.
Saxagliptin and Metformin
Product Details
Saxagliptin and Metformin
Product Details
Saxagliptin and Metformin
Product Details
Drug Labeling Information
Complete FDA-approved labeling information including indications, dosage, warnings, contraindications, and other essential prescribing details.
DESCRIPTION SECTION
11 DESCRIPTION
Saxagliptin and metformin hydrochloride extended-release tablets contain two oral antihyperglycemic medications used in the management of type 2 diabetes: saxagliptin and metformin hydrochloride.
**Saxagliptin:******Saxagliptin is an orally active inhibitor of the dipeptidyl-peptidase-4 (DPP4) enzyme.
Saxagliptin hydrochloride dihydrate is described chemically as (1S,3S,5S)-2-[(2S)-Amino-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride dihydrate or (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride dihydrate. The molecular formula is C18H25N3O2•HCl•2 H2O and the molecular weight is 387.92. The structural formula is:
Saxagliptin hydrochloride dihydrate is a white to off white, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400).
**Metformin Hydrochloride:******Metformin hydrochloride, USP (1,1-Dimethylbiguanide monohydrochloride) is a white, crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.36. The structural formula is:
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets:** **Saxagliptin and metformin hydrochloride extended-release tablets are available for oral administration as tablets containing either 6.149 mg saxagliptin hydrochloride dihydrate equivalent to 5 mg saxagliptin and 500 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended- release tablets 5 mg/500 mg), or 6.149 mg saxagliptin hydrochloride dihydrate equivalent to 5 mg saxagliptin and 1000 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended-release tablets 5 mg/1000 mg), or 3.075 mg saxagliptin hydrochloride dihydrate equivalent to 2.5 mg saxagliptin and 1000 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1000 mg). Each film-coated tablet of saxagliptin and metformin hydrochloride extended-release contains the following inactive ingredients: carbomer homopolymer type A, colloidal silicon dioxide, hypromellose, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, red iron oxide, stearic acid, talc and titanium dioxide. The 2.5 mg/1000 mg tablets also contain yellow iron oxide. In addition, the black imprinting ink contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.
The biologically inert components of the tablet may occasionally remain intact during gastrointestinal transit and will be eliminated in the feces as a soft, hydrated mass.
CLINICAL PHARMACOLOGY SECTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets
Saxagliptin and metformin hydrochloride extended-release tablets combine two antihyperglycemic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, a biguanide.
Saxagliptin
Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.
Metformin Hydrochloride
Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in unusual circumstances [see Warnings and Precautions (5.6)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
12.2 Pharmacodynamics
Saxagliptin
In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
Cardiac Electrophysiology
Saxagliptin
In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the MRHD).
12.3 Pharmacokinetics
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets
Bioequivalence and food effect of saxagliptin and metformin hydrochloride extended-release tablets were 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 saxagliptin and metformin hydrochloride extended-release combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA®) and metformin hydrochloride extended-release (GLUCOPHAGE® XR) 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 Cmax and 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 Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for 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 Hydrochloride
Metformin extended-release Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release within the range of 500 to 2000 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.
Absorption
Saxagliptin
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. Administration with a high-fat meal resulted in an increase in Tmax of 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 saxagliptin and metformin hydrochloride extended-release combination tablets.
Metformin Hydrochloride
Following a single oral dose of metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. 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 Cmax and Tmax of 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 saxagliptin and metformin hydrochloride extended-release combination tablets.
Distribution
Saxagliptin
The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.
Metformin Hydrochloride
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.
Metabolism
Saxagliptin
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 [see Drug Interactions (7.1)].
Metformin Hydrochloride
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.
Excretion
Saxagliptin
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-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.
Metformin Hydrochloride
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.
Specific Populations
Renal Impairment
Saxagliptin
A single-dose, open-label study 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 Cmax of 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.
Metformin Hydrochloride
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)].
Hepatic Impairment
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Body Mass Index
Saxagliptin
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.
Gender
Saxagliptin
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 Hydrochloride
Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Geriatric
Saxagliptin
No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and 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.
Metformin Hydrochloride
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 Cmax is 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.
Race and Ethnicity
Saxagliptin
No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 Caucasian subjects with 105 non-Caucasian subjects (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.
Metformin Hydrochloride
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n = 249), Blacks (n = 51), and Hispanics (n = 24).
Drug Interaction Studies
Specific pharmacokinetic drug interaction studies with saxagliptin and metformin hydrochloride extended-release tablets have not been performed, although such studies have been conducted with the individual saxagliptin and metformin components.
In Vitro Assessment of Drug Interactions
In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate, but is not a significant inhibitor or inducer of P-gp.
In Vivo Assessment of Drug Interactions:
Table 3: Effect of Coadministered Drug on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin|
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* |
Dosage of Saxagliptin* |
Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|
AUC† |
C****max | ||||
|
No dosing adjustments required for the following: | |||||
|
Metformin |
1000 mg |
100 mg |
saxagliptin |
0.98 |
0.79 |
|
5-hydroxy saxagliptin |
0.99 |
0.88 | |||
|
Glyburide |
5 mg |
10 mg |
saxagliptin |
0.98 |
1.08 |
|
5-hydroxy saxagliptin |
ND |
ND | |||
|
Pioglitazone‡ |
45 mg QD for 10 days |
10 mg QD for 5 days |
saxagliptin |
1.11 |
1.11 |
|
5-hydroxy saxagliptin |
ND |
ND | |||
|
Digoxin |
0.25 mg q6h first day followed by q12h second day followed by QD for 5 days |
10 mg QD for 7 days |
saxagliptin |
1.05 |
0.99 |
|
5-hydroxy saxagliptin |
1.06 |
1.02 | |||
|
Dapagliflozin |
10 mg single dose |
5 mg single dose |
saxagliptin |
↓ 1% |
↓ 7% |
|
5-hydroxy saxagliptin |
↑ 9% |
↑ 6% | |||
|
Simvastatin |
40 mg QD for 8 days |
10 mg QD for 4 days |
saxagliptin |
1.12 |
1.21 |
|
5-hydroxy saxagliptin |
1.02 |
1.08 | |||
|
Diltiazem |
360 mg LA QD for 9 days |
10 mg |
saxagliptin |
2.09 |
1.63 |
|
5-hydroxy saxagliptin |
0.66 |
0.57 | |||
|
Rifampin§ |
600 mg QD for 6 days |
5 mg |
saxagliptin |
0.24 |
0.47 |
|
5-hydroxy saxagliptin |
1.03 |
1.39 | |||
|
Omeprazole |
40 mg QD for 5 days |
10 mg |
saxagliptin |
1.13 |
0.98 |
|
5-hydroxy saxagliptin |
ND |
ND | |||
|
Aluminum hydroxide + magnesium hydroxide + simethicone |
aluminum hydroxide: 2400 mg |
10 mg |
saxagliptin |
0.97 |
0.74 |
|
5-hydroxy saxagliptin |
ND |
ND | |||
|
Famotidine |
40 mg |
10 mg |
saxagliptin |
1.03 |
1.14 |
|
5-hydroxy saxagliptin |
ND |
ND | |||
|
Limit saxagliptin and metformin hydrochloride extended-release tablet dose to 2.5 mg/1000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [seeDrug Interactions (7.1)** andDosage and Administration (2.2)]:** | |||||
|
Ketoconazole |
200 mg BID for 9 days |
100 mg |
saxagliptin |
2.45 |
1.62 |
|
5-hydroxy saxagliptin |
0.12 |
0.05 | |||
|
Ketoconazole |
200 mg BID for 7 days |
20 mg |
saxagliptin |
3.67 |
2.44 |
|
5-hydroxy saxagliptin |
ND |
ND |
|
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* |
Dosage of Saxagliptin* |
Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00 | ||
|
AUC† |
C****max | ||||
|
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 |
|
Pioglitazone‡ |
45 mg QD for 10 days |
10 mg QD for 5 days |
pioglitazone |
1.08 |
1.14 |
|
hydroxy-pioglitazone |
ND |
ND | |||
|
Digoxin |
0.25 mg q6h first day followed by q12h second day followed by QD for 5 days |
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 |
|
simvastatin acid |
1.16 |
1.00 | |||
|
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 |
|
norelgestromin |
1.10 |
1.09 | |||
|
norgestrel |
1.13 |
1.17 |
| |||||
|
Coadministered Drug |
Dose of Coadministered Drug* |
Dose of Metformin* |
Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|
AUC† |
C****max | ||||
|
No dosing adjustments required for the following: | |||||
|
Glyburide |
5 mg |
850 mg |
metformin |
0.91‡ |
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 [seeDrug Interactions (7.3)****]. | |||||
|
Cimetidine |
400 mg |
850 mg |
metformin |
1.40 |
1.61 |
| |||||
|
Coadministered Drug |
Dose of Coadministered Drug* |
Dose of Metformin* |
Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 | ||
|
AUC† |
C****max | ||||
|
No dosing adjustments required for the following: | |||||
|
Glyburide |
5 mg |
850 mg |
glyburide |
0.78‡ |
0.63‡ |
|
Furosemide |
40 mg |
850 mg |
furosemide |
0.87‡ |
0.69‡ |
|
Nifedipine |
10 mg |
850 mg |
nifedipine |
1.10§ |
1.08 |
|
Propranolol |
40 mg |
850 mg |
propranolol |
1.01§ |
1.02 |
|
Ibuprofen |
400 mg |
850 mg |
ibuprofen |
0.97¶ |
1.01¶ |
|
Cimetidine |
400 mg |
850 mg |
cimetidine |
0.95§ |
1.01 |
INDICATIONS & USAGE SECTION
Highlight: Saxagliptin and metformin hydrochloride extended-release tablets are 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)
1 INDICATIONS AND USAGE
Saxagliptin and metformin hydrochloride extended-release tablets are 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
Saxagliptin and metformin hydrochloride extended-release tablets are not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
DOSAGE FORMS & STRENGTHS SECTION
Highlight: 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)
3 DOSAGE FORMS AND STRENGTHS
•
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 5 mg/500 mg, are pink, film-coated, round, unscored tablets imprinted with**SM3** over**M**in black ink on one side of the tablet and blank on the other side.
•
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 5 mg/1000 mg, are pink, film-coated, capsule shaped, unscored tablets imprinted with**SM6** over**M**in black ink on one side of the tablet and blank on the other side.
•
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 2.5 mg/1000 mg, are light peach, film-coated, capsule shaped, unscored tablets imprinted with**SM4** over**M**in black ink on one side of the tablet and blank on the other side.
CONTRAINDICATIONS SECTION
Highlight: •
Severe renal impairment (eGFR below 30 mL/min/1.73 m2). (4)
•
Hypersensitivity to metformin hydrochloride. (4)
•
Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
•
History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin. (4)
4 CONTRAINDICATIONS
Saxagliptin and metformin hydrochloride extended-release tablets are 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 saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions [see Warnings and Precautions (5.7) and Adverse Reactions (6.2)].
Boxed Warning section
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
•
**Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, 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 saxagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (****5.1****)**
USE IN SPECIFIC POPULATIONS SECTION
Highlight: •
Geriatric Use: Assess renal function more frequently. (8.5)
•
Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Limited available data with saxagliptin and metformin hydrochloride extended- release tablets or saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data].
No adverse developmental effects independent of maternal toxicity were observed when saxagliptin and metformin were administered separately or in combination to pregnant rats and rabbits during the period of organogenesis [see Data].
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c greater than 7 and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data
Animal Data
Saxagliptin
In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.
In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on AUC.
Metformin Hydrochloride
Metformin hydrochloride did not cause adverse developmental effect when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.
Saxagliptin and Metformin
Saxagliptin and metformin coadministered to pregnant rats and rabbits during the period of organogenesis did not result in adverse developmental effects considered clinically relevant in either species. Doses tested in rats provided exposure up to 100- and 10-times clinical exposure, and doses tested in rabbits provided exposure up to 249- and 1-times clinical exposure relative to the clinical dose of 5 mg saxagliptin and 2000 mg metformin. Minor skeletal abnormalities associated with maternal toxicity were observed in rats. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29, associated with fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid bone.
8.2 Lactation
Risk Summary
There is no information regarding the presence of saxagliptin and metformin or saxagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Saxagliptin is present in the milk of lactating rats [see Data].
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for saxagliptin and metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from saxagliptin and metformin hydrochloride extended- release tablets or from the underlying maternal condition.
Data
Human
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
Animals
No studies in lactating animals have been conducted with the combined components of saxagliptin and metformin hydrochloride extended-release tablets. In studies performed with the individual components, both saxagliptin and metformin are secreted in the milk of lactating rats. Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations.
8.4 Pediatric Use
Safety and effectiveness of saxagliptin and metformin hydrochloride extended- release tablets in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of saxagliptin and metformin hydrochloride extended-release tablets in pediatric patients have not been performed.
8.5 Geriatric Use
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets
Elderly 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)].
Saxagliptin
In 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 subjects ≥ 65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
Metformin Hydrochloride
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney. 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 Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
8.6 Renal Impairment
Saxagliptin
In a 12-week randomized placebo-controlled trial, saxagliptin 2.5 mg was administered to 85 subjects with moderate (n = 48) or severe (n = 18) renal impairment or end-stage renal disease (ESRD) (n = 19) [see Clinical Studies (14)]. The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo. The overall incidence of reported hypoglycemia was 20% among subjects treated with saxagliptin 2.5 mg and 22% among subjects treated with placebo. Four saxagliptin-treated subjects (4.7%) and three placebo-treated subjects (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤ 50 mg/dL).
Metformin Hydrochloride
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Saxagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].
INFORMATION FOR PATIENTS SECTION
17 PATIENT COUNSELING INFORMATION
Advise the patient to read FDA-approved patient labeling (Medication Guide).
**Medication Guide:**Healthcare providers should instruct their patients to read the Medication Guide before starting saxagliptin and metformin hydrochloride extended-release tablet therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom or if any existing symptom persists or worsens.
Patients should be informed of the potential risks and benefits of saxagliptin and metformin hydrochloride extended-release tablets and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.
**Lactic Acidosis:**The risks of lactic acidosis due to the metformin component, its symptoms and conditions that predispose to its development, as noted in Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to discontinue saxagliptin and metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of saxagliptin and metformin hydrochloride extended-release tablet therapy; however, patients should consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol intake while receiving saxagliptin and metformin hydrochloride extended-release tablets.
Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with saxagliptin and metformin hydrochloride extended-release tablets.
Instruct patients to inform their doctor that they are taking saxagliptin and metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation of saxagliptin and metformin hydrochloride extended-release tablets may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1)].
**Pancreatitis:**Patients should be informed that acute pancreatitis has been reported during post-marketing use of saxagliptin. Before initiating saxagliptin and metformin hydrochloride extended-release tablets, patients should be questioned about other risk factors for pancreatitis, such as a history of pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should also be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets and contact their healthcare provider if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].
Heart Failure: Patients should be informed of the signs and symptoms of heart failure. Before initiating saxagliptin and metformin hydrochloride extended-release tablets, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Patients should be instructed to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.3)].
**Hypoglycemia:**Patients should be informed that the incidence of hypoglycemia may be increased when saxagliptin and metformin hydrochloride extended-release tablets are added to an insulin secretagogue (e.g., sulfonylurea) or insulin.
**Hypersensitivity Reactions:**Patients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during post-marketing use of saxagliptin. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking saxagliptin and metformin hydrochloride extended-release tablets and seek medical advice promptly.
Severe and Disabling Arthralgia: Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.8)].
Bullous Pemphigoid: Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.9)].
**Administration Instructions:**Patients should be informed that saxagliptin and metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
**Missed Dose:**Patients should be informed that if they miss a dose of saxagliptin and metformin hydrochloride extended-release tablets, they should take the next dose as prescribed, unless otherwise instructed by their healthcare provider. Patients should be instructed not to take an extra dose the next day.
SPL MEDGUIDE SECTION
Medication Guide
|
Saxagliptin and Metformin Hydrochloride Extended-Release Tablets | |||
|
What is the most important information I should know about saxagliptin and metformin hydrochloride extended-release tablets? Serious side effects can happen in people taking saxagliptin and metformin hydrochloride extended-release tablets, including: 1. Lactic acidosis. Metformin, one of the medicines in saxagliptin and metformin hydrochloride extended-release tablets, can cause a rare but serious condition called lactic acidosis (a build-up of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis: • • • • • • • • Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with saxagliptin and metformin hydrochloride extended- release tablets if you: • • • • • • The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your saxagliptin and metformin hydrochloride extended-release tablets for a while if you have any of these things. Saxagliptin and metformin hydrochloride extended-release tablets can have other serious side effects. See**“What are the possible side effects of saxagliptin and metformin hydrochloride extended-release tablets?”** 2. Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. ****Tell your healthcare provider if you have ever had: | |||
|
• • |
• • | ||
Stop taking saxagliptin and metformin hydrochloride extended-release tablets and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis. 3. Heart failure. Heart failure means your heart does not pump blood well enough. • | |||
|
• • |
• • | ||
| |||
|
What are saxagliptin and metformin hydrochloride extended-release tablets? • • • It is not known if saxagliptin and metformin hydrochloride extended-release tablets are safe and effective in children younger than 18 years old. | |||
|
Who should not take saxagliptin and metformin hydrochloride extended-release tablets? Do not take saxagliptin and metformin hydrochloride extended-release tablets if you: • • | |||
|
• • |
• • | ||
• | |||
|
Before taking saxagliptin and metformin hydrochloride extended-release tablets, tell your healthcare provider about all of your medical conditions, including if you: • • • • • • • • • • • Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Saxagliptin and metformin hydrochloride extended-release tablets may affect the way other medicines work, and other medicines may affect how saxagliptin and metformin hydrochloride extended-release tablets work. Tell your healthcare provider if you will be starting or stopping certain other types of medicines, such as antibiotics, or medicines that treat fungus or HIV/AIDS, because your dose of saxagliptin and metformin hydrochloride extended-release tablets might need to be changed. | |||
|
How should I take saxagliptin and metformin hydrochloride extended-release tablets? • • • • • • • • • • • • | |||
|
What are the possible side effects of saxagliptin and metformin hydrochloride extended-release tablets? Saxagliptin and metformin hydrochloride extended-release tablets can cause serious side effects, including: • • | |||
|
• • |
• • | ||
• | |||
|
• • |
• • |
• • |
• |
|
• • Common side effects of saxagliptin and metformin hydrochloride extended- release tablets include: | |||
|
• • |
• • |
• • | |
|
Taking saxagliptin and metformin hydrochloride extended-release tablets with meals can help lessen the common stomach side effects of metformin. If you have unexplained stomach problems, tell your healthcare provider. Stomach problems that start later during treatment may be a sign of something more serious. These are not all of the possible side effects of saxagliptin and metformin hydrochloride extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. | |||
|
How should I store saxagliptin and metformin hydrochloride extended-release tablets? Store saxagliptin and metformin hydrochloride extended-release tablets between 20° to 25°C (68° to 77°F). Keep saxagliptin and metformin hydrochloride extended-release tablets and all medicines out of the reach of children. | |||
|
General information about the use of saxagliptin and metformin hydrochloride extended-release tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use saxagliptin and metformin hydrochloride extended- release tablets for a condition for which they were not prescribed. Do not give saxagliptin and metformin hydrochloride extended-release tablets to other people, even if they have the same symptoms you have. They may harm them. You can ask your pharmacist or healthcare provider for information about saxagliptin and metformin hydrochloride extended-release tablets that is written for health professionals. | |||
|
What are the ingredients of saxagliptin and metformin hydrochloride extended-release tablets? Active ingredients: saxagliptin and metformin hydrochloride. Inactive ingredients in each tablet: carbomer homopolymer type A, colloidal silicon dioxide, hypromellose, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, red iron oxide, stearic acid, talc and titanium dioxide. The 2.5 mg/1000 mg tablets also contain yellow iron oxide. In addition, the black imprinting ink contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze. | |||
|
What is type 2 diabetes? Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems. The main goal of treating diabetes is to lower your blood sugar so that it is as close to normal as possible. High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary. Talk to your healthcare provider about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes. | |||
|
Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited, Hyderabad — 500 096, India For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). The brands listed are trademarks of their respective owners. |
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Mylan Pharmaceuticals Inc.
****Morgantown, WV 26505 U.S.A.
Manufactured by:
Mylan Laboratories Limited
****Hyderabad — 500 096, India
75097144
Revised: 4/2023
MXA:SAXMET:R1/MXA:MG:SAXMET:R1m