Saxagliptin and Metformin

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 [ see Clinical Studies (14) ]. Saxagliptin and metformin hydrochloride extended-release tablets are a combination of saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use:

• Not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1.1 )

1.1 Limitations of Use Saxagliptin and metformin hydrochloride extended-release tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

Extended-Release Tablets:

• 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.
• 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 )

Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ).
• 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 saxagliptin and metformin hydrochloride extended-release tablets. 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 m 2 ). ( 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 saxagliptin and metformin hydrochloride extended-release tablets. ( 4 )

• Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets. ( 5.2 )
• Heart Failure: Consider the risks and benefits of saxagliptin and metformin hydrochloride extended-release tablets in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.3 )
• Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.4 )
• Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues: Consider a lower dosage of insulin or insulin secretagogue when used in combination with saxagliptin and metformin hydrochloride extended-release tablets. ( 5.5 )
• Hypersensitivity-Related Events: There have been post-marketing reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions in patients treated with saxagliptin. If hypersensitivity reactions occur, discontinue saxagliptin and metformin hydrochloride extended-release tablets, treat promptly, and monitor until signs and symptoms resolve. ( 5.6 )
• Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.7 )
• Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue saxagliptin and metformin hydrochloride extended-release tablets ( 5.8 ).

5.1 Lactic Acidosis 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 saxagliptin and metformin hydrochloride extended-release tablets. In saxagliptin and metformin hydrochloride extended-release tablet-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 saxagliptin and metformin hydrochloride extended-release tablets 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 [ see Clinical Pharmacology (12.3) ]:

• Before initiating saxagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).
• Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [ see Contraindications (4) ].
• Initiation of saxagliptin and metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m 2 .
• Obtain an eGFR at least annually in all patients taking saxagliptin and metformin hydrochloride extended-release tablets. 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 saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit and risk of continuing therapy. Drug Interactions The concomitant use of saxagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [ see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [ see Use in Specific Populations (8.5) ]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop saxagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart saxagliptin and metformin hydrochloride extended-release tablets if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Saxagliptin and metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the post-marketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue saxagliptin and metformin hydrochloride extended-release tablets. Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving saxagliptin and metformin hydrochloride extended-release tablets. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of saxagliptin and metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. […]

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Lactic Acidosis [ see Boxed Warning and Warnings and Precautions (5.1) ]
• Pancreatitis [ see Warnings and Precautions (5.2) ]
• Heart Failure [ see Warnings and Precautions (5.3) ]
• Vitamin B 12 Deficiency [ see Warnings and Precautions (5.4) ]
• Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [ see Warnings and Precautions (5.5) ]
• Hypersensitivity Reactions [ see Warnings and Precautions (5.6) ]
• Severe and disabling arthralgia [ see Warnings and Precautions (5.7) ]
• Bullous pemphigoid [ see Warnings and Precautions (5.8) ]
• Most common adverse reactions with metformin HCl extended-release (incidence > 5% and more often than placebo) are: diarrhea and nausea/vomiting. ( 6.1 )
• Most common adverse reactions with saxagliptin (incidence ≥ 5% and more often than placebo) are: upper respiratory tract infection, urinary tract infection, and headache. ( 6.1 )
• Adverse reactions with coadministered saxagliptin and metformin HCl (incidence ≥ 5% and more often than placebo) are: headache and nasopharyngitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Placebo-Controlled Trials in Adults with Type 2 Diabetes Mellitus Metformin HCl In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in > 5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of trial medication in 0.6% of the patients treated with metformin HCl extended-release. Saxagliptin The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [ see Clinical Studies (14) ]. These data shown in the table reflect exposure of 882 patients to saxagliptin and a mean duration of exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, 10.5% other races and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥ 60 mL/min/1.73 m 2 ) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin. Table 1: Adverse Reactions in Placebo-Controlled Trials The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin HCl, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. Reported in ≥ 5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo % of Patients Saxagliptin 5 mg N = 882 Placebo N = 799 Upper respiratory tract infection 7.7

7.6 Urinary tract infection 6.8

6.1 Headache 6.5

5.9 In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥ 5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in trial drug discontinuation. Rates of peripheral edema for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin HCl, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg saxagliptin dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known. Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 patients treated with saxagliptin 2.5 mg or at least 2 patients treated with saxagliptin 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). Adverse Reactions with Concomitant Use with Insulin In the add-on to insulin trial [ see Clinical Studies (14.1) ], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia [ see Adverse Reactions (6.1) ]. Adverse Reactions Associated with Saxagliptin Coadministered with Metformin HCl Immediate-Release in Treatment-Naive Patients with Type 2 Diabetes Mellitus Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥ 5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin HCl in treatment-naive patients. Table 2: Coadministration of Saxagliptin and Metformin HCl Immediate-Release in Treatment-Naive Patients: Adverse Reactions Reported in ≥ 5% of Patients Treated with Combination Therapy of Saxagliptin 5 mg Plus Metformin HCl Immediate-Release (and More Commonly than in Patients Treated with Metformin HCl Immediate-Release Alone) Number (%) of Patients Saxagliptin 5 mg + Metformin HCl Metformin HCl immediate-release was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2,000 mg daily. N = 320 Placebo + Metformin HCl N = 328 Headache 24 (7.5) 17 (5.2) Nasopharyngitis 22 (6.9) 13 (4.0) In patients treated with the combination of saxagliptin and metformin HCl immediate-release, either as saxagliptin add-on to metformin HCl immediate-release therapy or as coadministration in treatment-naive patients, diarrhea was the only gastrointestinal-related event that occurred with an incidence ≥ 5% in any treatment group in both trials. In the saxagliptin add-on to metformin HCl immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When saxagliptin and metformin HCl immediate-release were coadministered in treatment-naive patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg + metformin HCl immediate-release group and 7.3% in the placebo + metformin HCl immediate-release group. Hypoglycemia In the saxagliptin clinical trials, adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. […]

The concomitant use of saxagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [ see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients.

7 DRUG INTERACTIONS

• Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with saxagliptin and metformin hydrochloride extended-release tablets significantly increases saxagliptin concentrations. Limit saxagliptin and metformin hydrochloride extended-release tablets dosage to 2.5 mg/1,000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor. ( 2.3 , 7.1 )
• 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. ( 7 )

7.1 Strong Inhibitors of CYP3A4/5 Enzymes 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 saxagliptin and metformin hydrochloride extended-release tablets should be limited to 2.5 mg of saxagliptin when coadministered with a strong CYP3A4/5 inhibitor [ see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

7.2 Carbonic Anhydrase Inhibitors 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 saxagliptin and metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis.

7.3 Drugs that Reduce Metformin Clearance 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 [ see Clinical Pharmacology (12.3) ]. Consider the benefits and risks of concomitant use.

7.4 Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving saxagliptin and metformin hydrochloride extended-release tablets.

7.5 Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. Concomitant use of saxagliptin and metformin hydrochloride extended-release tablets with insulin or an insulin secretagogue may require lower dosages of insulin or the insulin secretagogue to reduce the risk of hypoglycemia [ see Warnings and Precautions (5.5) ].

7.6 Drugs Affecting Glycemic Control 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 saxagliptin and metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving saxagliptin and metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.

• Geriatric Use: Assess renal function more frequently. ( 8.5 )
• Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 )

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 trials 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 HCl Metformin HCl 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 2,000 mg clinical dose based on body surface area (mg/m 2 ) 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 2,000 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 Data 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. Animal Data 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 The safety and effectiveness of saxagliptin and metformin hydrochloride extended-release tablets as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients. Effectiveness of saxagliptin was not demonstrated in a 26-week, placebo-controlled, double-blind randomized clinical trial with a 26-week safety extension (NCT03199053) in 164 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.

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 patients 65 years of age and older and younger adult patients. Metformin HCl Controlled 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) ].

8.6 Renal Impairment Saxagliptin 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) [ 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 patients treated with saxagliptin 2.5 mg and 22% among patients treated with placebo. Four saxagliptin-treated patients (4.7%) and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤ 50 mg/dL). […]

Saxagliptin and Metformin Hydrochloride Extended-Release Tablets Saxagliptin and metformin hydrochloride extended-release tablets contain two antihyperglycemic medications: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin HCl, 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 mellitus, 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 HCl Metformin improves glucose tolerance in patients with type 2 diabetes mellitus, 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 mellitus or in healthy subjects except in unusual circumstances [ see Warnings and Precautions (5.5) ] 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.