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 [ 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.

6 ADVERSE REACTIONS 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 Concentrations [ 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.

Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.

The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively.

In the add-on to metformin HCl immediate-release trial, the incidence of reported hypoglycemia was 7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin 5 mg, and 5% with placebo.

When saxagliptin and metformin HCl immediate-release were coadministered in treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in patients given saxagliptin 5 mg + metformin HCl immediate-release and 4% in patients given placebo + metformin HCl immediate-release.

In the active-controlled trial comparing add-on therapy with saxagliptin 5 mg to glipizide in patients inadequately controlled on metformin HCl alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin 5 mg versus 36.3% (750 events in 156 patients) with glipizide.

Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was reported in none of the saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%) (p < 0.0001).

In the saxagliptin add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo.

However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was higher with saxagliptin 5 mg (5.3%) versus placebo (3.3%).

Among the patients using insulin in combination with metformin HCl, the incidence of confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with placebo.

In the saxagliptin add-on to metformin HCl plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo.

Confirmed hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in none of the placebo-treated patients [ see Warnings and Precautions (5.5) ].

Hypersensitivity Reactions Saxagliptin Hypersensitivity reactions, such as urticaria and facial edema in the 5-trial pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively.

None of these events in patients who received saxagliptin required hospitalization or were reported as life-threatening by the investigators.

One saxagliptin-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema.

Renal Impairment In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e., doubling of serum creatinine compared with baseline and serum creatinine > 6 mg/dL), were reported in 5.8% (483/8280) of saxagliptin-treated patients and 5.1% (422/8212) of placebo-treated patients.

The most frequently reported adverse reactions included renal impairment (2.1% vs.

1.9%), acute renal failure (1.4% vs.

1.2%), and renal failure (0.8% vs.

0.9%), in the saxagliptin versus placebo groups, respectively.

From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5 mL/min/1.73 m 2 for saxagliptin-treated patients and a mean decrease of 2.4 mL/min/1.73 m 2 for placebo-treated patients.

More patients randomized to saxagliptin (421/5227, 8.1%) compared to patients randomized to placebo (344/5073, 6.8%) had downward shifts in eGFR from > 50 mL/min/1.73 m 2 (i.e., normal or mild renal impairment) to ≤ 50 mL/min/1.73 m 2 (i.e., moderate or severe renal impairment).

The proportions of patients with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment.

Infections Saxagliptin In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 saxagliptin-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients.

Two of these six cases were confirmed with laboratory testing.

The remaining cases had limited information or had presumptive diagnoses of tuberculosis.

None of the six cases occurred in the United States or in Western Europe.

One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia.

The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days.

Post-treatment lymphocyte counts were consistently within the reference range for four cases.

One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment.

The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis.

There have been no spontaneous reports of tuberculosis associated with saxagliptin use.

Causality has not been established and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use.

There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy.

There have been no spontaneous reports of opportunistic infections associated with saxagliptin use.

Vital Signs Saxagliptin No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin alone or in combination with metformin HCl.

Laboratory Tests Absolute Lymphocyte Counts Saxagliptin There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin.

From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical trials.

Similar effects were observed when saxagliptin 5 mg and metformin HCl were coadministered in treatment-naive patients compared to placebo and metformin HCl.

There was no difference observed for saxagliptin 2.5 mg relative to placebo.

The proportion of patients who were reported to have a lymphocyte count ≤ 750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively.

In most patients, recurrence was not observed with repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin.

The decreases in lymphocyte count were not associated with clinically relevant adverse reactions.

The 10 mg saxagliptin dosage is not an approved dosage.

In the SAVOR trial mean decreases of approximately 84 cells/microL with saxagliptin relative to placebo was observed.

The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤ 750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on saxagliptin and placebo, respectively.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known.

When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured.

The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Vitamin B 12 Concentrations Metformin HCl In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.

6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of saxagliptin and metformin hydrochloride extended-release tablets, 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