Saxagliptin and Metformin Hydrochloride
Tablet, Film Coated, Extended Release · Oral
• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1 ) ].
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with…
Uses
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.
Dosage and administration
Administer once daily with the evening meal. ( 2.1 ) Individualize the starting dosage based on the patient’s current regimen then adjust the dosage based on effectiveness and tolerability. ( 2.1 ) Do not exceed a daily dosage of 5 mg saxagliptin/2,000 mg metformin HCl extended-release. ( 2.1 ) Swallow whole. Never crush, cut, or chew. ( 2.1 ) Limit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). ( 2.3 , 7.1 ) Assess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and periodically thereafter. ( 2.2 ) o Do not use in patients with eGFR below 30 mL/min/1.73 m 2 . o Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . o Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 . o Limit the saxagliptin component to 2.5 mg daily if eGFR is less than 45 mL/min/1.73 m 2 . o Discontinue if eGFR falls below 30 mL/min/1.73 m 2 . Saxagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.4 ) 2.1 Recommended Dosage and Administration Individualize the starting dosage of saxagliptin and metformin hydrochloride extended-release tablets based on the patient’s current regimen and the available strengths of saxagliptin and metformin hydrochloride extended-release tablets [see Dosage Forms and Strengths ( 3 )] . Administer saxagliptin and metformin hydrochloride extended-release tablets once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin HCl [see Adverse Reactions ( 6.1 )] . The recommended starting dosage of saxagliptin and metformin hydrochloride extended-release tablets in patients who need 5 mg of saxagliptin and who are not currently treated with metformin HCl is one saxagliptin and metformin hydrochloride extended-release tablet containing 5 mg saxagliptin and 500 mg metformin HCl extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin HCl. In patients treated with metformin HCl, the recommended starting dosage of saxagliptin and metformin hydrochloride extended-release tablets should provide metformin HCl at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin HCl immediate-release to saxagliptin and metformin hydrochloride extended-release tablets, closely monitor glycemic control and adjust the dosage accordingly. Patients who need 2.5 mg saxagliptin in combination with metformin HCl extended-release may be treated with saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1,000 mg. Patients who need 2.5 mg saxagliptin who are either metformin HCl naive or who require a dose of metformin HCl higher than 1,000 mg should use the individual components. Gradually titrate the dosage of saxagliptin and metformin hydrochloride extended-release tablets, as needed, after assessing therapeutic response and tolerability, up to a maximum recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets (5 mg for saxagliptin and 2,000 mg for metformin HCl extended-release orally once daily). Inform patients that saxagliptin and metformin hydrochloride extended-release tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of saxagliptin and metformin hydrochloride extended-release tablets will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet. If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. 2.2 Recommendations for Dosage and Administration in Renal Impairment Assess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and then as clinically indicated [see Use in Specific Populations ( 8.6 )]. The recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/minute/1.73 m 2 is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration ( 2.1 )]. 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 risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily. Initiation of saxagliptin and metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR below 30 mL/minute/1.73 m 2 . Discontinue saxagliptin and metformin hydrochloride extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m 2 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. 2.3 Dosage Modifications with Concomitant Use of Strong CYP3A4/5 Inhibitors The maximum recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets is 2.5 mg of saxagliptin and 1,000 mg of metformin HCl given orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.3 )].
Dosage forms and strengths
Saxagliptin and metformin hydrochloride extended-release tablets 5 mg/500 mg are light brown to brown colored, capsule shaped film-coated tablets imprinted with SM3 on one side and plain on other side and free from physical defects. Saxagliptin and metformin hydrochloride extended-release tablets 5 mg/1,000 mg are pink, colored, modified oval shaped film-coated tablets imprinted with SM2 on one side and plain on other side and free from physical defects. Saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1,000 mg are pale yellow to light yellow colored, modified oval shaped film-coated tablets imprinted with SM1 on one side and plain on other side and free from physical defects.
• 5 mg saxagliptin/500 mg metformin HCl extended-release ( 3 )
• 5 mg saxagliptin/1,000 mg metformin HCl extended-release ( 3 )
• 2.5 mg saxagliptin/1,000 mg metformin HCl extended-release ( 3 )
Contraindications
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 )
Warnings and precautions
• 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 tablets-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 are 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.
Side effects
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 Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 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 ≥60mL/min/1.73m 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* 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 * 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. 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 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 )].
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 saxagliptinwhen 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 Secretagogue s 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.
Use in specific populations
• 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 1,503- 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 hydrochloride extended-release 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. Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for AstraZeneca AB’s Kombiglyze XR (saxagliptin and metformin hydrochloride extended-release) tablets.
Pregnancy
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 1,503- 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.
Pediatric use
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. Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for AstraZeneca AB’s Kombiglyze XR (saxagliptin and metformin hydrochloride extended-release) tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.
Geriatric use
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 4,751 (42%) of the 11,301 patients randomized to saxagliptin were 65 years and over, and 1,210 (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 ) ].
Overdosage
Saxagliptin In a controlled clinical trial, once-daily, orally administered saxagliptin in healthy subjects at doses up to 400 mg daily for 2 weeks (80-times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate. In the event of an overdose, initiate appropriate supportive treatment as dictated by the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours). Contact the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Metformin HCl Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions ( 5.1 )] . Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected .
Description
Saxagliptin and metformin hydrochloride extended-release tablets contain two oral antihyperglycemic medications used in the management of type 2 diabetes mellitus: saxagliptin and metformin HCl. Saxagliptin Saxagliptin is an orally active inhibitor of the dipeptidyl-peptidase-4 (DPP4) enzyme. Saxagliptin monohydrate is described chemically as (1 S ,3 S ,5 S )-2-[(2 S )-2-Amino-2-(3-hydroxytricyclo[3.3.1.1 3,7 ]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate or (1 S ,3 S ,5 S )-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile monohydrate. The molecular formula is C 18 H 25 N 3 O 2
• H 2 O and the molecular weight is 333.43. The structural formula is: Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic powder. It is very soluble at room temperate in methanol, freely soluble in ethanol, soluble in acetone, sparingly soluble in ethyl acetate and water, and slightly soluble in 1-octanol. Metformin Hydrochloride, USP Metformin HCl (N,N-dimethyl imido-dicarbonimidic diamide HCl) is a white crystalline powder with a molecular formula of C 4 H 11 N 5
• HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water, slightly soluble in alcohol, and practically insoluble in acetone and in methylene chloride. The pK a of metformin HCl is 8.6. 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 5.58 mg saxagliptin HCl (anhydrous) equivalent to 5 mg saxagliptin and 500 mg metformin HCl, USP (saxagliptin and metformin hydrochloride extended-release tablets 5 mg/500 mg), or 5.58 mg saxagliptin HCl (anhydrous) equivalent to 5 mg saxagliptin and 1,000 mg metformin HCl, USP (saxagliptin and metformin hydrochloride extended-release tablets 5 mg/1,000 mg), or 2.79 saxagliptin HCl (anhydrous) equivalent to 2.5 mg saxagliptin and 1,000 mg metformin HCl, USP (saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1,000 mg). Each film-coated tablet of saxagliptin and metformin hydrochloride extended-release tablets contains the following inactive ingredients: colloidal silicon dioxide, hydrochloric acid, hypromellose, iron oxide black, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, propylene glycol, shellac, talc, titanium dioxide. In addition, 5 mg/500 mg tablets contain iron oxide red and iron oxide yellow; 5 mg/1,000 mg tablets contain iron oxide red; 2.5 mg/1,000 mg tablets contain iron oxide yellow. 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. structure1 structure2
Mechanism of action
12.1 Mechanism of Action Saxagliptin and Metformin Hydrochloride Extended-release Tablets Saxagliptin and metformin hydrochloride extended-release tablets contains 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 mrllitus 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.
How supplied
How Supplied Saxagliptin and metformin hydrochloride extended-release tablets are available as follows: Saxagliptin and metformin hydrochloride extended-release tablets 5 mg/500 mg are light brown to brown colored, capsule shaped film-coated tablets imprinted with SM3 on one side and plain on other side and free from physical defects. They are available in packages as listed below. Bottles of 30 43598-620-30 Bottles of 100 43598-620-01 Saxagliptin and metformin hydrochloride extended-release tablets 5 mg/1,000 mg are pink, colored, modified oval shaped film-coated tablets imprinted with SM2 on one side and plain on other side and free from physical defects. They are available in packages as listed below. Bottles of 30 43598-619-30 Bottles of 100 43598-619-01 Saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1,000 mg are pale yellow to light yellow colored, modified oval shaped film-coated tablets imprinted with SM1 on one side and plain on other side and free from physical defects. They are available in packages as listed below. Bottles of 30 43598-618-30 Bottles of 60 43598-618-60 Bottles of 100 43598-618-01 Storage and Handling Store at 20ºC to 25ºC (68ºF to 77ºF) [see USP Controlled Room Temperature].
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). 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 health care 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 tablets 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 Inform patients that acute pancreatitis has been reported during post-marketing use of saxagliptin. Educate patients 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. Instruct patients to promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets and contact their health care provider if persistent severe abdominal pain occurs [see Warnings and Precautions ( 5.2 )]. Heart Failure Inform patients of the signs and symptoms of heart failure. Before initiating saxagliptin and metformin hydrochloride extended-release tablets, ask patients if they have a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care 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 with Concomitant Use with Insulin or Insulin Secretagogues Inform patients that hypoglycemia can occur, particularly when insulin or an insulin secretagogue is used in combination with saxagliptin and metformin hydrochloride extended-release tablets. Educate patients about the risks, symptoms and appropriate management of hypoglycemia [see Warnings and Precautions ( 5.5 )]. 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 [see Warnings and Precautions ( 5.6 )]. 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 ( 5.7 )]. 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 ( 5.8 )] . 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 If a dose is missed, advise patients to take saxagliptin and metformin hydrochloride extended-release tablets as soon as they remember unless it is time for their next dose. Instruct patients not to take two doses of saxagliptin and metformin hydrochloride extended-release tablets at the same time. *The brands listed are trademarks of their respective owners and are not trademarks of Dr. Reddy’s Laboratories Limited. Rx only Distributor: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 Made in India Revised: 06/2026
Label text from the FDA structured product label by Dr.Reddys Laboratories Inc (revised Jul 8, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Saxagliptin in 3 products
- Metformin Hydrochloride in 3 products
Saxagliptin and Metformin Hydrochloride NDC products (3)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 43598-618 | Saxagliptin 2.5 mg/1; Metformin Hydrochloride 1000 mg/1 Tablet, Film Coated, Extended Release | Dr.Reddys Laboratories Inc | ANDA |
| 43598-619 | Saxagliptin 5 mg/1; Metformin Hydrochloride 1000 mg/1 Tablet, Film Coated, Extended Release | Dr.Reddys Laboratories Inc | ANDA |
| 43598-620 | Saxagliptin 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated, Extended Release | Dr.Reddys Laboratories Inc | ANDA |
Frequently asked questions
What is Saxagliptin and Metformin Hydrochloride used for?
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…
What are the side effects of Saxagliptin and Metformin Hydrochloride?
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… See the full label for the complete list.
Who makes Saxagliptin and Metformin Hydrochloride?
Saxagliptin and Metformin Hydrochloride is listed by 1 labeler in the FDA NDC directory, including Dr.Reddys Laboratories Inc.