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Saxagliptin And Metformin Hydrochloride

FDA Drug Information • Also known as: Kombiglyze Xr, Saxagliptin And Metformin Hydrochloride

Brand Names
Kombiglyze Xr, Saxagliptin And Metformin Hydrochloride
Route
ORAL
Dosage Form
TABLET, FILM COATED, EXTENDED RELEASE
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: LACTIC ACIDOSIS

  • 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 contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
  • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [ see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7 ) ].
  • If metformin-associated lactic acidosis is suspected, immediately discontinue KOMBIGLYZE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [ see Warnings and Precautions (5.1) ]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.
  • Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1)
  • Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)
  • If lactic acidosis is suspected, discontinue KOMBIGLYZE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)

    • Description

    11 DESCRIPTION KOMBIGLYZE XR (saxagliptin and metformin HCl 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. 13,7 ]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate or (1 S ,3 S ,5 S )-2-[(2 S )-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical 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, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400). saxagliptin structure Metformin HCl Metformin HCl ( N,N -dimethylimidodicarbonimidic diamide HCl) is a white to off-white crystalline compound 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 is practically insoluble in acetone, ether, and chloroform. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is: metformin hydrochloride structural formula KOMBIGLYZE XR KOMBIGLYZE XR is available for oral administration as tablets containing either 5.58 mg saxagliptin HCl (anhydrous) equivalent to 5 mg saxagliptin and 500 mg metformin HCl (KOMBIGLYZE XR 5 mg/500 mg), or 5.58 mg saxagliptin HCl (anhydrous) equivalent to 5 mg saxagliptin and 1,000 mg metformin HCl (KOMBIGLYZE XR 5 mg/1,000 mg), or 2.79 mg saxagliptin HCl (anhydrous) equivalent to 2.5 mg saxagliptin and 1,000 mg metformin...

    • What Is Saxagliptin And Metformin Hydrochloride Used For?

    1 INDICATIONS AND USAGE KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [ see Clinical Studies (14) ]. KOMBIGLYZE XR is 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 KOMBIGLYZE XR is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. 1.1 Limitations of Use KOMBIGLYZE XR is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

    • Dosage and Administration

    2 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 KOMBIGLYZE XR 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 - 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 .
  • KOMBIGLYZE XR 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 KOMBIGLYZE XR based on the patient’s current regimen and the available strengths of KOMBIGLYZE XR [ see Dosage Forms and Strengths (3) ]. Administer KOMBIGLYZE XR 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 KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin HCl is one KOMBIGLYZE XR tablet containing 5 mg saxagliptin and 500 mg metformin HCl extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin HCl. In patients treated with metformin HCl, the recommended starting dosage of KOMBIGLYZE XR should provide metformin HCl at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin HCl immediate-release to KOMBIGLYZE XR, closely monitor glycemic control and adjust the dosage accordingly. Patients who need 2.5 mg saxagliptin in combination with metformin HCl extended-release may be treated with KOMBIGLYZE XR 2.5 mg/1,000 mg. Patients who need 2.5 mg saxagliptin who are either metformin HCl naive or who require a dose of metformin HCl higher than 1,000 mg should use the individual components. Gradually titrate the dosage of KOMBIGLYZE XR, as needed, after assessing therapeutic response and tolerability, up to a maximum recommended dosage of KOMBIGLYZE XR (5 mg for saxagliptin and 2,000 mg for metformin HCl extended-release orally once daily). Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the feces as a soft, hydrated mass that may...

    • Side Effects (Adverse Reactions)

    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 AstraZeneca at 1-800-236-9933 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 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...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Strong CYP3A4/5 inhibitors (e.g., ketoconazole) : Coadministration with KOMBIGLYZE XR significantly increases saxagliptin concentrations. Limit KOMBIGLYZE XR dosage to 2.5 mg/1,000 mg once daily when coadministered with a strong CYP3A4/5 inhibitor. ( 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 KOMBIGLYZE XR 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 KOMBIGLYZE XR 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 KOMBIGLYZE XR. 7.5 Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. Concomitant use of KOMBIGLYZE XR with insulin or an insulin secretagogue may require lower dosages of insulin or the insulin secretagogue to reduce the risk of hypoglycemia [ 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 KOMBIGLYZE XR, observe the patient closely for loss of blood glucose control. When such...

    • Contraindications

    4 CONTRAINDICATIONS KOMBIGLYZE XR is contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
  • A history of a serious hypersensitivity reaction to saxagliptin, metformin HCl, or any of the ingredients in KOMBLIGLYZE XR. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported [ see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ].
  • Severe renal impairment (eGFR below 30 mL/min/1.73 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 KOMBIGLYZE XR. (4)

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Limited available data with KOMBIGLYZE XR 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...

    Overdosage

    10 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 HCI 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. 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 HCI Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but...

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied KOMBIGLYZE ® XR (saxagliptin and metformin HCl extended-release) tablets have markings on both sides and are available in the strengths and packages listed in Table 15. Table 15: KOMBIGLYZE XR Tablet Presentations Tablet Strength (saxagliptin and metformin HCl extended-release) Film-Coated Tablet Color/Shape Tablet Markings Package Size NDC Code 5 mg/500 mg light brown to brown, biconvex, capsule-shaped “5/500” on one side and “4221” on the reverse, in blue ink Bottles of 30 0310-6135-30 5 mg/1,000 mg pink, biconvex, capsule-shaped “5/1000” on one side and “4223” on the reverse, in blue ink Bottles of 30 0310-6145-30 2.5 mg/1,000 mg pale yellow to light yellow, biconvex, capsule-shaped “2.5/1000” on one side and “4222” on the reverse, in blue ink Bottles of 60 0310-6125-60 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. How Supplied KOMBIGLYZE ® XR (saxagliptin and metformin HCl extended-release) tablets have markings on both sides and are available in the strengths and packages listed in Table 15. Table 15: KOMBIGLYZE XR Tablet Presentations Tablet Strength (saxagliptin and metformin HCl extended-release) Film-Coated Tablet Color/Shape Tablet Markings Package Size NDC Code 5 mg/500 mg light brown to brown, biconvex, capsule-shaped “5/500” on one side and “4221” on the reverse, in blue ink Bottles of 30 0310-6135-30 5 mg/1,000 mg pink, biconvex, capsule-shaped “5/1000” on one side and “4223” on the reverse, in blue ink Bottles of 30 0310-6145-30 2.5 mg/1,000 mg pale yellow to light yellow, biconvex, capsule-shaped “2.5/1000” on one side and “4222” on the reverse, in blue ink Bottles of 60 0310-6125-60 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.