Data from FDA - Curated by EPG Health - Last updated 09 February 2018

Indication(s)

1 INDICATIONS AND USAGE GLYXAMBI is a combination of empagliflozin and linagliptin indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate. Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease [see Clinical Studies (14.2)]. However, the effectiveness of GLYXAMBI on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established. Limitations of Use GLYXAMBI is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis [see Warnings and Precautions (5.4)]. GLYXAMBI has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI [see Warnings and Precautions (5.1)]. GLYXAMBI is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate. Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. However, the effectiveness of GLYXAMBI on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established. (1) Limitations of use: Not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis (1) Has not been studied in patients with a history of pancreatitis (1)

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Communicating Metastatic Breast Cancer Learning Zone

Communicating Metastatic Breast Cancer Learning Zone

This learning zone offers a short overview of the challenges faced by both healthcare professionals and patient when communicating end-stage or metastatic cancer.

Cushing's Syndrome

Cushing's Syndrome

Cushing’s syndrome shares symptoms such as hypertension, glucose intolerance and obesity with other common conditions – how can you confidently diagnose this rare disorder?

+ 2 more

Cardiovascular Metabolism Knowledge Centre

Cardiovascular Metabolism Knowledge Centre

The Cardiovascular Metabolism Knowledge Centre is an information hub providing expert insight into the management of hypertension and type 2 diabetes. This Knowledge Centre contains a wealth of scientific video content offering insights and opinion from some of the leading experts in the field.

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS GLYXAMBI is contraindicated in patients with: Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)]. A history of serious hypersensitivity reaction to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity [see Warnings and Precautions (5.9) and Adverse Reactions (6)]. Severe renal impairment, end-stage renal disease, or dialysis (4) History of serious hypersensitivity reaction to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity (4)
Adverse reactions
6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Pancreatitis [see Warnings and Precautions (5.1)] Heart Failure [see Warnings and Precautions (5.2)] Hypotension [see Warnings and Precautions (5.3)] Ketoacidosis [see Warnings and Precautions (5.4)] Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.5)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.7)] Genital Mycotic Infections [see Warnings and Precautions (5.8)] Hypersensitivity Reactions [see Warnings and Precautions (5.9)] Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.10)] Severe and Disabling Arthralgia [see Warnings and Precautions (5.11)] Bullous Pemphigoid [see Warnings and Precautions (5.12)] The most common adverse reactions associated with GLYXAMBI (a 5% or greater incidence) were urinary tract infections, nasopharyngitis, and upper respiratory tract infections (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906 TTY, 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. Empagliflozin and Linagliptin The safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose 5 mg) has been evaluated in a total of 1363 patients with type 2 diabetes treated for up to 52 weeks in active-controlled clinical trials. The most common adverse reactions with concomitant administration of empagliflozin and linagliptin based on a pooled analyses of these studies are shown in Table 1. Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin and Linagliptin aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis GLYXAMBI 10 mg/5 mg n=272 GLYXAMBI 25 mg/5 mg n=273 n (%) n (%) Urinary tract infectiona 34 (12.5) 31 (11.4) Nasopharyngitis 16 (5.9) 18 (6.6) Upper respiratory tract infection 19 (7.0) 19 (7.0) Empagliflozin Adverse reactions that occurred in ≥2% of patients receiving empagliflozin and more commonly than in patients given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%), increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and 2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%). Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Linagliptin Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0% and 6.1%), diarrhea (3.3% and 3.0%), and cough (2.1% and 1.4%). Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Hypoglycemia Table 2 summarizes the reports of hypoglycemia with empagliflozin and linagliptin over a treatment period of 52 weeks. Table 2 Incidence of Overalla and Severeb Hypoglycemic Adverse Reactions aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistance bSevere hypoglycemic events: requiring assistance regardless of blood glucose Add-on to Metformin (52 weeks) GLYXAMBI 10 mg/5 mg (n=136) GLYXAMBI 25 mg/5 mg (n=137) Overall (%) 2.2% 3.6% Severe (%) 0% 0% Laboratory Tests Empagliflozin and Linagliptin Changes in laboratory findings in patients treated with the combination of empagliflozin and linagliptin included increases in cholesterol and hematocrit compared to baseline. Empagliflozin Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions (5.10)]. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups. Increase in Hematocrit: Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Linagliptin Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group). Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of linagliptin and empagliflozin. 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. Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1) and Warnings and Precautions (5.1)] Ketoacidosis [see Warnings and Precautions (5.4)] Urosepsis and pyelonephritis [see Warnings and Precautions (5.6)] Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [see Warnings and Precautions (5.9)] Severe and disabling arthralgia [see Warnings and Precautions (5.11)] Bullous pemphigoid [see Warnings and Precautions (5.12)] Skin reactions (e.g., rash, urticaria) Mouth ulceration, stomatitis

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily, taken in the morning, with or without food (2.1) Dose may be increased to 25 mg empagliflozin/5 mg linagliptin once daily (2.1) Assess renal function before initiating GLYXAMBI. Do not initiate GLYXAMBI if eGFR is below 45 mL/min/1.73 m2 (2.2) Discontinue GLYXAMBI if eGFR falls persistently below 45 mL/min/1.73 m2 (2.2) 2.1 Recommended Dosage The recommended dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning, taken with or without food. In patients tolerating GLYXAMBI, the dose may be increased to 25 mg empagliflozin/5 mg linagliptin once daily. In patients with volume depletion, correcting this condition prior to initiation of GLYXAMBI is recommended [see Warnings and Precautions (5.3), Use in Specific Populations (8.5) and Patient Counseling Information (17)]. No studies have been performed specifically examining the safety and efficacy of GLYXAMBI in patients previously treated with other oral antihyperglycemic agents and switched to GLYXAMBI. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur. 2.2 Patients with Renal Impairment Assessment of renal function is recommended prior to initiation of GLYXAMBI and periodically thereafter. GLYXAMBI should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2. No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2. GLYXAMBI should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and Precautions (5.3, 5.5) and Use in Specific Populations (8.6)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters (8.1) Lactation: GLYXAMBI is not recommended when breastfeeding (8.2) Pediatric Patients: Safety and effectiveness of GLYXAMBI in pediatric patients have not been established (8.4) Geriatric Patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function (5.2, 5.4, 8.5) Renal Impairment: Higher incidence of adverse reactions related to reduced renal function (2.2, 5.4, 8.6) 8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, from empagliflozin, GLYXAMBI is not recommended during the second and third trimesters of pregnancy. The limited available data with GLYXAMBI, linagliptin, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when the combination of linagliptin and empagliflozin was administered to pregnant rats during the period of organogenesis at exposures approximately 253 and 353 times the clinical exposure (see Data). The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >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 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data The combined components administered during the period of organogenesis were not teratogenic in rats up to and including a combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin, which is 253 and 353 times the clinical exposure. A pre- and post-natal development study was not conducted with the combined components of GLYXAMBI. Empagliflozin: Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30 and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after a 13 week drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose. In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16 times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum clinical dose). Linagliptin: No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943 times (rats) and 1943 times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose, based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. 8.2 Lactation Risk Summary There is no information regarding the presence of GLYXAMBI, or its individual components in human milk, the effects on the breastfed infant, or the effects on milk production. Empagliflozin and linagliptin are present in rat milk (see Data). Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of GLYXAMBI is not recommended while breastfeeding. Data Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 -5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. 8.4 Pediatric Use Safety and effectiveness of GLYXAMBI in pediatric patients under 18 years of age have not been established. 8.5 Geriatric Use GLYXAMBI Empagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older. Empagliflozin No empagliflozin dosage change is recommended based on age [see Dosage and Administration (2)]. A total of 2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older. Empagliflozin is expected to have diminished efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)]. The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. Linagliptin There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of linagliptin; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 double-blind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment Empagliflozin The efficacy and safety of empagliflozin have not been established in patients with severe renal impairment, with ESRD, or receiving dialysis. Empagliflozin is not expected to be effective in these patient populations [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.3, 5.5)]. The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment [see Warnings and Precautions (5.5)], volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function. 8.7 Hepatic Impairment GLYXAMBI may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
Pregnancy and lactation
5.6 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].

Interactions

7 DRUG INTERACTIONS 7.1 Drug Interactions with Empagliflozin Diuretics Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion [see Warnings and Precautions (5.3)]. Insulin or Insulin Secretagogues Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia [see Warnings and Precautions (5.7)]. Positive Urine Glucose Test Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. 7.2 Drug Interactions with Linagliptin Inducers of P-glycoprotein or CYP3A4 Enzymes Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer [see Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA206073
Agency product number HDC1R2M35U
Orphan designation No
Product NDC 0597-0164,0597-0182
Date Last Revised 10-01-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Boehringer Ingelheim Pharmaceuticals, Inc.