FDA Label for Glyxambi
View Indications, Usage & Precautions
- 1 INDICATIONS AND USAGE
- 2.1 RECOMMENDED DOSAGE
- 2.2 PATIENTS WITH RENAL IMPAIRMENT
- 3 DOSAGE FORMS AND STRENGTHS
- 4 CONTRAINDICATIONS
- 5.1 PANCREATITIS
- 5.2 HEART FAILURE
- 5.3 HYPOTENSION
- 5.4 KETOACIDOSIS
- 5.5 ACUTE KIDNEY INJURY AND IMPAIRMENT IN RENAL FUNCTION
- 5.6 UROSEPSIS AND PYELONEPHRITIS
- 5.7 HYPOGLYCEMIA WITH CONCOMITANT USE WITH INSULIN AND INSULIN SECRETAGOGUES
- 5.8 GENITAL MYCOTIC INFECTIONS
- 5.9 HYPERSENSITIVITY REACTIONS
- 5.10 INCREASED LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C)
- 5.11 SEVERE AND DISABLING ARTHRALGIA
- 5.12 BULLOUS PEMPHIGOID
- 5.13 MACROVASCULAR OUTCOMES
- 6 ADVERSE REACTIONS
- 6.1 CLINICAL TRIALS EXPERIENCE
- 6.2 POSTMARKETING EXPERIENCE
- 7.1 DRUG INTERACTIONS WITH EMPAGLIFLOZIN
- OTHER
- 8.2 LACTATION
- 8.4 PEDIATRIC USE
- 8.5 GERIATRIC USE
- 8.6 RENAL IMPAIRMENT
- 8.7 HEPATIC IMPAIRMENT
- 10 OVERDOSAGE
- 11 DESCRIPTION
- 12.1 MECHANISM OF ACTION
- 12.2 PHARMACODYNAMICS
- 12.3 PHARMACOKINETICS
- 13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
- 14.1 GLYXAMBI GLYCEMIC CONTROL STUDIES
- 14.2 EMPAGLIFLOZIN CARDIOVASCULAR OUTCOME STUDY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE
- 16 HOW SUPPLIED/STORAGE AND HANDLING
- 17 PATIENT COUNSELING INFORMATION
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
Glyxambi Product Label
The following document was submitted to the FDA by the labeler of this product Boehringer Ingelheim Pharmaceuticals, Inc.. The document includes published materials associated whith this product with the essential scientific information about this product as well as other prescribing information. Product labels may durg indications and usage, generic names, contraindications, active ingredients, strength dosage, routes of administration, appearance, warnings, inactive ingredients, etc.
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)].
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)].
3 Dosage Forms And Strengths
GLYXAMBI is a combination of empagliflozin and linagliptin. GLYXAMBI is available in the following dosage forms and strengths:
- 10 mg empagliflozin/5 mg linagliptin tablets are pale yellow,
arc triangular, flat-faced, bevel-edged, film-coated tablets. One
side is debossed with the Boehringer Ingelheim company symbol; the
other side is debossed with “10/5”.
- 25 mg empagliflozin/5 mg linagliptin tablets are pale pink, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with “25/5”.
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)].
5.1 Pancreatitis
There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue GLYXAMBI and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using GLYXAMBI.
5.2 Heart Failure
An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
Consider the risks and benefits of GLYXAMBI prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of GLYXAMBI.
5.3 Hypotension
Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating empagliflozin [see Adverse Reactions (6.1)] particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Before initiating GLYXAMBI, assess for volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see Use in Specific Populations (8.5)].
5.4 Ketoacidosis
Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. GLYXAMBI is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].
Patients treated with GLYXAMBI who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with GLYXAMBI may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, GLYXAMBI should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.
Before initiating GLYXAMBI, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with GLYXAMBI consider monitoring for ketoacidosis and temporarily discontinuing GLYXAMBI in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
5.5 Acute Kidney Injury And Impairment In Renal Function
Empagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.1)] and can cause renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.
Before initiating GLYXAMBI, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing GLYXAMBI in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue GLYXAMBI promptly and institute treatment.
Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating GLYXAMBI [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of GLYXAMBI and monitored periodically thereafter. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Use of GLYXAMBI is not recommended when eGFR is persistently less than 45 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4) and Use in Specific Populations (8.6)].
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)].
5.7 Hypoglycemia With Concomitant Use With Insulin And Insulin Secretagogues
Insulin and insulin secretagogues are known to cause hypoglycemia. The use of empagliflozin or linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.
5.8 Genital Mycotic Infections
Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate.
5.9 Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of GLYXAMBI). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose.
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with GLYXAMBI.
There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empaglifozin (one of the components of GLYXAMBI).
If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with a previous serious hypersensitivity reaction to linagliptin or empagliflozin [see Contraindications (4)].
5.10 Increased Low-Density Lipoprotein Cholesterol (Ldl-C)
Increases in LDL-C can occur with empagliflozin [see Adverse Reactions (6.1)]. Monitor and treat as appropriate.
5.11 Severe And Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.
5.12 Bullous Pemphigoid
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving GLYXAMBI. If bullous pemphigoid is suspected, GLYXAMBI should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
5.13 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLYXAMBI.
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)]
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.
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.
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
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.
Other
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)].
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.
Distributed by:
Boehringer Ingelheim
Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Marketed by:
Boehringer
Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA
and
Eli Lilly and Company
Indianapolis, IN
46285 USA
Licensed
from:
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Germany
Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the Glyxambi®, Jardiance®, Tradjenta® and EMPA-REG OUTCOME® trademarks under license.
The other trademarks referenced are owned by third parties not affiliated with Boehringer Ingelheim Pharmaceuticals, Inc.
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IT5885KL112017
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)].
10 Overdosage
In the event of an overdose with GLYXAMBI, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of empagliflozin by hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.
11 Description
GLYXAMBI tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: empagliflozin and linagliptin.
Empagliflozin
Empagliflozin is an orally-active inhibitor of the sodium-glucose
co-transporter (SGLT2).
The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S).
The molecular formula is C23H27ClO7 and the molecular weight is 450.91. The structural formula is:
Empagliflozin is a white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile; soluble in 50% acetonitrile/water; and practically insoluble in toluene.
Linagliptin
Linagliptin is an orally-active
inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
The chemical name of linagliptin is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-
The molecular formula is C25H28N8O2 and the molecular weight is 472.54. The structural formula is:
Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water. Linagliptin is soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol, and very slightly soluble in acetone.
GLYXAMBI
GLYXAMBI tablets for oral administration
are available in two dosage strengths containing 10 mg or 25 mg empagliflozin
in combination with 5 mg linagliptin. The inactive ingredients of
GLYXAMBI are the following: Tablet Core: mannitol, pregelatinized
starch, corn starch, copovidone, crospovidone, talc and magnesium
stearate. Coating: hypromellose, mannitol, talc, titanium dioxide,
polyethylene glycol and ferric oxide, yellow (10 mg/5 mg) or ferric
oxide, red (25 mg/5 mg).
12.1 Mechanism Of Action
GLYXAMBI
GLYXAMBI
combines 2 antihyperglycemic agents with complementary mechanisms
of action to improve glycemic control in patients with type 2 diabetes:
empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor,
and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor.
Empagliflozin
Sodium-glucose co-transporter 2 (SGLT2) is the predominant
transporter responsible for reabsorption of glucose from the glomerular
filtrate back into the circulation. Empagliflozin is an inhibitor
of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption
of filtered glucose and lowers the renal threshold for glucose, and
thereby increases urinary glucose excretion.
Linagliptin
Linagliptin
is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones
glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP). Thus, linagliptin increases the concentrations
of active incretin hormones, stimulating the release of insulin in
a glucose-dependent manner and decreasing the levels of glucagon in
the circulation. Both incretin hormones are involved in the physiological
regulation of glucose homeostasis. Incretin hormones are secreted
at a low basal level throughout the day and levels rise immediately
after meal intake. GLP-1 and GIP increase insulin biosynthesis and
secretion from pancreatic beta cells in the presence of normal and
elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon
secretion from pancreatic alpha cells, resulting in a reduction in
hepatic glucose output.
12.2 Pharmacodynamics
Empagliflozin
Urinary Glucose Excretion
In patients with
type 2 diabetes, urinary glucose excretion increased immediately following
a dose of empagliflozin and was maintained at the end of a 4-week
treatment period averaging at approximately 64 grams per day with
10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin
once daily.
Urinary Volume
In a 5-day study, mean 24-hour
urine volume increase from baseline was 341 mL on Day 1 and 135 mL
on Day 5 of empagliflozin 25 mg once daily treatment.
Cardiac Electrophysiology
In a randomized, placebo-controlled, active-comparator,
crossover study, 30 healthy subjects were administered a single oral
dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum
recommended dose), moxifloxacin, and placebo. No increase in QTc
was observed with either 25 mg or 200 mg empagliflozin.
Linagliptin
Linagliptin binds to DPP-4 in a reversible manner and
increases the concentrations of incretin hormones. Linagliptin glucose-dependently
increases insulin secretion and lowers glucagon secretion, thus resulting
in a better regulation of the glucose homeostasis. Linagliptin binds
selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8
or DPP-9 activity in vitro at concentrations approximating
therapeutic exposures.
Cardiac Electrophysiology
In a
randomized, placebo-controlled, active-comparator, 4-way crossover
study, 36 healthy subjects were administered a single oral dose of
linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose),
moxifloxacin, and placebo. No increase in QTc was observed with either
the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose,
peak linagliptin plasma concentrations were approximately 38-fold
higher than the peak concentrations following a 5-mg dose.
12.3 Pharmacokinetics
GLYXAMBI
The
results of the bioequivalence study in healthy subjects demonstrated
that GLYXAMBI (25 mg empagliflozin/5 mg linagliptin) combination tablets
are bioequivalent to coadministration of corresponding doses of empagliflozin
and linagliptin as individual tablets. Administration of the fixed-dose
combination with food resulted in no change in overall exposure of
empagliflozin or linagliptin; however, the peak exposure was decreased
39% and 32% for empagliflozin and linagliptin, respectively. These
changes are not likely to be clinically significant.
Absorption
Empagliflozin
The pharmacokinetics of empagliflozin
has been characterized in healthy volunteers and patients with type
2 diabetes and no clinically relevant differences were noted between
the two populations. After oral administration, peak plasma concentrations
of empagliflozin were reached at 1.5 hours post-dose. Thereafter,
plasma concentrations declined in a biphasic manner with a rapid distribution
phase and a relatively slow terminal phase. The steady state mean
plasma AUC and Cmax were 1870 nmol·h/L and
259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment,
and 4740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin
once daily treatment. Systemic exposure of empagliflozin increased
in a dose-proportional manner in the therapeutic dose range. The
single-dose and steady-state pharmacokinetic parameters of empagliflozin
were similar, suggesting linear pharmacokinetics with respect to time.
Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.
Linagliptin
The absolute bioavailability
of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not
clinically relevant. Linagliptin may be administered with or without
food.
Distribution
Empagliflozin
The apparent
steady-state volume of distribution was estimated to be 73.8 L based
on a population pharmacokinetic analysis. Following administration
of an oral [14C]-empagliflozin solution
to healthy subjects, the red blood cell partitioning was approximately
36.8% and plasma protein binding was 86.2%.
Linagliptin
The mean apparent volume of distribution at steady state following
a single intravenous dose of linagliptin 5 mg to healthy subjects
is approximately 1110 L, indicating that linagliptin extensively distributes
to the tissues. Plasma protein binding of linagliptin is concentration-dependent,
decreasing from about 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L,
reflecting saturation of binding to DPP-4 with increasing concentration
of linagliptin. At high concentrations, where DPP-4 is fully saturated,
70% to 80% of linagliptin remains bound to plasma proteins and 20%
to 30% is unbound in plasma. Plasma binding is not altered in patients
with renal or hepatic impairment.
Metabolism
Empagliflozin
No major metabolites of empagliflozin
were detected in human plasma and the most abundant metabolites were
three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic
exposure of each metabolite was less than 10% of total drug-related
material. In vitro studies suggested that the primary
route of metabolism of empagliflozin in humans is glucuronidation
by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3,
UGT1A8, and UGT1A9.
Linagliptin
Following oral administration,
the majority (about 90%) of linagliptin is excreted unchanged, indicating
that metabolism represents a minor elimination pathway. A small fraction
of absorbed linagliptin is metabolized to a pharmacologically inactive
metabolite, which shows a steady-state exposure of 13.3% relative
to linagliptin.
Elimination
Empagliflozin
The apparent terminal elimination half-life of empagliflozin
was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h
based on the population pharmacokinetic analysis. Following once-daily
dosing, up to 22% accumulation, with respect to plasma AUC, was observed
at steady-state, which was consistent with empagliflozin half-life.
Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6%
of the drug-related radioactivity was eliminated in feces (41.2%)
or urine (54.4%). The majority of drug-related radioactivity recovered
in feces was unchanged parent drug and approximately half of drug-related
radioactivity excreted in urine was unchanged parent drug.
Linagliptin
Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the
administered radioactivity was eliminated via the enterohepatic system
(80%) or urine (5%) within 4 days of dosing. Renal clearance at steady
state was approximately 70 mL/min.
Specific Populations
Renal Impairment
GLYXAMBI:
Studies characterizing the pharmacokinetics of empagliflozin
and linagliptin after administration of GLYXAMBI in renally impaired
patients have not been performed [see Dosage and Administration
(2.2)].
Empagliflozin: In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and subjects with kidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with a decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.
Linagliptin: An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes and severe renal impairment (CrCl <30 mL/min), and 11 patients with type 2 diabetes and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.
Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.
In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with type 2 diabetes and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2 diabetes groups, renal excretion was below 7% of the administered dose.
These findings were further supported by the results of population pharmacokinetic analyses.
Hepatic Impairment
GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and
linagliptin after administration of GLYXAMBI in hepatically impaired
patients have not been performed.
Empagliflozin: In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75% and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.
Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.
Effects of Age, Body
Mass Index, Gender, and Race
Empagliflozin: Based on the population PK analysis, age, body mass index (BMI),
gender and race (Asians versus primarily Whites) do not have a clinically
meaningful effect on pharmacokinetics of empagliflozin [see
Use in Specific Populations (8.5)].
Linagliptin: Based on the population PK analysis, age, body mass index (BMI), gender and race do not have a clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (8.5)].
Pediatric
Studies characterizing the pharmacokinetics of empagliflozin or
linagliptin after administration of GLYXAMBI in pediatric patients
have not been performed.
Drug Interactions
Pharmacokinetic drug
interaction studies with GLYXAMBI have not been performed; however,
such studies have been conducted with the individual components of
GLYXAMBI (empagliflozin and linagliptin).
Empagliflozin
In vitro Assessment of Drug Interactions
In vitro data suggest that the primary
route of metabolism of empagliflozin in humans is glucuronidation
by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3,
UGT1A8, and UGT1A9. Empagliflozin does not inhibit, inactivate, or
induce CYP450 isoforms. Empagliflozin also does not inhibit UGT1A1.
Therefore, no effect of empagliflozin is anticipated on concomitantly
administered drugs that are substrates of the major CYP450 isoforms
or UGT1A1. The effect of UGT induction (e.g., induction by rifampicin
or any other UGT enzyme inducer) on empagliflozin exposure has not
been evaluated.
Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.
In vivo Assessment
of Drug Interactions
No dose adjustment of empagliflozin is recommended when coadministered
with commonly prescribed medicinal products based on results of the
described pharmacokinetic studies. Empagliflozin pharmacokinetics
were similar with and without coadministration of metformin, glimepiride,
pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril,
and simvastatin in healthy volunteers and with or without coadministration
of hydrochlorothiazide and torsemide in patients with type 2 diabetes
(see Figure 1). The observed increases in overall exposure (AUC)
of empagliflozin following coadministration with gemfibrozil, rifampicin,
or probenecid are not clinically relevant. In subjects with normal
renal function, coadministration of empagliflozin with probenecid
resulted in a 30% decrease in the fraction of empagliflozin excreted
in urine without any effect on 24-hour urinary glucose excretion.
The relevance of this observation to patients with renal impairment
is unknown.
Figure 1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% - 125%)]
aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin,
10 mg, single dose
Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2).
Figure 2 Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% - 125%)]
aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon®; gadministered as ramipril
Linagliptin
In vitro Assessment of Drug Interactions
Linagliptin is a weak to moderate inhibitor of CYP isozyme
CYP3A4, but does not inhibit other CYP isozymes and is not an inducer
of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,
2E1, and 4A11.
Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.
In vivo Assessment of Drug Interactions
Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease
exposure to linagliptin to subtherapeutic and likely ineffective concentrations.
For patients requiring use of such drugs, an alternative to linagliptin
is strongly recommended. In vivo studies indicated
evidence of a low propensity for causing drug interactions with substrates
of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).
No dose adjustment of linagliptin is recommended based on results
of the described pharmacokinetic studies.
aMultiple dose (steady state) unless otherwise noted | ||||
bSingle dose | ||||
cAUC = AUC(0 to 24 hours) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments | ||||
QD = once daily | ||||
BID = twice daily | ||||
TID = three times daily | ||||
Coadministered Drug | Dosing of Coadministered Druga | Dosing of Linagliptina | Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.0 | |
AUCc | Cmax | |||
No dosing adjustments required for linagliptin when given with the following coadministered drugs: | ||||
Metformin | 850 mg TID | 10 mg QD | 1.20 | 1.03 |
Glyburide | 1.75 mgb | 5 mg QD | 1.02 | 1.01 |
Pioglitazone | 45 mg QD | 10 mg QD | 1.13 | 1.07 |
Ritonavir | 200 mg BID | 5 mgb | 2.01 | 2.96 |
The efficacy of linagliptin may be reduced when administered in combination with strong inducers of CYP3A4 or P-gp (e.g., rifampin). Use of alternative treatments is strongly recommended [see Drug Interactions (7.2)]. | ||||
Rifampin | 600 mg QD | 5 mg QD | 0.60 | 0.56 |
aMultiple dose (steady state) unless otherwise noted | |||||
bSingle dose | |||||
cAUC = AUC(INF) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments | |||||
dAUC=AUC(0-168) and Cmax=Emaxfor pharmacodynamic end points | |||||
INR = International Normalized Ratio | |||||
PT = Prothrombin Time | |||||
QD = once daily | |||||
TID = three times daily | |||||
Coadministered Drug | Dosing of Coadministered Druga | Dosing of Linagliptina | Geometric
Mean Ratio | ||
AUCc | Cmax | ||||
No dosing adjustments required for the following coadministered drugs: | |||||
Metformin | 850 mg TID | 10 mg QD | metformin | 1.01 | 0.89 |
Glyburide | 1.75 mgb | 5 mg QD | glyburide | 0.86 | 0.86 |
Pioglitazone | 45 mg QD | 10 mg QD | pioglitazone metabolite M-III metabolite M-IV | 0.94 0.98 1.04 | 0.86 0.96 1.05 |
Digoxin | 0.25 mg QD | 5 mg QD | digoxin | 1.02 | 0.94 |
Simvastatin | 40 mg QD | 10 mg QD | simvastatin | 1.34 1.33 | 1.10 1.21 |
Warfarin | 10 mgb | 5 mg QD | R-warfarin S-warfarin INR PT | 0.99 1.03 0.93d 1.03d | 1.00 1.01 1.04d 1.15d |
Ethinylestradiol and levonorgestrel | ethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD | 5 mg QD | ethinylestradiol levonorgestrel | 1.01 1.09 | 1.08 1.13 |
13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
GLYXAMBI
No animal studies have been conducted with the combination of empagliflozin
and linagliptin to evaluate carcinogenesis, mutagenesis, or impairment
of fertility. General toxicity studies in rats up to 13 weeks were
performed with the combined components. These studies indicated that
no additive toxicity is caused by the combination of empagliflozin
and linagliptin.
Empagliflozin
Carcinogenesis
was evaluated in 2-year studies conducted in CD-1 mice and Wistar
rats. Empagliflozin did not increase the incidence of tumors in female
rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure
from the maximum clinical dose of 25 mg). In male rats, hemangiomas
of the mesenteric lymph node were increased significantly at 700 mg/kg/day
or approximately 42 times the exposure from a 25 mg clinical dose.
Empagliflozin did not increase the incidence of tumors in female
mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the exposure
from a 25 mg clinical dose). Renal tubule adenomas and carcinomas
were observed in male mice at 1000 mg/kg/day, which is approximately
45 times the exposure of the maximum clinical dose of 25 mg. These
tumors may be associated with a metabolic pathway predominantly present
in the male mouse kidney.
Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.
Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).
Linagliptin
Linagliptin did not increase the
incidence of tumors in male and female rats in a 2-year study at doses
of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately
418 times the clinical dose of 5 mg/day based on AUC exposure. Linagliptin
did not increase the incidence of tumors in mice in a 2-year study
at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately
35- and 270-times the clinical dose based on AUC exposure. Higher
doses of linagliptin in female mice (80 mg/kg) increased the incidence
of lymphoma at approximately 215-times the clinical dose based on
AUC exposure.
Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.
In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943-times the clinical dose based on AUC exposure).
14.1 Glyxambi Glycemic Control Studies
Add-on Combination Therapy with
Metformin
A total of 686 patients with type 2
diabetes participated in a double-blind, active-controlled study to
evaluate the efficacy and safety of empagliflozin 10 mg or 25 mg in
combination with linagliptin 5 mg compared to the individual components.
Patients with type 2 diabetes inadequately controlled on at least 1500 mg of metformin per day entered a single-blind placebo run-in period for 2 weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7 and 10.5% were randomized 1:1:1:1:1 to one of 5 active-treatment arms of empagliflozin 10 mg or 25 mg, linagliptin 5 mg, or linagliptin 5 mg in combination with 10 mg or 25 mg empagliflozin as a fixed dose combination tablet.
At Week 24, empagliflozin 10 mg or 25 mg used in combination with linagliptin 5 mg provided statistically significant improvement in HbA1c (p-value <0.0001) and FPG (p-value <0.001) compared to the individual components in patients who had been inadequately controlled on metformin (see Table 5, Figure 3). Treatment with GLYXAMBI 25 mg/5 mg or GLYXAMBI 10 mg/5 mg daily also resulted in a statistically significant reduction in body weight compared to linagliptin 5 mg (p-value <0.0001). There was no statistically significant difference compared to empagliflozin alone.
a Full analysis population (observed case) using MMRM. MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c. | ||||||
bPatients with HbA1c above 7% at baseline: GLYXAMBI 25 mg/5 mg, n=123; GLYXAMBI 10 mg/5 mg, n=128; empagliflozin 25 mg, n=132; empagliflozin 10 mg, n=125; linagliptin 5 mg, n=119. Non-completers were considered failures (NCF). | ||||||
cFull analysis population using last observation carried forward. ANCOVA model included treatment, renal function, region, baseline weight, and baseline HbA1c. | ||||||
dp<0.001 for FPG; p<0.0001 for HbA1c and body weight | ||||||
GLYXAMBI 10 mg/5 mg | GLYXAMBI 25 mg/5 mg | Empagliflozin 10 mg | Empagliflozin 25 mg | Linagliptin 5 mg | ||
HbA1c (%) | ||||||
Number of patients | n=135 | n=133 | n=137 | n=139 | n=128 | |
Baseline (mean) | 8.0 | 7.9 | 8.0 | 8.0 | 8.0 | |
Change from baseline (adjusted mean) | -1.1 | -1.2 | -0.7 | -0.6 | -0.7 | |
Comparison vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)a | -0.4 (-0.6, -0.2)d | -0.6 (-0.7, -0.4)d | -- | -- | -- | |
Comparison vs linagliptin 5 mg (adjusted mean) (95% CI)a | -0.4 (-0.6, -0.2)d | -0.5 (-0.7, -0.3)d | -- | -- | -- | |
Patients [n (%)] achieving HbA1c <7%b | 74 (58) | 76 (62) | 35 (28) | 43 (33) | 43 (36) | |
FPG (mg/dL) | ||||||
Number of patients | n=133 | n=131 | n=136 | n=137 | n=125 | |
Baseline (mean) | 157 | 155 | 162 | 160 | 156 | |
Change from baseline (adjusted mean) | -33 | -36 | -21 | -21 | -13 | |
Comparison vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)a | -12 (-18, -5)d | -15 (-22, -9)d | -- | -- | -- | |
Comparison vs linagliptin 5 mg (adjusted mean) (95% CI)a | -20 (-27, -13)d | -23 (-29, -16)d | -- | -- | -- | |
Body Weight | ||||||
Number of patients | n=135 | n=134 | n=137 | n=140 | n=128 | |
Baseline (mean) in kg | 87 | 85 | 86 | 88 | 85 | |
% change from baseline (adjusted mean) | -3.1 | -3.4 | -3.0 | -3.5 | -0.7 | |
Comparison vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)c | 0.0 (-0.9, 0.8) | 0.1 (-0.8, 0.9) | -- | -- | -- | |
Comparison vs linagliptin 5 mg (adjusted mean) (95% CI)c | -2.4 (-3.3, -1.5)d | -2.7 (-3.6, -1.8)d | -- | -- | -- |
Figure 3 Adjusted Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT population)
14.2 Empagliflozin Cardiovascular Outcome Study In Patients With Type 2 Diabetes Mellitus And Atherosclerotic Cardiovascular Disease
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 established cardiovascular disease has not been established. The effect of empagliflozin on cardiovascular risk in adult patients with type 2 diabetes and established, stable, atherosclerotic cardiovascular disease is presented below.
The EMPA-REG OUTCOME study, a multicenter, multi-national, randomized, double-blind parallel group trial compared the risk of experiencing a major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. Coadministered antidiabetic medications were to be kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.
A total of 7020 patients were treated (empagliflozin 10 mg = 2345; empagliflozin 25 mg = 2342; placebo = 2333) and followed for a median of 3.1 years. Approximately 72% of the study population was Caucasian, 22% was Asian, and 5% was Black. The mean age was 63 years and approximately 72% were male.
All patients in the study had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had had diabetes for more than 10 years. Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators respectively and the mean eGFR was 74 mL/min/1.73 m2. At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), sulfonylurea (43%) and dipeptidyl peptidase-4 inhibitor (11%).
All patients had established atherosclerotic cardiovascular disease at baseline including one (82%) or more (18%) of the following; a documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).
The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.
Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI 0.74, 0.99). The treatment effect was due to a significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin (HR: 0.62; 95% CI 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 6 and Figure 4 and 5). Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.
aTreated set (patients
who had received at least one dose of study drug) bp−value for superiority (2−sided) 0.04 cTotal number of events | |||
Placebo N=2333 | Empagliflozin N=4687 | Hazard
ratio vs placebo (95% CI) | |
Composite of
cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b | 282 (12.1%) | 490 (10.5%) | 0.86 (0.74, 0.99) |
Non-fatal myocardial infarctionc | 121 (5.2%) | 213 (4.5%) | 0.87 (0.70, 1.09) |
Non-fatal strokec | 60 (2.6%) | 150 (3.2%) | 1.24 (0.92, 1.67) |
Cardiovascular deathc | 137 (5.9%) | 172 (3.7%) | 0.62 (0.49, 0.77) |
Figure 4 Estimated Cumulative Incidence of First MACE
Figure 5 Estimated Cumulative Incidence of Cardiovascular Death
The efficacy of empagliflozin on cardiovascular death was generally consistent across major demographic and disease subgroups.
Vital status was obtained for 99.2% of subjects in the trial. A total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as cardiovascular deaths. The non-cardiovascular deaths were only a small proportion of deaths, and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).
16 How Supplied/Storage And Handling
GLYXAMBI (empagliflozin and linagliptin) tablets are available in 10 mg/5 mg and 25 mg/5 mg strengths as follows:
10 mg/5 mg tablets: pale yellow, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with "10/5".
Bottles of 30 (NDC 0597-0182-30)
Bottles of 90 (NDC 0597-0182-90)
Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0182-39), institutional
pack.
25 mg/5 mg tablets: pale pink, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with "25/5".
Bottles of 30 (NDC 0597-0164-30)
Bottles of 90 (NDC 0597-0164-90)
Cartons containing 3
blister cards of 10 tablets each (3 x 10) (NDC 0597-0164-39), institutional
pack.
If repackaging is required, dispense in a tight container as defined in USP.
Storage
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Store in a safe place out
of reach of children.
17 Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Instructions
Instruct patients to read the
Medication Guide before starting GLYXAMBI therapy and to reread it
each time the prescription is renewed. Instruct patients to inform
their doctor or pharmacist if they develop any unusual symptom, or
if any known symptom persists or worsens.
Inform patients of the potential risks and benefits of GLYXAMBI and of alternative modes of therapy. Also, inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.
Instruct patients to take GLYXAMBI only as prescribed. If a dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.
Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with GLYXAMBI [see Use in Specific Populations (8.1)]. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.
Advise women that breastfeeding is not recommended during treatment with GLYXAMBI [see Use in Specific Populations (8.2)].
Pancreatitis
Inform patients that acute pancreatitis has been reported
during postmarketing use of linagliptin. Inform 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 discontinue GLYXAMBI promptly
and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].
Heart Failure
Inform patients of the signs
and symptoms of heart failure. Before initiating GLYXAMBI, patients
should be asked about a history of heart failure or other risk factors
for heart failure including moderate to severe renal impairment. Instruct
patients to contact their healthcare 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 (5.2)].
Hypoglycemia
Inform patients that the incidence
of hypoglycemia is increased when empagliflozin, linagliptin, or GLYXAMBI
is added to a sulfonylurea or insulin and that a lower dose of the
sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
Hypotension
Inform patients that hypotension may occur with GLYXAMBI
and advise them to contact their healthcare provider if they experience
such symptoms [see Warnings and Precautions (5.3)]. Inform patients that dehydration
may increase the risk for hypotension, and to have adequate fluid
intake.
Ketoacidosis
Inform patients that ketoacidosis
is a serious life-threatening condition. Cases of ketoacidosis have
been reported during use of empagliflozin. Instruct patients to check
ketones (when possible) if symptoms consistent with ketoacidosis occur
even if blood glucose is not elevated. If symptoms of ketoacidosis
(including nausea, vomiting, abdominal pain, tiredness, and labored
breathing) occur, instruct patients to discontinue GLYXAMBI and seek
medical advice immediately [see Warnings and Precautions (5.4)].
Acute Kidney Injury
Inform patients that acute kidney injury has been reported
during use of empagliflozin. Advise patients to seek medical advice
immediately if they have reduced oral intake (such as due to acute
illness or fasting) or increased fluid losses (such as due to vomiting,
diarrhea, or excessive heat exposure), as it may be appropriate to
temporarily discontinue GLYXAMBI use in those settings [see
Warnings and Precautions (5.5)].
Serious
Urinary Tract Infections
Inform patients of
the potential for urinary tract infections, which may be serious.
Provide them with information on the symptoms of urinary tract infections.
Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.6)].
Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections
may occur and provide them with information on the signs and symptoms
of vaginal yeast infections. Advise them of treatment options and
when to seek medical advice [see Warnings and Precautions
(5.8)].
Genital Mycotic Infections in
Males (e.g., Balanitis or Balanoposthitis)
Inform
male patients that yeast infection of penis (e.g., balanitis or balanoposthitis)
may occur, especially in uncircumcised males and patients with chronic
and recurrent infections. Provide them with information on the signs
and symptoms of balanitis and balanoposthitis (rash or redness of
the glans or foreskin of the penis). Advise them of treatment options
and when to seek medical advice [see Warnings and Precautions
(5.8)].
Hypersensitivity Reactions
Inform patients that serious allergic reactions, such
as anaphylaxis, angioedema, and exfoliative skin conditions, have
been reported during postmarketing use of linagliptin or empagliflozin,
components of GLYXAMBI. If symptoms of 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 GLYXAMBI
and seek medical advice promptly [see Warnings and Precautions
(5.9)].
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
(5.11)].
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 (5.12)].
Laboratory Tests
Inform patients that renal function should be assessed prior to
initiation of GLYXAMBI and monitored periodically thereafter.
Inform patients that elevated glucose in urinalysis is expected when taking GLYXAMBI.
Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels toward the normal range. Hemoglobin A1c is especially useful for evaluating long-term glycemic control.
Package Label.Principal Display Panel
Glyxambi 10 mg/5 mg Label
Glyxambi 10 mg/5 mg Label, Professional Sample
Glyxambi 10 mg/5 mg Carton
Glyxambi 25 mg/5 mg Label
Glyxambi 25 mg/5 mg Carton
Glyxambi 25 mg/5 mg Carton, Professional Sample
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