Glyxambi
(empagliflozin / linagliptin)Dosage & Administration
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Glyxambi Prescribing Information
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.
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)].
Limitations of Use
GLYXAMBI is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.1)].
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 (5.2)].
GLYXAMBI is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. GLYXAMBI is likely to be ineffective in this setting based upon its mechanism of action.
Testing Prior to Initiation of GLYXAMBI
- Assess renal function before initiating GLYXAMBI and as clinically indicated [see Warnings and Precautions (5.3)].
- Assess volume status. In patients with volume depletion, correct this condition before initiating GLYXAMBI [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5, 8.6)].
Recommended Dosage and Administration
The recommended dosage of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning, taken with or without food. GLYXAMBI may be increased to 25 mg empagliflozin/5 mg linagliptin once daily for additional glycemic control.
Dosage Recommendations in Patients with Renal Impairment
GLYXAMBI is not recommended for use in patients with an eGFR less than 30 mL/min/1.73 m2 and contraindicated in patients on dialysis [see Indications and Usage (1), Contraindications (4), Warnings and Precautions (5.3), and Use in Specific Populations (8.6)].
Recommendations Regarding Missed Dose
- If a dose is missed, instruct patients to take the dose as soon as possible.
- Do not double up the next dose.
Temporary Interruption for Surgery
Withhold GLYXAMBI for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume GLYXAMBI when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
GLYXAMBI tablets available as:
- 10 mg empagliflozin/5 mg linagliptin 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 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".
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, empagliflozin, a component of GLYXAMBI, resulted in adverse renal changes in rats when 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 (see Data).
The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20% to 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% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, 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 postnatal 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 1,943-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.
Lactation
Risk Summary
There is limited 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 to 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.
Pediatric Use
Safety and effectiveness of GLYXAMBI have not been established in pediatric patients.
Geriatric Use
GLYXAMBI
Empagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older [see Warnings and Precautions (5.3)].
Empagliflozin
In empagliflozin type 2 diabetes mellitus trials, 2,721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these trials, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.
Linagliptin
In linagliptin trials, 1,085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin trials, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.
Renal Impairment
Empagliflozin
The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment [see Warnings and Precautions (5.3)], volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function.
Efficacy and safety trials with empagliflozin did not enroll patients with ESRD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. Empagliflozin is contraindicated in patients on dialysis [see Indications and Usage (1) and Contraindications (4)].
Hepatic Impairment
GLYXAMBI may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
GLYXAMBI is contraindicated in patients:
- on dialysis [see Use in Specific Populations (8.6)].
- with a hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.9) and Adverse Reactions (6)].
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, empagliflozin, a component of GLYXAMBI, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients who received placebo and fatal ketoacidosis has occurred with empagliflozin. GLYXAMBI is not indicated for glycemic control in patients with type 1 diabetes mellitus.
Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including GLYXAMBI.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.
Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing GLYXAMBI [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue GLYXAMBI, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting GLYXAMBI.
Withhold GLYXAMBI, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume GLYXAMBI when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue GLYXAMBI and seek medical attention immediately if signs and symptoms occur.
Pancreatitis
Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14.3)], acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with 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.
Volume Depletion
Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating GLYXAMBI in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating GLYXAMBI. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
Urosepsis and Pyelonephritis
There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving empagliflozin. Treatment with empagliflozin 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)].
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when GLYXAMBI is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)
Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with GLYXAMBI presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue GLYXAMBI, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
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.
Lower Limb Amputation
In some clinical studies with SGLT2 inhibitors an imbalance in the incidence of lower limb amputation has been observed. Across four empagliflozin outcome trials, lower limb amputation event rates were 4.3 and 5.0 events per 1,000 patient-years in the placebo group and the empagliflozin 10 mg or 25 mg dose group, respectively, with a HR of 1.05 (95 % CI) (0.81, 1.36).
In a long-term cardio-renal outcome trial, in patients with chronic kidney disease, the occurrence of lower limb amputations was reported with event rates of 2.9, and 4.3 events per 1,000 patient-years in the placebo, and empagliflozin 10 mg treatment arms, respectively. Amputation of the toe and mid-foot were most frequent (21 out of 28 empagliflozin 10 mg treated patients with lower limb amputations), and some involving above and below the knee. Some patients had multiple amputations. GLYXAMBI is not indicated for the treatment of chronic kidney disease.
Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes.
Counsel patients about the importance of routine preventative foot care. Monitor patients receiving GLYXAMBI for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly 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 empagliflozin.
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 hypersensitivity to linagliptin, empagliflozin or any of the excipients in GLYXAMBI [see Contraindications (4)].
Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. 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 DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous Pemphigoid
Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.3)], and 3 of these patients were hospitalized due to 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.
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.