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Empagliflozin and Linagliptin

Pronunciation

(em pa gli FLOE zin & lin a GLIP tin)

Index Terms

  • Empagliflozin/Linagliptin
  • Linagliptin and Empagliflozin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Glyxambi: Empagliflozin 10 mg and linagliptin 5 mg, Empagliflozin 25 mg and linagliptin 5 mg [contains corn starch]

Brand Names: U.S.

  • Glyxambi

Pharmacologic Category

  • Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor
  • Antidiabetic Agent, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
  • Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor

Pharmacology

Empagliflozin: By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, empagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.

Linagliptin: Inhibits dipeptidyl peptidase IV (DPP-IV) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by the DPP-IV enzyme.

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (noninsulin dependent, NIDDM) when treatment with both empagliflozin and linagliptin is appropriate.

Contraindications

History of serious hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyper-reactivity) to empagliflozin, linagliptin, or any component of the formulation; severe renal impairment, end-stage renal disease (ESRD), or dialysis

Dosing: Adult

Note: If present, correct volume depletion prior to initiation.

Diabetes mellitus, type 2: Oral: Initial: Empagliflozin 10 mg/linagliptin 5 mg once daily; may increase to empagliflozin 25 mg/linagliptin 5 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <45 mL/minute/1.73 m2: Do not initiate therapy; discontinue therapy when eGFR is persistently <45 mL/minute/1.73 m2.

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

End-stage renal disease (ESRD) or dialysis: Use is contraindicated.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; may be used in patients with hepatic impairment.

Administration

Oral: Administer once daily in the morning, with or without food.

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

ACE Inhibitors: DPP-IV Inhibitors may enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antihepaciviral Combination Products: May increase the serum concentration of Linagliptin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: SGLT2 Inhibitors may enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Insulin: DPP-IV Inhibitors may enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Loop Diuretics: Empagliflozin may enhance the hypotensive effect of Loop Diuretics. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Ritonavir: May increase the serum concentration of Linagliptin. Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Sulfonylureas: SGLT2 Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Sulfonylureas: DPP-IV Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Teriflunomide: May increase the serum concentration of OAT3 Substrates. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

See individual monographs for additional adverse effects reported with each agent. Frequency not always defined.

>10%: Genitourinary: Urinary tract infection (11% to 13%)

1% to 10%:

Endocrine & metabolic: Hypoglycemia (2% to 4%), increased serum cholesterol

Hematologic & oncologic: Increased hematocrit

Respiratory: Upper respiratory tract infection (7%), nasopharyngitis (6% to 7%)

<1% (Limited to important or life-threatening): Ketoacidosis (FDA Safety Communication, December 4, 2015), severe arthralgia (FDA Safety Alert, Aug 28, 2015), pyelonephritis (FDA Safety Communication, December 4, 2015), urosepsis (FDA Safety Communication, December 4, 2015)

Warnings/Precautions

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-IV inhibitor use; onset may occur within 1 day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-IV inhibitor therapy resumed.

• Bone fracture: According to the American Diabetes Association guidelines, sodium glucose co-transporter-2 (SGLT2) inhibitors should be avoided in patients with fracture risk factors (ADA 2016a).

• Genital mycotic infections: May increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.

• Hypersensitivity reactions: Rare hypersensitivity reactions (including anaphylaxis, angioedema, and exfoliative skin conditions) have been reported in patients treated with linagliptin; discontinue if signs/symptoms of hypersensitivity reactions occur. Events have generally been noted within the first 3 months of therapy, and may occur with the initial dose. Use with caution if patient has experienced angioedema with other DPP-IV inhibitor use.

• Hypotension: May cause symptomatic hypotension because of intravascular volume depletion, especially in patients with renal impairment, elderly patients, patients on diuretics, or those with low systolic blood pressure. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted; monitor signs and symptoms of hypotension after initiation and increase monitoring in clinical situations where volume contraction is expected.

• Ketoacidosis: Cases of ketoacidosis, a serious and life-threatening condition resulting in urgent hospitalization have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors; before initiating treatment consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse). Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis regardless of blood glucose levels; if indicated, consider interruption or discontinuation of therapy.

• Lipid abnormality: Empagliflozin may cause low-density lipoprotein cholesterol (LDL-C) elevation; monitor LDL-C and treat as needed.

• Pancreatitis: Cases of acute pancreatitis, including fatalities, have been reported with linagliptin. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis because it is not known if this population is at greater risk. Empagliflozin/linagliptin has not been studied in patients with a history of pancreatitis.

• Renal effects: Abnormalities in renal function (decreased eGFR, increased serum creatinine) may occur; elderly patients and patients with preexisting renal impairment may be at greater risk. Assess renal function prior to initiation and periodically during treatment.

• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported; treatment with SGLT2 inhibitors increases the risk for urinary tract infections (UTI); monitor for signs and symptoms of UTI and treat as needed.

Disease-related concerns:

• Renal impairment: Glycemic efficacy may be decreased and risk of adverse reactions (eg, adverse reaction related to volume depletion, renal impairment, UTI) may be increased with worsening renal function; empagliflozin/linagliptin should not be initiated in patients with eGFR <45 mL/minute/1.73 m2 and should be discontinued when eGFR is persistently <45 mL/minute/1.73 m2. Use is contraindicated in severe renal impairment, ESRD, and in dialysis patients.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution; risk of intravascular volume depletion, renal impairment, and UTI may be increased in elderly patients.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Blood glucose, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change (ADA 2016b); renal function and volume status (baseline and periodically during treatment); LDL-C; genital mycotic infections and UTI; blood pressure; signs and symptoms of pancreatitis; signs and symptoms of metabolic acidosis

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Refer to individual monographs.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pharyngitis, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of lactic acidosis (fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, or muscle pain or cramps), signs of a urinary tract infection (blood in the urine, burning or pain when passing urine, polyuria, fever, lower abdominal pain, or pelvic pain), vaginal yeast infection, penile yeast infection, dysphagia, severe headache, severe joint pain, skin edema, or flaking or peeling skin (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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