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Linagliptin and Metformin

Pronunciation

(lin a GLIP tin & met FOR min)

Index Terms

  • Linagliptin and Metformin Hydrochloride
  • Linagliptin/Metformin HCl
  • Metformin and Linagliptin
  • Metformin Hydrochloride and Linagliptin

Dosage Forms

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

Tablet, oral:

Jentadueto 2.5/500: Linagliptin 2.5 mg and metformin hydrochloride 500 mg

Jentadueto 2.5/850: Linagliptin 2.5 mg and metformin hydrochloride 850 mg

Jentadueto 2.5/1000: Linagliptin 2.5 mg and metformin hydrochloride 1000 mg

Tablet Extended Release, oral:

Jentadueto XR 2.5/1000: Linagliptin 2.5 mg and metformin hydrochloride 1000 mg

Jentadueto XR 5/1000: Linagliptin 5 mg and metformin hydrochloride 1000 mg

Brand Names: U.S.

  • Jentadueto
  • Jentadueto XR

Pharmacologic Category

  • Antidiabetic Agent, Biguanide
  • Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor

Pharmacology

Linagliptin inhibits dipeptidyl peptidase IV (DPP-IV) enzymes 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 DPP-IV enzymes.

Metformin decreases hepatic glucose production, decreasing intestinal absorption of glucose, and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

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 linagliptin and metformin is appropriate.

Contraindications

US labeling: Hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyper-reactivity) to linagliptin, metformin, or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2) acute or chronic metabolic acidosis including diabetic ketoacidosis.

Canadian labeling: Hypersensitivity to linagliptin, metformin, or any component of the formulation; renal function unknown, renal disease or renal dysfunction (serum creatinine ≥136 micromole/L in males or ≥124 micromole/L in females), or abnormal creatinine clearance (<60 mL/minute) which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia; severe hepatic dysfunction; unstable and/or insulin-dependent (Type 1) diabetes mellitus; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma; history of lactic acidosis regardless of precipitating factors; excessive alcohol intake (acute or chronic); cardiovascular collapse and disease states associated with hypoxemia such as cardiorespiratory insufficiency that often are associated with hyperlactacidemia; stress conditions (eg, severe infection, trauma or surgery, and postoperative recovery phase); severe dehydration; pregnancy; breast-feeding; postoperative periods where food and fluid intake are restricted

Dosing: Adult

Type 2 diabetes mellitus: Oral: Initial doses should be based on current dose of linagliptin and metformin.

Patients currently on metformin: Initial dose: Linagliptin 5 mg daily plus current daily dose of metformin given in 2 equally divided doses or once daily if using extended-release product; maximum daily dose: linagliptin 5 mg/metformin 2,000 mg daily.

Patients not on metformin: Initial dose: Linagliptin 5 mg daily plus metformin 1000 mg daily given in 2 equally divided doses or once daily if using extended-release product; maximum daily dose: linagliptin 5 mg/metformin 2,000 mg daily.

Conversion from immediate-release to extended-release product: May switch to extended-release product containing linagliptin 5 mg and current daily dose of metformin once daily.

Concomitant use with insulin and/or insulin secretagogues (eg, sulfonylureas): Reduced dose of insulin and/or insulin secretagogues may be needed.

Dosing adjustment: Metformin component may be gradually increased up to the maximum dose. Maximum dose: Linagliptin 5 mg/metformin 2,000 mg daily

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor). Do not use in patients ≥80 years of age unless normal renal function has been established.

Dosing: Renal Impairment

US labeling:

eGFR >45 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer’s labeling.

eGFR 30 to 45 mL/minute/1.73 m2: Use is not recommended for initiation of therapy; if eGFR falls to <45 mL/minute/1.73 m2 during therapy, consider benefits/risks of continuing therapy.

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

Canadian labeling:

CrCl ≥60 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling.

CrCl <60 mL/minute: Use is contraindicated.

Serum creatinine (SCr) ≥1.5 mg/dL (136 micromol/L) (males) or ≥1.4 mg/dL (124 micromol/L) (females): Use is contraindicated.

Dosing: Hepatic Impairment

The manufacturer recommends avoiding metformin since liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with liver dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett, 2010; Zhang, 2014).

Administration

Administer with food at the same time(s) each day. Extended-release tablet: Swallow whole; do not split, crush, dissolve, or chew.

Dietary Considerations

Should be taken with food (to decrease GI upset). Take at the same time each day. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy. Monitor for signs and symptoms of vitamin B12 and/or folic acid deficiency; supplementation may be required.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from exposure to high humidity.

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

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

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

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

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

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

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

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

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

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

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: 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

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Ethiodized Oil. Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Monitor therapy

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. 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

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

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 MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

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: 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

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

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Adverse Reactions

Reactions/percentages reported with combination product; also see individual agents. Frequency not always defined.

Dermatologic: Pruritus

Gastrointestinal: Diarrhea (6%), decreased appetite, nausea, pancreatitis, vomiting

Hypersensitivity: Hypersensitivity reaction

Respiratory: Nasopharyngitis (6%), cough

<1% (limited to important or life-threatening): Severe arthralgia (FDA Safety Alert, Aug 28, 2015)

ALERT: U.S. Boxed Warning

Risk of lactic acidosis:

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms, such as malaise, myalgias, respiratory distress, increasing somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years or older, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue linagliptin and metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-IV inhibitor use; onset may occur within one 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. Discontinue use if severe joint pain results from DPP-IV inhibitor therapy.

• Hematologic: Dose-related decrease in lymphocyte count has been observed with other dipeptidyl peptidase-4 inhibitors; clinical significance is not known. Monitoring of lymphocyte counts may be warranted in patients with unusual or persistent infection.

• 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.

• Lactic acidosis: [US Boxed Warning]: Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin that requires urgent care and hospitalization. The risk is increased in patients with acute congestive heart failure, dehydration, excessive alcohol intake, hepatic or renal impairment, concurrent drug therapy with specific agents, or sepsis. Symptoms may be nonspecific (eg, abdominal distress, malaise, myalgia, respiratory distress, somnolence); low pH, increased anion gap and elevated blood lactate (>5 mmol/L) may be observed. Discontinue immediately if acidosis is suspected. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. Metformin is dialyzable and prompt initiation of hemodialysis may result in reversal of symptoms and recovery. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function and the patient's age. Patients and their caregivers should be educated about the symptoms of lactic acidosis and should be advised to discontinue therapy and consult health care provider promptly if symptoms occur.

• 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 as it is not known if this population is at greater risk.

Disease-related concerns:

• Heart failure: Use with caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable or acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion.

• Hepatic impairment: Use with caution in patients with hepatic impairment due to potential for lactic acidosis.

• Renal impairment: Metformin is substantially excreted by the kidney; use with caution in patients with renal impairment (use is contraindicated in some patients). Evaluate renal function prior to initiation of therapy and then monitor renal function at least annually. May assess more frequently in patients at increased risk of developing renal impairment (eg, elderly). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (eg, fever, trauma, infection, surgery).

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: Metformin should not be initiated in patients ≥80 years of age unless normal renal function is confirmed; risk of acidosis increases with age.

Other warnings/precautions:

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

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: Temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015).

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

• Surgical procedures: Therapy should be suspended for any surgical procedures excluding minor procedures not associated with restricted food and fluid intake. Restart only after normal intake resumed and normal renal function is verified.

• Vitamin B12 concentrations: Metformin may impair vitamin B12 absorption, particularly in those with inadequate vitamin B12 or calcium intake/absorption; very rarely associated with anemia. Rapid reversal of vitamin B12 deficiency may be observed with discontinuation of therapy or supplementation. Monitor vitamin B12 serum concentrations periodically with long-term therapy.

Monitoring Parameters

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 2016a]); serum glucose; hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) annually; lymphocyte counts if unusual or persistent infection; hepatic function, renal function (prior to initiation of therapy then at least annually or more frequently if necessary); vitamin B12 (periodically with long-term treatment) and folate (if megaloblastic anemia is suspected), signs/symptoms of pancreatitis

Pregnancy Risk Factor

B

Pregnancy Considerations

Canadian labeling contraindicates use in pregnancy.

Adverse events were not observed in animal reproduction studies using this combination, except with doses that were maternally toxic. Metformin crosses the placenta. Refer to individual agents.

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 abdominal pain, nausea, vomiting, diarrhea, flatulence, loss of strength and energy, headache, pharyngitis, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of too much lactic acid in the blood (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), eczema, dysphagia, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), or severe joint pain (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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