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Alogliptin and Metformin

Pronunciation

(al oh GLIP tin & met FOR min)

Index Terms

  • Alogliptin and Metformin Hydrochloride
  • Alogliptin Benz/Metformin HCl
  • Metformin and Alogliptin
  • Metformin Hydrochloride and Alogliptin

Dosage Forms

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

Tablet, Oral:

Kazano: Alogliptin 12.5 mg and metformin hydrochloride 500 mg, Alogliptin 12.5 mg and metformin hydrochloride 1000 mg

Brand Names: U.S.

  • Kazano

Pharmacologic Category

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

Pharmacology

Alogliptin inhibits dipeptidyl peptidase 4 (DPP-4) 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-4 enzyme.

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 when treatment with both alogliptin and metformin is appropriate as monotherapy or combination therapy.

Contraindications

Serious hypersensitivity (eg, anaphylaxis, angioedema, severe dermatologic reactions) to products that contain alogliptin, metformin, or any component of the formulation; renal disease or renal dysfunction (serum creatinine ≥1.5 mg/dL [≥136 micromole/L] in males or ≥1.4 mg/dL [≥124 micromole/L] in females), or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia); acute or chronic metabolic acidosis including diabetic ketoacidosis (with or without coma)

Canadian labeling: Additional contraindications (not in US labeling): Unstable and/or insulin-dependent (type 1) diabetes mellitus; history of ketoacidosis with or without coma; history of lactic acidosis (regardless of precipitating factors); unknown renal function; excessive alcohol intake, acute or chronic; severe hepatic dysfunction; cardiovascular collapse and disease states associated with hypoxemia (eg, cardiorespiratory insufficiency), which are often associated with hyperlactacidemia; stress conditions (eg, severe infections, trauma or surgery and the recovery period); severe dehydration; pregnancy; breast-feeding.

Note: The manufacturer recommends to temporarily discontinue metformin in patients undergoing radiologic studies in which intravascular iodinated contrast media are utilized.

Dosing: Adult

Type 2 diabetes mellitus: Oral: Initial doses should be based on current dose of alogliptin and metformin; doses should be given twice daily with meals. Maximum: Alogliptin 25 mg/metformin 2000 mg daily

Patients inadequately controlled on metformin alone: Initial dose: Alogliptin 25 mg daily plus current daily dose of metformin given in 2 equally divided doses

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

Patients inadequately controlled on metformin and pioglitazone (Canadian labeling): Initial dose: Alogliptin 25 mg daily given in 2 equally divided doses plus current daily dose of pioglitazone and metformin

Dosing: Geriatric

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

Dosing: Renal Impairment

Manufacturer's labeling:

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

Abnormal CrCl (US labeling: Not defined; Canadian labeling: <60 mL/minute): Use is contraindicated.

Alternate recommendations: Note: The United Kingdom National Institute for Health and Clinical Excellence (NICE) Guidelines recommend prescribing metformin with caution in those patients who are at risk of sudden deterioration in renal function and at risk of an estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73 m2 (NICE, 2008]). Some evidence suggests that use of metformin is unsafe when eGFR <30 mL/minute/1.73 m2 (calculated using MDRD) (Shaw, 2007). A review of the available data by members of the American Diabetes Association proposed the following recommendations based on eGFR (Lipska, 2011):

eGFR ≥60 mL/minute/1.73 m2: No contraindications. Monitor renal function annually.

eGFR ≥45 to <60 mL/minute/1.73 m2: Continue use; monitor renal function every 3 to 6 months. Note: The manufacturer’s labeling for alogliptin recommends a maximum dose of 12.5 mg once daily in patients with CrCl 30 to <60 mL/minute.

eGFR ≥30 to <45 mL/minute/1.73 m2: In patients currently receiving metformin, use with caution, consider dosage reduction (eg, 50% reduction or 50% of maximal dose), monitor renal function every 3 months. Do not initiate therapy in patients with eGFR <45 mL/minute/1.73 m2. Note: The manufacturer’s labeling for alogliptin recommends a maximum dose of 12.5 mg once daily in patients with CrCl 30 to <60 mL/minute.

eGFR <30 mL/minute/1.73 m2: Discontinue use.

Dosing: Hepatic Impairment

The manufacturer recommends to avoid metformin because liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in patients with diabetes 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). Alogliptin has not been studied in patients with severe impairment.

Administration

Administer twice daily with food. Swallow tablets whole; do not split or divide.

Dietary Considerations

Should be taken with meals (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 moisture.

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

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

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

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

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

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

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

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

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

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

Percentages as reported with combination product. Also see individual agents.

1% to 10%:

Central nervous system: Headache (5%)

Endocrine & metabolic: Hypoglycemia (2% to 5%)

Gastrointestinal: Diarrhea (6%)

Genitourinary: Urinary tract infection (4%)

Neuromuscular & skeletal: Back pain (4%)

Respiratory: Upper respiratory tract infection (8%), nasopharyngitis (7%)

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

ALERT: U.S. Boxed Warning

Lactic acidosis:

Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure (CHF). The onset is often subtle, accompanied only by nonspecific symptoms, such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, alogliptin/metformin should be discontinued and the patient hospitalized immediately.

Warnings/Precautions

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-4 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-4 inhibitor therapy resumed. Discontinue use if severe joint pain results from DPP-4 inhibitor therapy.

• Hepatotoxicity: Cases of fatal and non-fatal hepatic failure have been reported in postmarketing surveillance with alogliptin. Baseline liver function tests (serum transaminases) are recommended to rule out underlying liver diseases. Use with caution in patients with abnormal serum transaminases. Monitor and promptly evaluate serum transaminase levels in patients with symptoms of hepatic injury (eg, fatigue, anorexia, jaundice, dark urine, and/or abdominal pain). In patients with clinically significant transaminase elevations and/or persistent or worsening elevations, therapy should be interrupted. Therapy should only be resumed with caution in patients where an alternative cause of transaminase elevations has been determined.

• Hypersensitivity reactions: Rare hypersensitivity reactions, including anaphylaxis, angioedema, and/or severe dermatologic reactions such as Stevens-Johnson syndrome, have been reported in postmarketing surveillance with alogliptin; discontinue if signs/symptoms of hypersensitivity reactions occur. Use with caution if patient has experienced angioedema with other DPP-4 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, or sepsis. Symptoms may be nonspecific (eg, abdominal distress, malaise, myalgia, respiratory distress, somnolence); low pH, increased anion gap and elevated blood lactate 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. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• Pancreatitis: Cases of acute pancreatitis have been reported with alogliptin use. 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:

• Diabetes mellitus (type 1): Not indicated for use in patients with type 1 diabetes mellitus (insulin dependent, IDDM) due to lack of efficacy in this population.

• Diabetic ketoacidosis (DKA): Not indicated for use in patients with DKA due to lack of efficacy in this patient population.

• Heart failure: Use with caution in patients with a history of heart failure and renal impairment. Monitor for signs and symptoms of heart failure during therapy and consider discontinuation of therapy if heart failure develops. Risk of lactic acidosis due to metformin may be increased secondary to hypoperfusion.

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

• Renal impairment: Use of alogliptin/metformin is contraindicated in renal impairment; evaluate renal function prior to therapy initiation and at least yearly thereafter. Discontinue use if renal dysfunction occurs during therapy.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (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 lactic acidosis may be increased.

Other warnings/precautions:

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

• Iodinated contrast: The FDA recommends temporary discontinuation of 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. 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). Temporary discontinuation of metformin should occur at the time of or prior to the procedure, withheld for 48 hours following the procedure, and then resumed only when normal renal function is confirmed.

• 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; resume only after normal intake resumed and normal renal function is verified.

• Vitamin B12 concentrations: 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); hepatic function (prior to initiation of therapy and as clinically indicated thereafter), renal function (prior to initiation of therapy then annually or more frequent if necessary); vitamin B12 (periodically with long-term treatment) and folate (if megaloblastic anemia is suspected)

Pregnancy Risk Factor

B

Pregnancy Considerations

The Canadian labeling contraindicates use in pregnant women.

Adverse events were not observed in animal reproduction studies. 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 signs of common cold, pharyngitis, rhinitis, diarrhea, back pain, or rhinorrhea. Have patient report immediately to prescriber signs 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 low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, tachycardia, confusion, increased hunger, or sweating), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe headache, severe dizziness, passing out, vision changes, angina, chills, painful urination, difficult urination, foul-smelling urine, severe joint pain, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes (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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