Alogliptin Benzoate

Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
VA Class: HS502
Chemical Name: 2 - [[6 - [(3R) - 3 - Amino - 1 - piperidinyl] - 3,4 - dihydro - 3 - methyl - 2,4 - dioxo - 1(2H) - pyrimidinyl]methyl] - benzonitrile monobenzoate
Molecular Formula: C18H21N5O2•C7H6O2
CAS Number: 850649-62-6
Brands: Nesina, Kazano, Oseni

Introduction

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.1 13

Uses for Alogliptin Benzoate

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 4

Used in combination with pioglitazone (given separately or as the fixed combination) as initial therapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus1 3 5 when treatment with both alogliptin and pioglitazone is appropriate.3

Slideshow: Flashback: FDA Drug Approvals 2013

Used in combination with metformin (given separately or as the fixed combination) as initialtherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus1 2 when treatment with both alogliptin and metformin is appropriate.2

Used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione [peroxisome proliferator-activated receptor-γ agonist]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.1 2 3 6 7 8 9 10 11 15

American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) suggests a DPP-4 inhibitor as one of several alternatives for initial monotherapy in patients with metformin contraindications (e.g., renal disease, hepatic disease, GI intolerance, risk of lactic acidosis).21 DPP-4 inhibitors also recommended as part of combination therapy, particularly when both postprandial and fasting plasma glucose concentrations are elevated.21

Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1 2 3

Alogliptin Benzoate Dosage and Administration

Administration

Oral Administration

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.1 2 3 If the missed dose is not remembered until time of next dose, skip missed dose and resume regular schedule.1 2 3 Do not double dose to replace missed dose.1 2 3

Alogliptin Monotherapy

Administer once daily without regard to food.1

Alogliptin/Metformin Hydrochloride Fixed Combination

Administer twice daily with food; titrate dosage gradually to minimize adverse GI effects of metformin hydrochloride component.2

Swallow tablets whole; do not split before swallowing.2

Alogliptin/Pioglitazone Fixed Combination

Administer once daily without regard to food.3

Swallow tablets whole; do not split before swallowing.3

Dosage

Available as alogliptin benzoate; dosage expressed in terms of alogliptin.1

Adults

Diabetes Mellitus
Monotherapy
Oral

25 mg once daily.1

Alogliptin/Metformin Hydrochloride Fixed-combination Therapy
Oral

Individualize dosage of alogliptin/metformin hydrochloride based on patient's current antidiabetic regimen, effectiveness, and tolerability.2

Alogliptin/Pioglitazone Fixed-combination Therapy
Oral

Patients inadequately controlled with diet and exercise: Alogliptin 25 mg and pioglitazone 15 or 30 mg once daily.3

Patients inadequately controlled on alogliptin: Alogliptin 25 mg and pioglitazone 15 or 30 mg once daily.3

Patients inadequately controlled on pioglitazone monotherapy: Alogliptin 25 mg and pioglitazone 15, 30, or 45 mg once daily, based on the patient’s current antidiabetic therapy.3

Patients inadequately controlled on metformin monotherapy: Alogliptin 25 mg and pioglitazone 15 or 30 mg once daily.3

Prescribing Limits

Adults

Diabetes Mellitus
Oral

Fixed combination with metformin hydrochloride: Maximum of 25 mg of alogliptin and 2 g of metformin hydrochloride daily.2

Fixed combination with pioglitazone: Maximum of 25 mg of alogliptin and 45 mg of pioglitazone.3

Special Populations

No dosage adjustment is necessary based on gender or race.1

Hepatic Impairment

Alogliptin Monotherapy

Mild or moderate hepatic impairment: No dosage adjustment is recommended.1

Severe hepatic impairment: Data are lacking.1

Alogliptin/Metformin Hydrochloride Fixed-combination Therapy

Fixed combination of alogliptin and metformin hydrochloride not recommended in patients with hepatic impairment.2

Renal Impairment

Alogliptin Monotherapy

Mild renal impairment (Clcr ≥60 mL/minute): No alogliptin dosage adjustment is necessary.1

Moderate renal impairment (Clcr 30 to <60 mL/minute): 12.5 mg once daily.1

Severe renal impairment (Clcr 15–30 mL/minute) or end-stage renal disease (Clcr <15 mL/minute or requiring hemodialysis): 6.25 mg once daily without regard to timing of hemodialysis.1

Alogliptin/Metformin Hydrochloride Fixed-combination Therapy

Fixed combination of alogliptin and metformin hydrochloride is contraindicated in patients with renal impairment.2

Alogliptin/Pioglitazone Fixed-combination Therapy

Mild renal impairment (Clcr ≥60 mL/minute): No dosage adjustment necessary.3

Moderate renal impairment (Clcr 30 to <60 mL/minute): Alogliptin 12.5 mg and pioglitazone 15, 30, or 45 mg once daily.3

Severe renal impairment or end-stage renal disease: Not recommended.3

Geriatric Patients

Dosage adjustment not necessary.1

Patients with CHF

NYHA class III or IV: Do not initiate fixed combination of alogliptin and pioglitazone.3

NYHA class I or II: 25 mg of alogliptin and 15 mg of pioglitazone once daily in fixed combination.3

Cautions for Alogliptin Benzoate

Contraindications

  • Known serious hypersensitivity (e.g., anaphylaxis, angioedema, severe adverse cutaneous reactions) to alogliptin.1

Warnings/Precautions

Pancreatitis and Precancerous Changes

Acute pancreatitis reported during postmarketing experience.1 FDA is evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous cellular changes in patients with type 2 diabetes mellitus receiving incretin mimetics.17 18 FDA has not yet reached any new conclusions about safety risks with incretin mimetics.17 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when FDA has additional information to report.17

FDA states that at this time clinicians should continue to follow the recommendations in the prescribing information for incretin mimetics.17 Manufacturer states that patients should be observed carefully for signs and symptoms of pancreatitis.1 If pancreatitis is suspected, promptly discontinue alogliptin and institute appropriate management.1

Not known if history of pancreatitis increases risk for pancreatitis with alogliptin.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, angioedema, severe adverse cutaneous reactions including Stevens-Johnson syndrome) reported.1

Promptly discontinue alogliptin if a serious hypersensitivity reaction is suspected, investigate other potential causes, and institute alternative antidiabetic therapy.1 (See Advice to Patients.)

Use with caution in patients with a history of angioedema to other DDP-4 inhibitors; unknown whether such patients will be predisposed to angioedema with alogliptin.1

Hepatic Effects

Fatal and nonfatal hepatic failure reported.1 Assess hepatic function prior to alogliptin initiation; use with caution in patients with abnormal liver function test results.1

Promptly assess liver function in patients with signs or symptoms indicating liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice).1 Interrupt alogliptin treatment if clinically important liver enzyme elevations and if liver function test abnormalities persist or worsen.1 Do not restart the drug in these patients without another explanation for the test abnormalities.1

Concomitant Therapy with Hypoglycemic Agents

When used in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider reducing the dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.1

Macrovascular Outcomes

Evidence of macrovascular risk reduction with alogliptin or any other antidiabetic agent not conclusively demonstrated in clinical trials.1

Use of Fixed Combinations

When used in fixed combination with metformin hydrochloride or pioglitazone, consider the cautions, precautions, and contraindications associated with metformin or pioglitazone.1

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy of alogliptin alone, in fixed combination with metformin, or in fixed combination with pioglitazone not established in pediatric patients1 2 3 <18 years of age.24

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Moderate hepatic impairment decreased alogliptin total exposure.1 (See Absorption: Special Populations, under Pharmacokinetics.) Data lacking in severe hepatic impairment.1

Fixed combination of alogliptin and metformin hydrochloride not recommended in patients with hepatic impairment.2

Renal Impairment

Renal impairment increases AUC.1 (See Absorption: Special Populations, under Pharmacokinetics.) Dosage adjustment recommended for patients with moderate or severe renal impairment or end-stage renal disease.1 (See Renal Impairment under Dosage and Administration.)

Fixed combination of alogliptin and metformin hydrochloride contraindicated in patients with renal impairment.2

Assess renal function prior to initiation of therapy and periodically thereafter.1

Common Adverse Effects

Alogliptin monotherapy: Nasopharyngitis,1 headache,1 upper respiratory tract infection.1

Alogliptin/metformin fixed combination: Upper respiratory tract infection,2 nasopharyngitis,2 diarrhea,2 hypertension,2 headache,2 back pain,2 urinary tract infection.2

Alogliptin/pioglitazone fixed combination: Nasopharyngitis,3 back pain,3 upper respiratory tract infection.3

Interactions for Alogliptin Benzoate

Mainly renally excreted; CYP-related metabolism is negligible.1

Does not induce CYP1A2, 2B6, 2C9, 2C19, or 3A4 and does not inhibit CYP1A2, 2C8, 2C9, 2C19, 3A4, or 2D6.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2C8, 2C9, and 3A4 inhibitors: No clinically important interactions observed with the inhibitors tested.1

CYP1A2, 2C8, 2C9, 2D6, and 3A4 substrates: No clinically important interactions observed with the substrates tested.1

Substrates or Inhibitors of P-glycoprotein Transport Systems

No clinically important interactions observed with the substrates or inhibitors tested.1

Specific Drugs

Drug

Interaction

Comments

Atorvastatin

Did not alter peak plasma concentrations or AUC of either drug1

No dosage adjustment necessary1

Caffeine

Did not alter peak plasma concentrations or AUC of caffeine1

No dosage adjustment necessary1

Cimetidine

Did not alter peak plasma concentrations or AUC of either drug1

No dosage adjustment necessary1

Contraceptives, hormonal

Did not alter peak plasma concentrations or AUC of ethinyl estradiol or norethindrone1 13

No dosage adjustment necessary1 13

Cyclosporine

Did not alter peak plasma concentrations or AUC of alogliptin1

No dosage adjustment necessary1

Dextromethorphan

Did not alter peak plasma concentrations or AUC of dextromethorphan1

No dosage adjustment necessary1

Digoxin

Did not alter peak plasma concentrations or AUC of either drug1

No dosage adjustment necessary1

Fexofenadine

Did not alter peak plasma concentrations or AUC of fexofenadine1

No dosage adjustment necessary1

Fluconazole

Did not alter peak plasma concentrations or AUC of alogliptin1 13

No dosage adjustment necessary1

Gemfibrozil

Did not alter peak plasma concentrations or AUC of alogliptin1 13

No dosage adjustment necessary1

Glyburide

Did not alter peak plasma concentrations or AUC of glyburide1 14

No dosage adjustment necessary1 14

Ketoconazole

Did not alter peak plasma concentrations or AUC of alogliptin1 13

No dosage adjustment necessary1

Metformin

Did not alter peak plasma concentrations or AUC of either drug1

No dosage adjustment necessary1

Midazolam

Did not alter peak plasma concentrations or AUC of midazolam1

No dosage adjustment necessary1

Pioglitazone

Did not alter peak plasma concentrations or AUC of either drug1 14

No dosage adjustment necessary1 14

Tolbutamide

Did not alter peak plasma concentrations or AUC of 1 tolbutamide

No dosage adjustment necessary1

Warfarin

No change in peak plasma concentrations or AUC of warfarin; no change in PT or INR1 13

No dosage adjustment necessary1

Alogliptin Benzoate Pharmacokinetics

Absorption

Bioavailability

Approximately 100%.1

Onset

Median time to peak plasma concentration was 1–2 hours following single oral dose.1 13 16

Food

Food does not appear to affect absorption.1 13

Special Populations

Total alogliptin exposure in patients with moderate hepatic impairment (Child-Pugh class B) is about 10% lower than in healthy individuals.1

In patients with renal impairment, AUC increased 1.2-fold in those with Clcr 60 to <90 mL/minute, twofold in those with Clcr 30 to <60 mL/minute, threefold in those with Clcr 15 to <30 mL/minute, and fourfold in those with end-stage renal disease (Clcr <15 mL/minute or requiring dialysis).1

Age does not substantially affect alogliptin pharmacokinetics.1

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

20%.1

Elimination

Metabolism

Does not undergo extensive metabolism.1

Elimination Route

Excreted in urine (76%) mainly as unchanged drug and in the feces (13%).1

Half-life

Approximately 21 hours.1

Special Populations

Hemodialysis (3-hour session) removes about 7% of the drug.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 2 3

Keep alogliptin/pioglitazone fixed-combination tablets in tightly closed container and protect from moisture and humidity.3

Keep alogliptin/metformin fixed-combination tablets in tightly closed container.2

Actions

  • Inhibits DPP-4, an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 13

  • Increases circulating concentrations of GLP-1 and GIP in a glucose-dependent manner.1

  • GLP-1 and GIP stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are elevated).1

  • GLP-1 also decreases glucagon secretion from pancreatic α-cells, leading to reduced hepatic glucose production.1

  • Selectively inhibits DPP-4 with no effect on DPP-8 or DPP-9 in vitro at concentrations approximating those from therapeutic exposures.1

Advice to Patients

  • Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1 24

  • Importance of informing patients of the potential risks and benefits of alogliptin.1 24 Importance of not using alogliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1 24

  • Risk of acute pancreatitis; may be severe or fatal.1 24 Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or kidney or liver problems.1 24 Importance of patient discontinuing alogliptin and promptly notifying clinician if signs and symptoms of pancreatitis, including persistent severe abdominal pain that may radiate to the back and may or may not be accompanied by vomiting, occur.1 24

  • Risk of hypoglycemia, particularly if concomitant therapy with a sulfonylurea (i.e., insulin secretagogue) or insulin is used.1 24

  • Risk of serious allergic (hypersensitivity) reaction.1 24 If signs or symptoms of such reactions occur (e.g., rash, hives, swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing), importance of discontinuing alogliptin and informing clinician promptly.1 24

  • Possibility of liver injury, sometimes fatal.1 24 If signs or symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, unusual/unexplained fatigue, anorexia, dark urine, jaundice) occur, importance of discontinuing alogliptin and informing clinician promptly.1 24

  • Importance of taking alogliptin exactly as directed by clinician.1 24 (See Administration under Dosage and Administration.)

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 24

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 24

  • Importance of informing patients of other important precautionary information. 1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Alogliptin Benzoate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

6.25 mg (of alogliptin)

Nesina

Takeda

12.5 mg (of alogliptin)

Nesina

Takeda

25 mg (of alogliptin)

Nesina

Takeda

Alogliptin Benzoate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

12.5 mg (of alogliptin) with Metformin Hydrochloride 500 mg

Kazano

Takeda

12.5 mg (of alogliptin) with Metformin Hydrochloride 1 g

Kazano

Takeda

12.5 mg (of alogliptin) with Pioglitazone Hydrochloride 15 mg (of pioglitazone)

Oseni

Takeda

12.5 mg (of alogliptin) with Pioglitazone Hydrochloride 30 mg (of pioglitazone)

Oseni

Takeda

12.5 mg (of alogliptin) with Pioglitazone Hydrochloride 45 mg (of pioglitazone)

Oseni

Takeda

25 mg (of alogliptin) with Pioglitazone Hydrochloride 15 mg (of pioglitazone)

Oseni

Takeda

25 mg (of alogliptin) with Pioglitazone Hydrochloride 30 mg (of pioglitazone)

Oseni

Takeda

25 mg (of alogliptin) with Pioglitazone Hydrochloride 45 mg (of pioglitazone)

Oseni

Takeda

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 26, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Takeda Pharmaceuticals America, Inc. Nesina (alogliptin) tablets prescribing information. Deerfield, IL; 2013 Jan.

2. Takeda Pharmaceuticals America, Inc. Kazano (alogliptin/metformin hydrochloride) tablets prescribing information. Deerfield, IL; 2013 Jan.

3. Takeda Pharmaceuticals America, Inc. Oseni (alogliptin/pioglitazone) tablets prescribing information. Deerfield, IL; 2013 Jan.

4. DeFronzo RA, Fleck PR, Wilson CA et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008; 31:2315-7. [PubMed 18809631]

5. Rosenstock J, Inzucchi SE, Seufert J et al. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care. 2010; 33:2406-8. [PubMed 20724648]

6. Nauck MA, Ellis GC, Fleck PR et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009; 63:46-55. [PubMed 19125992]

7. DeFronzo RA, Burant CF, Fleck P et al. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab. 2012; 97:1615-22. [PubMed 22419732]

8. Pratley RE, Reusch JE, Fleck PR et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 2009; 25:2361-71. [PubMed 19650752]

9. Bosi E, Ellis GC, Wilson CA et al. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes Metab. 2011; 13:1088-96. [PubMed 21733058]

10. Pratley RE, Kipnes MS, Fleck PR et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes Metab. 2009; 11:167-76. [PubMed 19125778]

11. Rosenstock J, Rendell MS, Gross JL et al. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009; 11:1145-52. [PubMed 19758359]

12. Rosenstock J, Wilson C, Fleck P. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. Diabetes Obes Metab. 2013; :15:906-14.

13. Christopher R, Karim A. Clinical pharmacology of alogliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of Type 2 diabetes. Expert Rev Clin Pharmacol. 2009; 2:589-600. [PubMed 22112254]

14. Karim A, Laurent A, Munsaka M et al. Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants. J Clin Pharmacol. 2009; 49:1210-9. [PubMed 19622714]

15. Berhan A, Berhan Y. Efficacy of alogliptin in type 2 diabetes treatment: a meta-analysis of randomized double-blind controlled studies. BMC Endocr Disord. 2013; 13:9. [PubMed 23452780]

16. Covington P, Christopher R, Davenport M et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther. 2008; 30:499-512. [PubMed 18405788]

17. Food and Drug Administration. Early communication: reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas. Silver Spring, MD; 2013 Mar 14. From FDA website. Accessed 31 July 2013.

18. Singh S, Chang HY, Richards TM et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013; 173:534-9. [PubMed 23440284]

19. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006; 368:1696-705. [PubMed 17098089]

20. Garber AJ, Abrahamson MJ, Barzilay JI et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013 Mar-Apr; 19:327-36.

21. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009 Sep-Oct; 15:540-59.

22. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009; 32:193-203. [PubMed 18945920]

23. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99. [PubMed 17638715]

24. Takeda Pharmaceuticals America, Inc. Nesina (alogliptin) tablets medication guide. Deerfield, IL; 2013 Jan.

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