Dexlansoprazole

Class: Proton-pump Inhibitors
Chemical Name: 2-[(R)-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole
Molecular Formula: C16H14F3N3O2S
CAS Number: 138530-94-6
Brands: Dexilant (formerly Kapidex)

Introduction

Acid- or proton-pump inhibitor; gastric antisecretory agent.1 5 The R-isomer of lansoprazole.1 5 32

Uses for Dexlansoprazole

Gastroesophageal Reflux (GERD)

Short-term treatment of all grades of erosive esophagitis.1 2 5

Maintenance therapy following healing of erosive esophagitis to reduce recurrence of the disease.1 4 5

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Short-term management of symptoms (e.g., heartburn) of GERD in patients without erosive esophagitis.1 3

Crohn’s Disease-associated Ulcers

Some evidence for use of proton-pump inhibitors (e.g., omeprazole) for gastric acid suppressive therapy as an adjunct in the management of upper GI Crohn’s disease, including esophageal, gastroduodenal, and jejunoileal disease.14 15 16 17 18 19 20

Dexlansoprazole Dosage and Administration

Administration

Oral Administration

Administer orally once daily.1

Administer without regard to food; however, if symptoms after a meal do not respond adequately to postprandial administration, consider preprandial administration (because the effect on gastric pH during the initial 4 hours after a dose may be decreased slightly when dexlansoprazole is taken after a meal).1 13

Swallow capsules whole; alternatively, open capsule and sprinkle contents on a tablespoonful of applesauce and swallow immediately without chewing.1

Dosage

Adults

Gastroesophageal Reflux

Chronic, lifelong therapy with a proton-pump inhibitor is appropriate for many GERD patients.6

Treatment of Erosive Esophagitis
Oral

60 mg once daily for up to 8 weeks.1

Maintenance of Healing of Erosive Esophagitis
Oral

30 mg once daily.1 Controlled studies beyond 6 months not performed.1

GERD without Erosive Esophagitis
Oral

30 mg once daily for 4 weeks.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary in mild hepatic impairment (Child-Pugh class A).1 Consider maximum dosage of 30 mg daily in moderate hepatic impairment (Child-Pugh class B).1 Not studied in severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

No dosage adjustment necessary.1

Geriatric Patients

No dosage adjustment necessary.1

Cautions for Dexlansoprazole

Contraindications

  • Known hypersensitivity to dexlansoprazole or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome) reported.1

Gastric Malignancy

Response to dexlansoprazole therapy does not preclude presence of occult gastric neoplasm.1

Clostridium difficile Infection

Proton-pump inhibitors associated with possible increased (1.4–2.75 times) risk of Clostridium difficile infection, including C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis).335 336 339 340 Many patients also had other risk factors for CDAD.335 May be severe; colectomy and, rarely, death reported.335

Use the lowest effective dosage and shortest duration of therapy appropriate for the patient's clinical condition.335

Consider CDAD if persistent diarrhea develops and manage accordingly; initiate supportive therapy (e.g., fluid and electrolyte management), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.335 336

Bone Fracture

Several observational studies suggest that use of proton-pump inhibitors, particularly in high dosages (i.e., multiple daily doses) and/or for prolonged periods of time (i.e., ≥1 year), may be associated with increased risk of osteoporosis-related fractures of the hip, wrist, or spine.1 9 300 301 302 303 304 305 Magnitude of risk is unclear;9 300 301 302 303 304 305 310 causality not established.305 FDA is continuing to evaluate this safety concern.305

Use the lowest effective dosage and shortest duration of therapy appropriate for the patient’s clinical condition.1 9 301 303 305 307

Individuals at risk for osteoporosis-related fractures should receive an adequate intake of calcium and vitamin D; assess and manage these patients’ bone health according to current standards of care.1 9 303 305 307

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, reported rarely in patients receiving long-term therapy (≥3 months or, in most cases, >1 year) with proton-pump inhibitors, including dexlansoprazole.1 317 318 319 320 321 322 323 324 325 326 327 328 329 330 Serious adverse effects include tetany, seizures, tremors, carpopedal spasm, arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia), and abnormal QT interval.1 318 319 321 322 323 325 327 328 329 Paresthesia, muscle weakness, muscle cramps, lethargy, fatigue, and unsteadiness may occur.319 320 321 325 330 Most patients required magnesium replacement and discontinuance of the proton-pump inhibitor.1 317 319 321 322 323 324 325 326 327 330 Hypomagnesemia resolved within 1 week (median) following discontinuance and recurred within 2 weeks (median) of rechallenge.327

In patients expected to receive long-term proton-pump inhibitor therapy or in patients currently receiving digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), consider measuring serum magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.1 319 326 327 328 330

Respiratory Effects

Administration of proton-pump inhibitors has been associated with an increased risk for developing certain infections (e.g., community-acquired pneumonia).7 8

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling of Kapidex (former trade name for dexlansoprazole) and Casodex (trade name for bicalutamide, a nonsteroidal antiandrogenic antineoplastic agent220 ) or Kadian (a trade name for morphine sulfate, an opiate agonist analgesic221 ) may result in errors.217 218 219 223 In April 2010, manufacturer changed trade name for dexlansoprazole from Kapidex to Dexilant to avoid future errors.1 217

Also be aware of potential for Kapidex to be confused with Capadex (fixed-combination propoxyphene/acetaminophen preparation that is available via the Internet and is marketed in certain other countries [e.g., Australia]).216 219

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether dexlansoprazole is distributed into milk; however, lansoprazole and its metabolites are distributed into milk in rats.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

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

Hepatic Impairment

Systemic exposure to dexlansoprazole is increased approximately twofold in individuals with moderate hepatic impairment.1 Not studied in severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,1 2 4 abdominal pain,1 2 nausea,1 2 upper respiratory infection,1 2 4 vomiting,1 2 flatulence.1 2

Interactions for Dexlansoprazole

Metabolized by CYP2C19 and CYP3A4.1

Unlikely to inhibit CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A: Pharmacokinetic interaction unlikely.1

Drugs that Cause Hypomagnesemia

Potential pharmacologic interaction (possible increased risk of hypomagnesemia).327 Consider monitoring magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter.1 327 (See Hypomagnesemia under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Atazanavir

Possible altered oral absorption of atazanavir, resulting in decreased plasma atazanavir concentrations;1 possible loss of virologic response11

Manufacturer of dexlansoprazole states that concomitant administration with atazanavir is not recommended1

Antiretroviral treatment-naive patients: If a proton-pump inhibitor is used concomitantly with atazanavir, administer ritonavir-boosted atazanavir (atazanavir 300 mg and ritonavir 100 mg once daily with food);11 administer the proton-pump inhibitor approximately 12 hours before ritonavir-boosted atazanavir10 11

For treatment-naive patients, dosage of proton-pump inhibitor should not exceed omeprazole 20 mg daily (or equivalent)10 11

Antiretroviral treatment-experienced patients: Concomitant use of proton-pump inhibitors with atazanavir not recommended10 11

Clopidogrel

Certain CYP2C19 inhibitors (e.g., omeprazole, esomeprazole) reduce exposure to clopidogrel’s active metabolite and decrease platelet inhibitory effect; potentially may reduce clopidogrel’s clinical efficacy30 31 40 41 42 224 225 228 229 230 235 236 237 238 240 311

Dexlansoprazole, lansoprazole, or pantoprazole had less effect on clopidogrel's antiplatelet activity than did omeprazole or esomeprazole;224 350 351

Dexlansoprazole decreased exposure to the metabolite by about 9%;1 350 observed effects on metabolite exposure and clopidogrel-induced platelet inhibition not considered clinically important1 350

Manufacturer of dexlansoprazole states clopidogrel dosage adjustment not required if used with recommended dexlansoprazole dosages1

Assess risks and benefits of concomitant proton-pump inhibitor and clopidogrel use in individual patients312 313 314 315 316

American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) states that GI bleeding risk reduction with concomitant proton-pump inhibitor in patients with risk factors for GI bleeding (e.g., advanced age; concomitant use of warfarin, corticosteroids, or NSAIAs; H. pylori infection) may outweigh potential reduction in cardiovascular efficacy of antiplatelet treatment associated with a drug-drug interaction.311 In patients without such risk factors, ACCF/ACG/AHA states that risk/benefit balance may favor use of antiplatelet therapy without a proton-pump inhibitor.311

If concomitant therapy with a proton-pump inhibitor and clopidogrel is deemed necessary, consider using an agent with little or no CYP2C19-inhibitory activity;30 31 46 224 230 350 alternatively, consider using a histamine H2-receptor antagonist (ranitidine, famotidine, nizatidine)30 31 230 but not cimetidine (also a potent CYP2C19 inhibitor)232 233

Diazepam

Effect on diazepam pharmacokinetics unlikely1 12

Digoxin

Hypomagnesemia (e.g., resulting from long-term use of proton-pump inhibitors) sensitizes the myocardium to digoxin and, thus, may increase risk of digoxin-induced cardiotoxic effects327 331

See table entry for gastric pH-dependent drugs

Consider monitoring magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter1 327

Diuretics (i.e., loop or thiazide diuretics)

Possible increased risk of hypomagnesemia327

Consider monitoring magnesium concentrations prior to initiation of prescription proton-pump inhibitor therapy and periodically thereafter1 327

Fosamprenavir

Use of esomeprazole with fosamprenavir (with or without ritonavir) did not substantially affect concentrations of amprenavir (active metabolite of fosamprenavir)345

No dosage adjustment required when proton-pump inhibitors used with fosamprenavir (with or without ritonavir)10 345

Gastric pH-dependent drugs (e.g., ampicillin esters, digoxin, iron salts, ketoconazole)

Dexlansoprazole may alter drug absorption1

Lopinavir

Lopinavir/ritonavir: Omeprazole had no clinically important effect on plasma concentrations or AUC of lopinavir10 344

No dosage adjustment required when proton-pump inhibitors used with lopinavir/ritonavir10

Methotrexate

Possible delayed clearance and increased serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate; possible methotrexate toxicity1 333 334

Reported mainly with high-dose methotrexate (300 mg/m2 to 12 g/m2),1 333 but also reported with low dosages (e.g., 15 mg per week)333

Manufacturer of dexlansoprazole recommends considering temporary discontinuance of proton-pump inhibitor therapy in some patients receiving high-dose methotrexate1

Some clinicians recommend withholding the proton-pump inhibitor for several days before and after administration of either high-dose or low-dose methotrexate or, alternatively, substituting a histamine H2-receptor antagonist for the proton-pump inhibitor333 334

Phenytoin

Effect on phenytoin pharmacokinetics unlikely1 12

Raltegravir

Omeprazole increased peak plasma concentration and AUC of raltegravir10 348

No dosage adjustment recommended when proton-pump inhibitors used with raltegravir10 348

Rilpivirine

Omeprazole decreased plasma concentrations and AUC of rilpivirine10 343

Concomitant use of rilpivirine and proton-pump inhibitors contraindicated10 343

Saquinavir

Ritonavir-boosted saquinavir: Omeprazole increased peak plasma concentration and AUC of saquinavir10 346

Caution advised if proton-pump inhibitor used with ritonavir-boosted saquinavir; monitor for saquinavir toxicity10 346

Tacrolimus

Possible increase in whole blood tacrolimus concentrations, particularly in transplant patients with intermediate or poor metabolizer phenotypes for CYPC191

Theophylline

Effect on theophylline pharmacokinetics unlikely1 12

Warfarin

No change in warfarin pharmacokinetics or INR observed in healthy individuals given warfarin 25 mg on day 6 of an 11-day course of dexlansoprazole 90 mg once daily;1 12 however, increased PT and INR reported in patients receiving warfarin concomitantly with proton-pump inhibitors1

May need to monitor PT and INR1

Dexlansoprazole Pharmacokinetics

Absorption

Bioavailability

Commercially available capsules contain 2 types of enteric-coated granules that dissolve at different pH values.1 Following oral administration, an initial (smaller) peak plasma concentration occurs at 1–2 hours followed by a second (larger) peak concentration at 4–5 hours.1 25

Duration

Following once-daily administration for 5 days, gastric pH is >4 for 17 hours per day with dexlansoprazole 60 mg versus 14 hours per day with lansoprazole 30 mg.1

Food

Administration in fed versus fasted state not associated with significant difference in mean gastric pH; however, effect on gastric pH during initial 4 hours after a dose may be decreased slightly when dexlansoprazole is taken after a meal.1 13 (See Oral Administration under Dosage and Administration.)

Distribution

Plasma Protein Binding

96–99%.1

Elimination

Metabolism

Extensively metabolized in the liver by oxidation, reduction, and subsequent formation of inactive sulfate, glucuronide, and glutathione conjugates.1 CYP2C19 and CYP3A4 are involved.1

Major circulating metabolite varies depending on CYP2C19 phenotype, but dexlansoprazole is the major circulating form of the drug regardless of CYP2C19 phenotype.1

Elimination Route

Eliminated in urine (51%) and feces (48%); unchanged drug is not recovered in urine.1

Half-life

Approximately 1–2 hours.1

Special Populations

Intermediate or poor metabolizers of CYP2C19 substrates: Systemic exposure to dexlansoprazole generally is increased.1 In Japanese men, AUC increased twofold in intermediate metabolizers and up to 12-fold in poor metabolizers compared with extensive metabolizers.1

Moderate hepatic impairment: Twofold increase in AUC.1

Renal impairment: Pharmacokinetic alterations not expected.1

Geriatric individuals: Half-life of 2.2 hours (versus 1.5 hours in younger individuals); not considered clinically important.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Oral

Capsules

Immediately use extemporaneous mixtures of capsule contents and applesauce.1

Actions

  • Dexlansoprazole is the R-isomer of lansoprazole (a racemic mixture of R- and S-isomers).1 5 22 Both isomers inhibit hydrogen-potassium ATPase, but plasma clearance of dexlansoprazole is slower than that of S-lansoprazole.25 32

  • Proton-pump inhibitors inhibit basal and stimulated gastric acid secretion.24

  • Dexlansoprazole binds to and inactivates hydrogen-potassium ATPase (proton, hydrogen, or acid pump) in gastric parietal cells, blocking the final step in secretion of hydrochloric acid; results in potent, long-lasting inhibition of gastric acid secretion.1 22

Advice to Patients

  • Importance of swallowing capsule whole or, alternatively, of opening capsule and sprinkling contents on a tablespoonful of applesauce and swallowing immediately without chewing.1 Dexlansoprazole may be administered without regard to food (see Oral Administration under Dosage and Administration).1

  • Importance of continuing therapy for the entire treatment course, unless directed otherwise.1

  • Importance of advising patients that use of multiple daily doses of the drug for an extended period of time may increase the risk of fractures of the hip, wrist, or spine.1 305

  • Risk of hypomagnesemia; importance of immediately reporting and seeking care for any cardiovascular or neurologic manifestations (e.g., palpitations, dizziness, seizures, tetany).1

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

  • Possible increased risk of Clostridium difficile infection; importance of contacting a clinician if persistent watery stools, abdominal pain, and fever occur.335

  • Importance of informing clinicians of any symptoms suggestive of an allergic reaction (e.g., facial swelling, rash).1

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

  • 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.

Dexlansoprazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, delayed-release (containing enteric-coated granules)

30 mg

Dexilant

Takeda

60 mg

Dexilant

Takeda

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Dexilant 30MG Delayed-release Capsules (TAKEDA PHARMACEUTICALS): 30/$153.45 or 90/$420.39

Dexilant 60MG Delayed-release Capsules (TAKEDA PHARMACEUTICALS): 30/$149.99 or 90/$420.44

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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