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Friday, October 7, 2016

Eltrombopag

Class: Hematopoietic Agents
ATC Class: B02BX05
VA Class: BL400
Chemical Name: 3′-{(2Z)-2-[1-(3, 4-dimethylphenyl)-3-methyl-5-oxo-1, 5-dihydro-4H-pyrazol-4-ylidene] hydrazino}-2′-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol (1:2)
Molecular Formula: C₂₅H₂₂N₄O₄2 ©₂H₇NO)
CAS Number: 496775-62-3
Brands: Promacta

Risk of hepatotoxicity.¹ (See Hepatotoxicity under Cautions and also see Laboratory Monitoring under Cautions.)

Measure serum ALT, AST, and bilirubin concentrations prior to initiation of eltrombopag therapy, every 2 weeks during the dosage adjustment phase, then monthly once a stable dosage has been achieved.¹

If serum bilirubin concentration is elevated, also obtain a fractionated bilirubin concentration.¹

In patients who develop liver function test abnormalities, repeat these tests within 3–5 days to confirm the results; if an abnormality is confirmed, monitor liver function tests weekly until the abnormality resolves, stabilizes, or returns to baseline.¹

Discontinue eltrombopag therapy if serum ALT levels increase to ≥3 times the ULN and are progressive, persistent (≥4 weeks), or are accompanied by an increased direct bilirubin concentration, clinical symptoms of hepatotoxicity, or evidence of hepatic decompensation.¹

REMS:

FDA approved a REMS for eltrombopag olamine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of eltrombopag olamine and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Small-molecule thrombopoietin-receptor agonist.¹ ²

Uses for Eltrombopag

Idiopathic Thrombocytopenic Purpura

Treatment of chronic idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura) in patients who have had an inadequate response to corticosteroids, immunoglobulins, or splenectomy and in whom the degree of thrombocytopenia and clinical status increase bleeding risk.¹ ² ³

Should not be used to normalize platelet counts since excessive increases in platelet count may increase the risk of thromboembolic complications.¹ ⁸ ⁹

Not indicated for the treatment of thrombocytopenia associated with myelodysplastic syndrome or thrombocytopenia associated with any condition other than chronic ITP.¹ ⁹

Not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.⁸ ⁹

Eltrombopag Dosage and Administration

General

Restricted Distribution

Because of hepatotoxicity and other risks, eltrombopag is available only under a restricted distribution program (PROMACTACARES).¹ ⁷ Only prescribers and patients registered with the program are able to prescribe, administer, or receive eltrombopag.¹ ⁷ Contact 877-9-PROMACTA for additional information and to enroll in GlaxoSmithKline's PROMACTACARES program for eltrombopag.¹ ⁷

FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for eltrombopag.¹⁰ Goals are to promote informed risk-benefit decisions before initiating the drug; to ensure appropriate use of the drug while patients are receiving therapy; and to establish the overall long-term safety and safe use of the drug by periodically monitoring all patients for various adverse effects.¹⁰

Administration

Oral Administration

Administer orally 1 hour before or 2 hours after a meal because food may decrease the rate and extent of absorption.¹

Do not administer within 4 hours of other drugs, food, or supplements that contain polyvalent cations (e.g., iron, calcium, aluminum, magnesium, selenium, zinc).¹ Consider administration of the drug in the evening, if possible (unless patients are also taking an antacid preparation containing polyvalent cations at that time), since calcium-containing food (e.g., dairy products) is more frequently consumed at breakfast.⁴

Dosage

Available as eltrombopag olamine; dosage expressed in terms of eltrombopag.¹

Adults

Idiopathic Thrombocytopenic Purpura

Oral

Usual initial dosage: 50 mg daily.¹

Adjust dosage to achieve and maintain a platelet count of ≥50,000/mm³.¹ If platelet count is <50,000/mm³ after at least 2 weeks of eltrombopag treatment, increase daily dosage by 25 mg, up to a maximum daily dosage of 75 mg. ¹ If the platelet count has not reached a level sufficient to avoid a clinically important bleeding episode after 4 weeks at the maximum daily dosage, discontinue eltrombopag.¹

Reduce the daily dosage by 25 mg if the platelet count is between 200,000/mm³ and 400,000/mm³ at any time during eltrombopag therapy; perform follow-up assessment 2 weeks later to assess the effect of the lower dosage before additional dosage adjustments are made.¹

Do not administer eltrombopag if the platelet count is >400,000/mm³.¹ If therapy is interrupted, assess the platelet count twice weekly and resume eltrombopag olamine at a dosage reduced by 25 mg daily once the platelet count is <150,000/mm³.¹ If the platelet count is persistently elevated (e.g., >400,000/mm³ after 2 weeks at the lowest dosage), discontinue eltrombopag permanently.¹

Prescribing Limits

Adults

Idiopathic Thrombocytopenic Purpura

Oral

Maximum daily dosage: 75 mg.¹ Do not give more often than once daily.¹

Special Populations

Hepatic Impairment

In patients with moderate or severe hepatic impairment, decrease initial dosage to 25 mg daily.¹ ⁸ ⁹ (See Hepatotoxicity under Cautions and also Laboratory Monitoring under Cautions.)

East Asian Ancestry

In patients of East Asian ancestry (e.g., Chinese, Japanese, Taiwanese, Korean), decrease initial dosage to 25 mg daily.¹ (See East Asian Ancestry under Cautions.)

Cautions for Eltrombopag

Contraindications

The manufacturer states that there are no known contraindications to the use of eltrombopag.¹

Warnings/Precautions

Warnings

Hepatotoxicity

Risk of hepatic and biliary impairment.¹ Abnormalities in serum ALT, AST, and bilirubin concentrations, predominantly grade 2 or less in severity, reported.¹ Grade 4 elevations in serum liver enzymes, as well as worsening of underlying cardiopulmonary disease and subsequent death, reported in one patient.¹

Discontinue eltrombopag if serum ALT levels increase to ≥3 times the ULN and are progressive, persistent (≥4 weeks), or are accompanied by an increased direct bilirubin concentration or clinical symptoms of hepatotoxicity or hepatic decompensation.¹ (See Laboratory Monitoring under Cautions.)

Retreatment with eltrombopag after discontinuance for hepatotoxicity is not recommended.¹ However, may consider retreatment if the anticipated clinical benefit of eltrombopag outweighs the potential risk of hepatotoxicity.¹ If treatment is reinitiated, evaluate serum ALT, AST, and bilirubin concentrations weekly during the dosage adjustment phase.¹ If abnormal liver function tests persist, worsen, or recur, permanently discontinue eltrombopag. ¹

General Precautions

Bone Marrow Reticulin Deposition and Bone Marrow Fibrosis

Thrombopoietin (TPO)-receptor agonists increase the risk of development or progression of reticulin fiber deposition within the bone marrow, thereby increasing the risk for bone marrow fibrosis or myelofibrosis.¹ Risk for bone marrow fibrosis with cytopenias in patients receiving eltrombopag not excluded in clinical studies.¹

Evaluate a peripheral blood smear prior to starting eltrombopag therapy and monthly thereafter once a stable dosage has been achieved.¹ Examination of the peripheral blood smear should include establishment of a baseline level of cellular morphologic abnormalities; monthly evaluations should include examinations for new or worsening morphologic abnormalities (e.g., teardrop or nucleated erythrocytes, immature leukocytes).¹ Perform CBC monthly to evaluate new or worsening cytopenias.¹ If a new or worsening morphologic abnormality or cytopenia develops, discontinue eltrombopag and consider a bone marrow biopsy, with additional staining for fibrosis.¹

Thrombocytopenia and Hemorrhage Following Eltrombopag Discontinuance

Risk of thrombocytopenia, which may be more severe than prior to therapy, after discontinuance of eltrombopag.¹ May result in increased risk of bleeding, especially if eltrombopag is discontinued while the patient is receiving concomitant antiplatelet or anticoagulation therapy.¹ Transient decrease in platelet count to levels lower than baseline reported in clinical studies following discontinuance of eltrombopag.¹ Serious hemorrhagic events occurring within 1 month of discontinuance of eltrombopag and requiring the use of additional ITP therapy also reported in patients with severe thrombocytopenia in clinical studies.¹

Perform CBC with platelet count weekly for at least 4 weeks following discontinuance of eltrombopag.¹ Consider additional ITP therapy for worsening thrombocytopenia.¹

Thrombosis/Thromboembolism

Risk of thrombosis or a thromboembolic complication as a result of excessive increase in platelet count secondary to excessive dosages of eltrombopag or medication errors resulting in excessive dosages.¹ Thrombosis also may occur even with normal or low platelet counts.⁷

Use eltrombopag with caution in patients with known risk factors for thromboembolism (e.g., factor V Leiden, antithrombin III [ATIII] deficiency, antiphospholipid syndrome).¹ To minimize the risk for a thrombotic or thromboembolic complication, do not use eltrombopag to normalize platelet counts; use drug only to maintain a platelet count of ≥50,000/mm³ according to the dosage adjustment guidelines.¹ ⁸ ⁹ (See Idiopathic Thrombocytopenic Purpura under Dosage and Administration.)

Thrombosis of the portal venous system reported in patients with chronic liver disease receiving eltrombopag.⁸ ⁹ Platelet counts >200,000/mm³ observed in some patients who received eltrombopag and experienced portal venous thrombosis.⁸ ⁹ Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.⁸ ⁹

Malignancy

Possible risk of progression to a hematologic malignancy, especially in patients with myelodysplastic syndrome (MDS), secondary to stimulation of the TPO receptor present on the surface of hematopoietic cells by eltrombopag. ¹ Do not use eltrombopag to treat or correct thrombocytopenia related to an underlying hematologic cause (e.g., myelodysplasia) or resulting from chemotherapy; use eltrombopag only for thrombocytopenia associated with chronic ITP.¹

Cataracts

Development or worsening of cataracts reported.¹ Perform a baseline ocular examination prior to eltrombopag therapy; while on therapy, monitor periodically for signs and symptoms of cataracts.¹

Laboratory Monitoring

Obtain CBC, including platelet count and peripheral blood smear, prior to starting therapy, weekly during the dosage adjustment phase, then monthly once a stable dosage has been achieved.¹ Baseline peripheral blood smears should establish the presence and extent of red and white cell abnormalities.¹ Once eltrombopag is discontinued, evaluate CBC with platelet count weekly for at least 4 weeks to monitor for worsening thrombocytopenia.¹

Evaluate serum ALT, AST, and bilirubin concentrations prior to starting therapy and every 2 weeks during the dosage adjustment phase, then monthly once a stable dosage has been achieved.¹ If serum bilirubin is elevated, also obtain a fractionated bilirubin concentration.¹ In patients who develop liver function test abnormalities, repeat these tests within 3–5 days to confirm the results; if an abnormality is confirmed, monitor liver function tests weekly until the abnormality resolves, stabilizes, or returns to baseline.¹ Discontinue eltrombopag therapy if important hepatic abnormalities occur.¹ (See Hepatotoxicity under Cautions.)

Specific Populations

Pregnancy

Category C.¹ Pregnancy registry at 888-825-5249.¹

Lactation

Not known whether eltrombopag is distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.¹ ⁷

Geriatric Use

No substantial differences in safety and efficacy in geriatric patients ≥65 years of age relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Decreased clearance; exercise caution, adjust dosage, and monitor closely in patients with moderate or severe hepatic impairment.¹ ⁸ ⁹ (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Thrombosis of the portal venous system reported in patients with thrombocytopenia and chronic liver disease receiving eltrombopag.⁸ ⁹ (See Thrombosis/Thromboembolism under Cautions.) Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease.⁸ ⁹ To minimize the risk for a thrombotic or thromboembolic complication, do not use eltrombopag to normalize platelet counts; only use the drug to maintain a platelet count of ≥50,000/mm³ according to the dosage adjustment recommendations.¹ ⁸ ⁹ (See Dosage under Dosage and Administration.)

Renal Impairment

Safety and efficacy of eltrombopag in patients with varying degrees of impaired renal function have not been established.¹ Closely monitor patients with impaired renal function.¹

East Asian Ancestry

Increased eltrombopag exposure reported in patients of East Asian ancestry (e.g., Chinese, Japanese, Taiwanese, Korean); dosage adjustment recommended.¹ Somewhat increased (but qualitatively similar) pharmacodynamic response also reported.¹ (See East Asian Ancestry under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Nausea,¹ vomiting,¹ menorrhagia,¹ myalgia,¹ paresthesia,¹ cataract,¹ dyspepsia,¹ ecchymosis,¹ thrombocytopenia,¹ increased serum transaminases (ALT, AST),¹ conjunctival hemorrhage.¹

In an extension study: headache, upper respiratory tract infection, diarrhea, nasopharyngitis.⁵

Interactions for Eltrombopag

Metabolized by CYP1A2 and CYP2C8; also undergoes glucuronidation by UGT isoenzymes 1A1 and 1A3. ¹ Inhibits CYP2C8 and CYP2C9 and the organic anion-transporting polypeptide (OATP) 1B1.¹

Drugs Affecting Hepatic Microsomal Enzymes

Moderate to strong inhibitors of CYP1A2 or CYP2C8: potential pharmacokinetic interaction (increased systemic exposure to eltrombopag).¹ Use with caution.¹

Moderate to strong inducers of CYP1A2 or CYP2C8: potential pharmacokinetic interaction (decreased systemic exposure to eltrombopag).¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2C8 or CYP2C9: potential pharmacokinetic interaction (altered metabolism of CYP2C8 or CYP2C9 substrates).¹ Inhibition or induction of the metabolism of a combination of probe substrates for CYP1A2, CYP2C19, CYP2C9, or CYP3A4) following administration of eltrombopag (75 mg once daily) for 7 days to healthy male individuals not demonstrated. ¹ Probe substrates for CYP2C8 not evaluated.¹

Drugs Transported by Organic Anion-transporting Polypeptide 1B1

Substrates of organic anion-transporting polypeptide (OATP) 1B1: Potential pharmacokinetic interaction (increased concentrations of concomitantly administered OATP1BI substrates.¹ Consider reduction of OATP1B1 substrate dosage if manifestations of excessive systemic exposure to these drugs occur.¹

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT)

Eltrombopag inhibits uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, and 2B15.¹

Substrates of UGTs: Potential pharmacokinetic interaction (increased systemic exposure to multiple UGT substrates.¹ Use with caution.¹

Moderate to strong inhibitors of UGT1A1 or UGT1A3: Potential pharmacokinetic interaction (increased systemic exposure to eltrombopag).¹ Use with caution.¹

Specific Drugs and Foods

Drug	Interaction	Comments
Acetaminophen	Potential increased systemic exposure to acetaminophen¹	Use with caution¹
Benzylpenicillin	Potential increased benzylpenicillin concentrations¹	Consider reduction of benzylpenicillin dosage if manifestations of excessive systemic exposure occur¹
Caffeine	Pharmacokinetics of caffeine unlikely to be affected¹
Cations, polyvalent (e.g., iron, calcium, aluminum, magnesium, selenium, zinc) found in food, mineral supplements, and antacids	Reduced plasma eltrombopag concentration in patients receiving concomitant antacid therapy containing aluminum hydroxide, magnesium carbonate, and sodium alginate¹ ⁴ Reduced eltrombopag AUC reported in association with high-calcium, high-fat breakfast⁴	Avoid medications and foods containing polyvalent cations, including antacids, dairy products, and mineral supplements, for 4 hours before and after each dose of eltrombopag¹ ⁴
Ciprofloxacin	Potential increased systemic exposure to eltrombopag¹	Use with caution¹
Flurbiprofen	Pharmacokinetics of flurbiprofen unlikely to be affected¹
Fluvoxamine	Potential increased systemic exposure to eltrombopag¹	Use with caution¹
Gemfibrozil	Potential increased systemic exposure to eltrombopag¹	Use with caution¹
HMG-CoA reductase inhibitors (statins; e.g., atorvastatin, fluvastatin, pravastatin, rosuvastatin)	Potential increased statin concentrations¹ Increased AUC and peak plasma concentration of rosuvastatin reported following administration of single 10-mg dose of rosuvastatin in healthy adults receiving 75 mg of eltrombopag daily for 5 days¹	Consider reduction of statin dosage if manifestations of excessive systemic exposure occur¹ Reduction in rosuvastatin dosage by 50% was recommended for patients receiving concomitant eltrombopag in clinical trials¹
Meglitinides (nateglinide, repaglinide)	Potential increased meglitinide concentrations¹	Consider reduction of meglitinide dosage if manifestations of excessive systemic exposure occur¹
Methotrexate	Potential increased methotrexate concentrations¹	Consider reduction of methotrexate dosage if manifestations of excessive systemic exposure occur¹
Midazolam	Pharmacokinetics of midazolam unlikely to be affected¹
NSAIAs	Potential increased systemic exposure to NSAIAs¹	Use with caution¹
Omeprazole	Potential decreased systemic exposure to eltrombopag; pharmacokinetics of omeprazole unlikely to be affected¹
Opiates	Potential increased systemic exposure to opiates¹	Use with caution¹
Rifampin	Potential decreased systemic exposure to eltrombopag¹ Potential increased rifampin concentrations¹ ¹	Consider reduction of rifampin dosage if manifestations of excessive systemic exposure occur¹
Tobacco	Potential decreased systemic exposure to eltrombopag¹
Trimethoprim	Potential increased systemic exposure to eltrombopag¹	Use with caution¹

Eltrombopag Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations occur 2–6 hours following oral administration.¹

Bioavailability of at least 52% reported following a single dose of 75 mg as an oral solution.¹

Onset

Increases in platelet counts generally observed within 1–2 weeks after beginning therapy.¹

Duration

Decreases in platelet counts generally observed within 1–2 weeks after discontinuance of therapy.¹

Food

Food (standard high-fat breakfast) decreases rate and extent of absorption;¹ calcium content of meal may contribute to decreased absorption.¹ ⁴

Distribution

Extent

Distributes into blood cells; concentrations in blood cells about 50–79% of plasma concentrations.¹

Not known whether eltrombopag is distributed into human milk.¹

Plasma Protein Binding

>99%.¹

Elimination

Metabolism

Extensively metabolized, predominantly through pathways including cleavage, oxidation (CYP1A2 and CYP2C8), and conjugation with glucuronic acid (via UGT1A1 and UGT1A3), glutathione, or cysteine.¹

Metabolites associated with glucuronidation and oxidation detected.¹

Elimination Route

Excreted in feces (59%) and urine (31%).¹ Unchanged drug excreted in feces accounts for 20% of the dose; no unchanged drug detectable in urine.¹

Half-life

Healthy individuals: 21–32 hours.¹

Patients with ITP: 26–35 hours.¹

Special Populations

Compared with healthy individuals, the AUC for eltrombopag was 41% higher in patients with mild hepatic impairment and 80–93% higher in patients with moderate to severe hepatic impairment. ¹ A corresponding reduction (50%) in apparent clearance of eltrombopag was reported in patients with moderate or severe hepatic impairment.¹ Prolonged half-life (twofold) of eltrombopag also reported in patients with moderate or severe hepatic impairment.¹ High interpatient variability observed in the impact of hepatic impairment on eltrombopag pharmacokinetics.¹

Increased eltrombopag exposure (approximately 70%) reported in some Asian individuals of Japanese, Chinese, Taiwanese, and Korean ancestry (i.e., East Asian) with ITP as compared with non-Asian subjects (who were predominantly Caucasian).¹

Increased eltrombopag exposure (approximately 40%) reported in healthy African-American individuals in at least one clinical pharmacology study.¹ Clinical importance unknown.¹

Increased apparent eltrombopag clearance (about 27%) after adjustment for body weight difference reported in males compared with females.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

Eltrombopag olamine is a small-molecule, nonpeptide, thrombopoietin (TPO)-receptor agonist.¹ ² ³

Interacts with the transmembrane domain of the TPO receptor, initiating a cascade of intracellular signaling events leading to proliferation and differentiation of bone marrow progenitor cells within the megakaryocytic lineage and subsequently increasing the production of platelets.¹ ² ³

Eltrombopag (up to 150 mg daily for 5 days) did not prolong QT or QT corrected for rate (QT_c) interval in healthy adults.¹

Advice to Patients

Importance of understanding that treatment can only be prescribed by a clinician registered with the PROMACTACARES program; all ITP patients receiving eltrombopag must be enrolled in the PROMACTACARES program.¹ ⁷ (See Restricted Distribution under Dosage and Administration.)

Under the REMS program approved by FDA, medication guide must be dispensed with every prescription for the drug.¹⁰

Importance of carefully reading patient information (medication guide) provided by the manufacturer before initiating therapy, and each time prescription is refilled.¹ ⁷

Importance of informing patients that risks associated with long-term administration of eltrombopag are not known.¹

Importance of understanding the goal of therapy is to achieve and maintain a platelet count of ≥50,000/mm ³ to reduce the risk of bleeding, not to normalize platelet count.¹ ⁷

Risk of hepatic failure; importance of immediately reporting symptoms suggestive of jaundice (e.g., yellowing of skin or eyes), unusual darkening of urine, unusual fatigue, or right-upper quadrant (i.e., stomach area) pain to clinician.¹ ⁷

Risk of worsening thrombocytopenia with possible bleeding shortly following discontinuance of eltrombopag, compared with such risks prior to starting therapy; increased risk if receiving concomitant anticoagulant or antiplatelet drugs.¹ ⁷

Risk of reticulin fiber formation in bone marrow with possible progression to bone marrow fibrosis.¹ ⁷

Increased risk of thrombosis or thromboembolism with high platelet counts resulting from excessive eltrombopag dosage.¹ ⁷ Risk of thrombosis even with normal or low platelet counts.⁷ Importance of immediately reporting symptoms suggestive of thrombosis (e.g., swelling, pain, or tenderness in leg) to clinician.⁷

Increased risk of developing a hematologic malignancy, especially in patients with myelodysplastic syndrome (MDS).¹ ⁷

Importance of avoiding situations or medications that may increase risk of bleeding.¹ ⁷

Risk of new or worsened cataracts.¹ ⁷

Importance of taking eltrombopag on an empty stomach (i.e., 1 hour before or 2 hours after a meal). ¹ ⁷ Importance of avoiding foods, supplements, and drugs that contain polyvalent cations (e.g., iron, calcium, aluminum, magnesium, selenium, zinc) for 4 hours before and after taking eltrombopag.¹ ⁷

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.¹ ⁷

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ ⁷

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.

Distribution of eltrombopag is restricted.¹

Eltrombopag Olamine
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablet	25 mg (of eltrombopag)	Promacta	GlaxoSmithKline
		50 mg (of eltrombopag)	Promacta	GlaxoSmithKline
		75 mg (of eltrombopag)	Promacta	GlaxoSmithKline

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Promacta (eltrombopag) tablets prescribing information. Research Triangle Park, NC; 2009 Oct.

2. Bussel JB, Cheng G, Saleh MN et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007; 357:2237-47. [PubMed 18046028]

3. Bussel JB, Provan D, Shamsi T et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009; 373:641-8. [PubMed 19231632]

4. Williams DD, Peng B, Bailey CK et al. Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: Two single-dose, open-label, randomized-sequence, crossover studies. Clin Ther. 2009; 31:764-76. [PubMed 19446149]

5. Bussel JB, Cheng G, Saleh MN et al. Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura. Blood. 2008; 112: Abstract 3420.

6. Fogarty PF, Bussel JB, Cheng G et al. Oral eltrombopag treatment reduces the need for concomitant medications in patients with chronic idiopathic thrombocytopenic purpura. Blood. 2008; 112: Abstract 3424.

7. GlaxoSmithKline. Promacta (eltrombopag) tablets medication guide. Research Triangle Park, NC; 2010 Mar.

8. Food and Drug Administration. Promacta (eltrombopag): portal venous system thromboses in study of patients with chronic liver disease. Rockville, MD; May 12, 2010. From FDA website.

9. Aivado M. Dear healthcare professional letter: Promacta (eltrombopag) notification of safety information: portal venous system thromboses in a study of patients with chronic liver disease (ELEVATE). Collegeville, PA: GlaxoSmithKline; 2010 May 4. From FDA website.

10. GlaxoSmithKline. Promacta (eltrombopag) NDA 22-291 proposed risk evaluation and mitigation strategy (REMS). Collegeville, PA; 2010 Jun 10. Available from FDA website. Accessed 2010 Nov 24.

More Eltrombopag resources

Eltrombopag Side Effects (in more detail)
Eltrombopag Dosage
Eltrombopag Use in Pregnancy & Breastfeeding
Eltrombopag Drug Interactions
Eltrombopag Support Group
1 Review for Eltrombopag - Add your own review/rating

Eltrombopag MedFacts Consumer Leaflet (Wolters Kluwer)

Eltrombopag Professional Patient Advice (Wolters Kluwer)

eltrombopag Advanced Consumer (Micromedex) - Includes Dosage Information

Promacta Prescribing Information (FDA)

Promacta Consumer Overview

Compare Eltrombopag with other medications

Idiopathic Thrombocytopenic Purpura
Thrombocytopenia Idiopathic

Emsam

Generic Name: selegiline (Transdermal route)

se-LE-ji-leen

Transdermal route(Patch, Extended Release)

Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies with major depressive disorder (MDD) and other psychiatric disorders. Short term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. This risk must be balanced with the clinical need. Monitor patients closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. The transdermal patch should not be used in pediatric patients under the age of 12, at any dose, even with dietary modifications .

Commonly used brand name(s)

In the U.S.

Emsam

Available Dosage Forms:

Patch, Extended Release

Therapeutic Class: Antidepressant

Pharmacologic Class: Monoamine Oxidase Inhibitor, Type B

Uses For Emsam

Selegiline transdermal is used to treat mental depression. This medicine is a monoamine oxidase (MAO) inhibitor .

This medicine is available only with your doctor's prescription .

Before Using Emsam

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated any benefit to using selegiline transdermal in children with depression. Studies have shown that some children, teenagers, and young adults think about suicide or attempt suicide when taking this medicine. Because of this toxicity, use in children is not recommended .

Selegiline transdermal should not be used in children below 12 years of age .

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of selegiline transdermal in the elderly .

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Amitriptyline

Amoxapine

Amphetamine

Apraclonidine

Atomoxetine

Benzphetamine

Brimonidine

Bupropion

Carbamazepine

Citalopram

Clomipramine

Cyclobenzaprine

Cyproheptadine

Desipramine

Desvenlafaxine

Dexfenfluramine

Dexmethylphenidate

Dextroamphetamine

Dextromethorphan

Diethylpropion

Duloxetine

Ephedrine

Escitalopram

Fenfluramine

Fluoxetine

Guanadrel

Guanethidine

Imipramine

Isocarboxazid

Isometheptene

Levodopa

Levomethadyl

Linezolid

Lisdexamfetamine

Maprotiline

Mazindol

Meperidine

Methadone

Methamphetamine

Methotrimeprazine

Methyldopa

Methylene Blue

Methylphenidate

Milnacipran

Mirtazapine

Morphine

Morphine Sulfate Liposome

Nefopam

Nortriptyline

Opipramol

Oxcarbazepine

Paroxetine

Phendimetrazine

Phenelzine

Phenmetrazine

Phentermine

Phenylalanine

Phenylephrine

Phenylpropanolamine

Procarbazine

Propoxyphene

Protriptyline

Pseudoephedrine

Rasagiline

Reserpine

Selegiline

Sertraline

Sibutramine

St John's Wort

Tapentadol

Tetrabenazine

Tramadol

Tranylcypromine

Trimipramine

Venlafaxine

Vilazodone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Albuterol

Altretamine

Arformoterol

Avocado

Bambuterol

Bitolterol

Bitter Orange

Broxaterol

Buspirone

Clenbuterol

Clovoxamine

Difenoxin

Diphenoxylate

Dothiepin

Doxepin

Droperidol

Ethchlorvynol

Femoxetine

Fenoterol

Fentanyl

Fluvoxamine

Formoterol

Guarana

Hexoprenaline

Hydromorphone

Indacaterol

Isoetharine

Kava

Levalbuterol

Licorice

Lofepramine

Ma Huang

Mate

Mephentermine

Metaraminol

Metoclopramide

Nefazodone

Oxycodone

Pentazocine

Pirbuterol

Procaterol

Reboxetine

Rimiterol

Ritodrine

Salmeterol

St John's Wort

Terbutaline

Tryptophan

Tulobuterol

Tyrosine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acarbose

Acetohexamide

Benfluorex

Chlorpropamide

Dopamine

Ginseng

Gliclazide

Glimepiride

Glipizide

Gliquidone

Glyburide

Guar Gum

Insulin

Insulin Aspart, Recombinant

Insulin Glulisine

Insulin Lispro, Recombinant

Metformin

Miglitol

Repaglinide

Tolazamide

Tolbutamide

Troglitazone

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

Tyramine Containing Food

Proper Use of Emsam

This medicine comes with a Medication Guide. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions .

To use the skin patch:

Apply the patch right away after removing it from the protective pouch. Do not cut it into smaller pieces and do not touch the sticky surface of the patch. Wear only one patch at a time.

Apply the patch to a dry, smooth skin area on your upper chest or back (below the neck and above the waist), upper thigh, or to the outer surface of the upper arm. Do not put the patch over hairy, oily, irritated, broken, scarred, or calloused skin. Avoid putting the patch on areas where it could be rubbed off by tight clothing.

Press the patch firmly in place with your fingertips to make sure that the edges of the patch stick well.

Put on a new patch if the old one has fallen off and cannot be reapplied.

After 24 hours, remove the patch. Choose a different place on your skin to apply the new patch. Do not put the new patch on the same place you wore the last one. Try to change the patch at the same time each day.

After removing a used patch, fold the patch in half with the sticky sides together. Make sure to dispose of it out of the reach of children and pets.

Wash the area of skin where you will apply the patch gently with soap and warm water. Rinse completely and dry with a clean dry towel.

Do not expose the patch to direct sources of heat, such as heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds, or direct sunlight for long periods of time.

Wash your hands with soap and water before and after applying a patch. Do not touch your eyes until after you have washed your hands .

Do not stop using this medicine without asking your doctor. If you have not used your medicine for several days in a row, do not start using it again without talking to your doctor first .

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For transdermal dosage form (patch):
- For mental depression:
  - Adults—At first, one 6 milligram (mg) patch once a day. Your doctor may increase your dose if needed.
  - Children 12 years of age and older—Use and dose must be determined by your doctor.
  - Children below 12 years of age—Use is not recommended .

Missed Dose

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed dose.

Storage

Store the patches at room temperature in a closed container, away from heat, moisture, and direct light.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Emsam

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects .

Selegiline transdermal may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you, your child, or your caregiver notice any of these side effects, tell your doctor or your child's doctor right away .

When selegiline transdermal is used at low doses, there are no restrictions on food or beverages you eat or drink. However, the chance exists that dangerous reactions, such as sudden high blood pressure, may occur if higher doses are used with certain foods or beverages. These foods or beverages include foods that have a high tyramine content (most common in foods that are aged or fermented to increase their flavor), such as cheeses; fava or broad bean pods; yeast or meat extracts; smoked or pickled meat, poultry, or fish; fermented sausage (bologna, pepperoni, salami, summer sausage) or other fermented meat; sauerkraut; any spoiled or improperly stored meat, poultry, fish, or animal livers; or any overripe fruit. These may also include alcoholic beverages or alcohol-free or reduced-alcohol beer and wine. Also, for at least 2 weeks after you stop using this medicine, these foods or beverages may continue to react with selegiline transdermal. If a list of these foods and beverages is not given to you, ask your health care professional to provide one .

Check with your doctor or hospital emergency room immediately if severe headache, stiff neck, chest pains, fast heartbeat, or nausea and vomiting occur while you are using this medicine. These may be symptoms of a serious side effect that should have a doctor's attention .

You should not use this medicine if you are taking other medicines to treat depression (such as amitriptyline, bupropion, doxepin, duloxetine, fluoxetine, imipramine, mirtazapine, nortriptyline, paroxetine, sertraline, venlafaxine, Celexa®, Cymbalta®, Effexor®, Elavil®, Lexapro™, Paxil®, Prozac®, Tofranil®, Wellbutrin®, or Zoloft®), anxiety medicine (such as buspirone or BuSpar®), MAO inhibitors (MAOI) (such as Eldepryl®, Marplan®, Nardil®, or Parnate®), St. John's wort, or pain medicines (such as meperidine, methadone, propoxyphene, tramadol, Darvon®, Demerol®, Dolophine®, or Ultram®). Do not use this medicine if you are taking seizure medicines (such as carbamazepine, oxcarbazepine, Tegretol®, or Trileptal®), cough medicines (such as dextromethorphan or Benylin®), medicine to treat muscle spasms (such as cyclobenzaprine or Flexeril®), over-the-counter diet pills, herbal weight-loss products, cold medicines (such as ephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, Neo-Synephrine®, Novafed®, or Sudafed®), any herbal or dietary supplement that contains tyramine, or medicines called amphetamines (also called stimulants or "uppers"). Do not use this medicine if you take selegiline capsules or tablets .

Before you have any kind of surgery, tell the medical doctor in charge that you are taking this medicine. Using selegiline together with medicines that are sometimes used during surgery may increase the effects of these medicines .

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If the problem continues or gets worse, check with your doctor .

Emsam Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

Chills

cold sweats

confusion

dizziness, faintness, or lightheadedness when getting up from lying or sitting position

headache

sleeplessness

trouble sleeping

unable to sleep

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Burning, itching, redness, skin rash, swelling, or soreness at site

diarrhea

dry mouth

Less common

Acid or sour stomach

belching

body aches or pain

change or problem with discharge of semen

congestion

cough

dryness or soreness of throat

fever

heartburn

hoarseness

indigestion

pain or tenderness around eyes and cheekbones

rash

runny nose

shortness of breath or troubled breathing

stomach discomfort, upset, or pain

stuffy or runny nose

tender, swollen glands in neck

tightness of chest or wheezing

trouble in swallowing

voice changes

weight changes

Rare

Decreased interest in sexual intercourse

inability to have or keep an erection

loss in sexual ability, desire, drive, or performance

not able to have an orgasm

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Emsam side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Emsam resources

Emsam Side Effects (in more detail)
Emsam Use in Pregnancy & Breastfeeding
Emsam Drug Interactions
Emsam Support Group
14 Reviews for Emsam - Add your own review/rating

Emsam Prescribing Information (FDA)

Emsam System MedFacts Consumer Leaflet (Wolters Kluwer)

Emsam Consumer Overview

Selegiline Prescribing Information (FDA)

Eldepryl Monograph (AHFS DI)

Eldepryl Consumer Overview

Eldepryl MedFacts Consumer Leaflet (Wolters Kluwer)

Zelapar Prescribing Information (FDA)

Zelapar Orally Disintegrating Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Zelapar Consumer Overview

Compare Emsam with other medications

Depression

eltrombopag

Generic Name: eltrombopag (el TROM boe pag)

Brand Names: Promacta

What is eltrombopag?

Eltrombopag is a man-made form of a protein that increases production of platelets (blood-clotting cells) in your body.

Eltrombopag is used to prevent bleeding episodes in people with chronic immune thrombocytopenic purpura (ITP), a bleeding condition caused by a lack of platelets in the blood.

Eltrombopag is usually given after other medications or surgery have been tried without successful treatment of symptoms.

Eltrombopag is not a cure for ITP and it will not make your platelet counts normal if you have this condition.

Eltrombopag may also be used for purposes not listed in this medication guide.

What is the most important information I should know about eltrombopag?

Eltrombopag is available only under a special program called PROMACTA Cares. You must be enrolled in this program and sign all required agreements in order to take the medication. Read all program brochures and agreements carefully.

Before you take eltrombopag, tell your doctor if you have liver or kidney disease, cataract, a history of stroke or blood clot, or if you are of Eastern Asian descent. Also tell your doctor about all other medications you use.

Avoid taking other medications, including antacids or vitamin and mineral supplements, within 4 hours before or after you take eltrombopag.

Eltrombopag can cause harmful effects on your liver or bone marrow that may result in serious medical problems. To be sure this medication is not causing harmful effects, your blood and liver function will need to be tested often. Visit your doctor regularly. There are many other drugs that can interact with eltrombopag. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you. After you stop taking eltrombopag, your risk of bleeding may be even higher than it was before you started treatment. Be extra careful to avoid cuts or injury for at least 4 weeks after you stop taking eltrombopag. Your blood will need to be tested weekly during this time.

What should I discuss with my health care provider before taking eltrombopag?

To make sure you can safely take eltrombopag, tell your doctor if you have any of these other conditions:

liver disease;

kidney disease;

a bleeding or blood clotting disorder;

high levels of platelets in your blood;

a blood cancer or bone marrow disorder;

if you have ever had cataracts or a blood clot;

if your spleen has been removed; or

if you are of Eastern Asian descent.

FDA pregnancy category C. It is not known whether eltrombopag will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of eltrombopag on the baby.

It is not known whether eltrombopag passes into breast milk or if it could harm a nursing baby. Do not take this medication without telling your doctor if you are breast-feeding a baby.

Taking eltrombopag may increase your risk of developing blood cancers, especially if you have myelodysplastic syndrome (also called "preleukemia"). Talk with your doctor if you have concerns about this risk.

How should I take eltrombopag?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Take eltrombopag on an empty stomach, at least 1 hour before or 2 hours after a meal. Do not take this medication with milk. Avoid all dairy products or products that contain calcium (including fortified fruit juice) for at least 4 hours before or after you take eltrombopag. Taking eltrombopag long-term can cause harmful effects on your bone marrow that may result in serious blood cell disorders.

To be sure this medication is not causing harmful effects, your blood and liver function will need to be tested often. Your eyes may also need to be checked for signs of cataract formation. Visit your doctor regularly.

It may take up to 4 weeks of taking this medicine before it is completely effective in preventing bleeding episodes. Keep taking the medication as directed and tell your doctor if you have any bruising or bleeding episodes after 4 weeks of treatment.

Store at room temperature away from moisture and heat. After you stop taking eltrombopag, your risk of bleeding may be even higher than it was before you started treatment. Be extra careful to avoid cuts or injury for at least 4 weeks after you stop taking eltrombopag. Your blood will need to be tested weekly during this time.

See also: Eltrombopag dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose can cause slow heart rate, skin rash, or signs of a blood clot such as sudden numbness or weakness, sudden headache or confusion, problems with vision or speech, loss of balance, chest pain, sudden cough, and pain or swelling in one or both legs.

What should I avoid while taking eltrombopag?

Avoid taking other medications, including antacids or vitamin and mineral supplements, within 4 hours before or after you take eltrombopag.

Eltrombopag side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking this medication and call your doctor at once if you have a serious side effect such as:

nausea, pain in your upper stomach, low fever, loss of appetite;

dark urine, clay-colored stools;

jaundice (yellowing of the skin or eyes);

sudden numbness or weakness, especially on one side of the body;

sudden severe headache, confusion, problems with vision, speech, or balance;

chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;

pain, swelling, warmth, or redness in one or both legs;

easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin; or

blurred vision, eye pain, or seeing halos around lights.

Less serious side effects may include:

mild nausea, vomiting, upset stomach;

muscle pain;

numbness or tingly feeling;

redness of the eyes; or

heavy vaginal bleeding.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Eltrombopag Dosing Information

Usual Adult Dose for Thrombocytopenia Idiopathic:

Initial dose: Oral: 50 mg once daily on an empty stomach
Maximum dose: Oral: 75 mg once daily on an empty stomach

Patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean): Initial dose: 25 mg orally once daily on an empty stomach.

Use the lowest dose of eltrombopag to achieve and maintain a platelet count greater than or equal to 50 X 10^9/L as necessary to reduce the risk of bleeding. Dose adjustments are based upon the platelet count response. Eltrombopag should not be used in an attempt to normalize platelet counts.

What other drugs will affect eltrombopag?

Many drugs can interact with eltrombopag. Below is just a partial list. Tell your doctor if you are using:

acetaminophen (Tylenol);

acyclovir (Zovirax);

atazanavir (Reyataz);

birth control pills;

fluvoxamine (Luvox);

methotrexate (Rheumatrex, Trexall);

penicillin G (Pfizerpen);

rifampin (Rifadin, Rifater, Rifamate);

ticlopidine (Ticlid);

trimethoprim (Proloprim, Bactrim, Septra);

zileuton (Zyflo);

an antibiotic such as ciprofloxacin (Cipro), ofloxacin (Floxin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), and others;

cholesterol-lowering medicines such as atorvastatin (Lipitor), fluvastatin (Lescol), gemfibrozil (Lopid), pravastatin (Pravachol), or rosuvastatin (Crestor);

diabetes medication you take by mouth, such as nateglinide (Starlix), pioglitazone (Actos), repaglinide (Prandin), rosiglitazone (Avandia);

heart rhythm medication such as amiodarone (Cordarone, Pacerone), mexiletine (Mexitil), propafenone (Rythmol), verapamil (Calan, Covera, Isoptin);

narcotic pain medication such as fentanyl (Actiq, Duragesic), hydrocodone (Lortab, Vicodin, Vicoprofen), oxycodone (OxyContin, Endocet, Percocet), and others;

an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Motrin, Advil), diclofenac (Cataflam, Voltaren), etodolac (Lodine), indomethacin (Indocin), meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve, Naprosyn), piroxicam (Feldene), and others; or

stomach acid reducers such as cimetidine (Tagamet), esomeprazole (Nexium), famotidine (Pepcid), omeprazole (Prilosec).

This list is not complete and there are many other drugs that can interact with eltrombopag. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

More eltrombopag resources

Eltrombopag Side Effects (in more detail)
Eltrombopag Dosage
Eltrombopag Use in Pregnancy & Breastfeeding
Eltrombopag Drug Interactions
Eltrombopag Support Group
1 Review for Eltrombopag - Add your own review/rating

eltrombopag Advanced Consumer (Micromedex) - Includes Dosage Information

Eltrombopag Professional Patient Advice (Wolters Kluwer)

Eltrombopag MedFacts Consumer Leaflet (Wolters Kluwer)

Eltrombopag Monograph (AHFS DI)

Promacta Prescribing Information (FDA)

Promacta Consumer Overview

Compare eltrombopag with other medications

Idiopathic Thrombocytopenic Purpura
Thrombocytopenia Idiopathic

Where can I get more information?

Your doctor or pharmacist can provide more information about eltrombopag.

See also: eltrombopag side effects (in more detail)

Emend Injection

fosaprepitant dimeglumine

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Emend Injection

EMEND for Injection is a substance P/neurokinin-1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the:

prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin [see Dosage and Administration (2.1)]

prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) [see Dosage and Administration (2.2)].

Limitations of Use

EMEND for Injection has not been studied for the treatment of established nausea and vomiting.

Chronic continuous administration is not recommended [see Warnings and Precautions (5.5)].

Emend Injection Dosage and Administration

Prevention of Nausea and Vomiting Associated with Highly Emetogenic Chemotherapy (HEC)

EMEND for Injection 150 mg (Single Dose Regimen of EMEND):

EMEND for Injection 150 mg is administered intravenously on Day 1 only as an infusion over 20-30 minutes initiated approximately 30 minutes prior to chemotherapy. No capsules of EMEND are administered on Days 2 and 3. EMEND for Injection should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in Table 1. The recommended dosage of dexamethasone with EMEND for Injection 150 mg differs from the recommended dosage of dexamethasone with EMEND for Injection 115 mg on Days 3 and 4.

Table 1: Recommended dosing (Single Dose Regimen of EMEND) for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy
	Day 1	Day 2	Day 3	Day 4
* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The dose of dexamethasone accounts for drug interactions. † Ondansetron should be administered 30 minutes prior to chemotherapy treatment on Day 1.
EMEND	150 mg intravenous	none	none	none
Dexamethasone*	12 mg orally	8 mg orally	8 mg orally twice daily	8 mg orally twice daily
Ondansetron†	32 mg intravenous	none	none	none

EMEND for Injection 115 mg (3-Day Dosing Regimen of EMEND):

EMEND for Injection 115 mg is administered on Day 1 only as an infusion over 15 minutes initiated 30 minutes prior to chemotherapy. Capsules of EMEND 80 mg should be administered on Days 2 and 3. EMEND for Injection 115 mg should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in Table 2. The recommended dosage of dexamethasone with EMEND for Injection 115 mg differs from the recommended dosage of dexamethasone with EMEND for Injection 150 mg on Days 3 and 4.

Capsules of EMEND 125 mg may be substituted for EMEND for Injection 115 mg on Day 1.

Table 2: Recommended dosing (3-Day Dosing Regimen of EMEND) for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy
	Day 1	Day 2	Day 3	Day 4
* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The dose of dexamethasone accounts for drug interactions. † Ondansetron should be administered 30 minutes prior to chemotherapy treatment on Day 1.
EMEND	115 mg intravenous	80 mg orally	80 mg orally	none
Dexamethasone*	12 mg orally	8 mg orally	8 mg orally once daily	8 mg orally once daily
Ondansetron†	32 mg intravenous	none	none	none

Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Chemotherapy (MEC)

EMEND for Injection 115 mg (3-Day Dosing Regimen of EMEND):

EMEND for Injection 115 mg is administered on Day 1 only as an infusion over 15 minutes initiated 30 minutes prior to chemotherapy. Capsules of EMEND 80 mg should be administered on Days 2 and 3. EMEND for Injection 115 mg should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in Table 3. The recommended dosage of dexamethasone with EMEND for Injection 115 mg differs from the recommended dosage of dexamethasone with EMEND for Injection 150 mg on Days 3 and 4.

Capsules of EMEND 125 mg may be substituted for EMEND for Injection 115 mg on Day 1.

Table 3: Recommended dosing (3-Day Dosing Regimen of EMEND) for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy
* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for drug interactions. † Ondansetron 8-mg capsule should be administered 30 to 60 minutes prior to chemotherapy treatment and one 8-mg capsule should be administered 8 hours after the first dose on Day 1.
	Day 1	Day 2	Day 3
EMEND	115 mg intravenous	80 mg orally	80 mg orally
Dexamethasone*	12 mg orally	none	none
Ondansetron†	8 mg orally twice daily	none	none

Preparation of EMEND for Injection

Table 4: Preparation Instructions for EMEND for Injection (115-mg and 150-mg)
	115 mg	150 mg
Step 1	Aseptically inject 5 mL 0.9% Sodium Chloride for Injection (normal saline) into the vial. Assure that normal saline is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting saline into the vial.	Aseptically inject 5 mL 0.9% Sodium Chloride for Injection (normal saline) into the vial. Assure that normal saline is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting saline into the vial.
Step 2	Aseptically prepare an infusion bag filled with 110 mL of normal saline.	Aseptically prepare an infusion bag filled with 145 mL of normal saline.
Step 3	Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag containing 110 mL of normal saline to yield a total volume of 115 mL and a final concentration of 1 mg/1 mL.	Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag containing 145 mL of normal saline to yield a total volume of 150 mL and a final concentration of 1 mg/1 mL.
Step 4	Gently invert the bag 2-3 times.	Gently invert the bag 2-3 times.
	Note: The differences in preparation for each dose are displayed as bolded text.

The reconstituted final drug solution is stable for 24 hours at ambient room temperature (at or below 25°C).

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Caution: EMEND for Injection should not be mixed or reconstituted with solutions for which physical and chemical compatibility have not been established. EMEND for Injection is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer’s Solution and Hartmann's Solution.

Dosage Forms and Strengths

One 150 mg single dose glass vial: White to off-white lyophilized solid (Sterile lyophilized powder for intravenous use only after reconstitution and dilution).

One 115 mg single dose glass vial: White to off-white lyophilized solid (Sterile lyophilized powder for intravenous use only after reconstitution and dilution).

Contraindications

Hypersensitivity

EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80 or any other components of the product. Known hypersensitivity reactions include: flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions (6.2)].

Concomitant Use with Pimozide or Cisapride

Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions (7.1)].

Warnings and Precautions

CYP3A4 Interactions

Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions (7.1)].

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered.

Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions (7.1)].

Hypersensitivity Reactions

Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use.

Coadministration with Warfarin (a CYP2C9 substrate)

Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions (7.1)].

Coadministration with Hormonal Contraceptives

Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions (7.1)].

Chronic Continuous Use

Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection.

The overall safety of fosaprepitant was evaluated in approximately 1100 individuals and the overall safety of aprepitant was evaluated in approximately 6500 individuals.

Oral Aprepitant

Highly Emetogenic Chemotherapy (HEC)

In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone.

In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy.

The most common adverse reactions reported in patients treated with the aprepitant regimen with an incidence ≥1% and greater than standard therapy are listed in Table 5.

Table 5: Adverse Reactions (incidence ≥1%) in patients receiving HEC with a greater incidence in the Aprepitant Regimen relative to Standard Therapy
	Aprepitant Regimen (N=544)	Standard Therapy (N=550)
Respiratory System
hiccups	4.6	2.9
Body as a Whole/Site Unspecified
asthenia/fatigue	2.9	1.6
Investigations
ALT increased	2.8	1.5
AST increased	1.1	0.9
Digestive System
constipation	2.2	2.0
dyspepsia	1.5	0.7
diarrhea	1.1	0.9
Nervous System
headache	2.2	1.8
Metabolism and Nutrition
anorexia	2.0	0.5

A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than standard therapy are presented in the Less Common Adverse Reactions subsection below.

In an additional active-controlled clinical study in 1169 patients receiving aprepitant and highly emetogenic chemotherapy, the adverse experience profile was generally similar to that seen in the other HEC studies with aprepitant.

Moderately Emetogenic Chemotherapy (MEC)

In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer chemotherapy, 868 patients were treated with the aprepitant during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In both studies, oral aprepitant was given in combination with ondansetron and dexamethasone (aprepitant regimen).

In the combined analysis of Cycle 1 data for these 2 studies, adverse reactions were reported in approximately 14% of patients treated with the aprepitant regimen compared with approximately 15% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.7% of patients treated with the aprepitant regimen compared with 0.2% of patients treated with standard therapy.

The most common adverse reactions reported in patients treated with the aprepitant regimen with an incidence ≥1% and greater than standard therapy are listed in Table 6.

Table 6: Adverse Reactions (incidence ≥1%) in patients receiving MEC with a greater incidence in the Aprepitant Regimen relative to Standard Therapy
	Aprepitant Regimen (N=868)	Standard Therapy (N=846)
Gastrointestinal disorders
eructation	1.0	0.1
General disorders and administration site conditions
fatigue	1.4	0.9

Less Common Adverse Reactions

Adverse reactions reported in either HEC or MEC studies in patients treated with the aprepitant regimen with an incidence <1% and greater than standard therapy are listed in Table 7.

Table 7: Adverse Reactions (incidence <1%) in patients observed in either HEC or MEC Studies with a greater incidence in the Aprepitant Regimen relative to Standard Therapy
Infection and infestations	candidiasis, staphylococcal infection
Blood and the lymphatic system disorders	anemia, febrile neutropenia
Metabolism and nutrition disorders	weight gain, polydipsia
Psychiatric disorders	disorientation, euphoria, anxiety
Nervous system disorders	dizziness, dream abnormality, cognitive disorder, lethargy, somnolence
Eye disorders	conjunctivitis
Ear and labyrinth disorders	tinnitus
Cardiac disorders	bradycardia, cardiovascular disorder, palpitations
Vascular disorders	hot flush, flushing
Respiratory, thoracic and mediastinal disorders	pharyngitis, sneezing, cough, postnasal drip, throat irritation
Gastrointestinal disorders	nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, faeces hard, neutropenic colitis, flatulence, stomatitis
Skin and subcutaneous tissue disorders	rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion
Musculoskeletal and connective tissue disorders	muscle cramp, myalgia, muscular weakness
Renal and urinary disorders	polyuria, dysuria, pollakiuria
General disorders and administration site condition	edema, chest discomfort, malaise, thirst, chills, gait disturbance
Investigations	alkaline phosphatase increased, hyperglycemia, microscopic hematuria, hyponatremia, weight decreased, neutrophil count decreased

In another chemotherapy induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy.

The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1.

Fosaprepitant

In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy, safety was evaluated for 1143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared to 1169 patients receiving the 3-day regimen of EMEND (aprepitant). The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above.

Table 8: Adverse Reactions (incidence >0.1%) in patients receiving Fosaprepitant 150 mg and not reported above for the Oral Aprepitant Regimen
General disorders and administration site conditions	infusion site erythema, infusion site pruritus, infusion site induration, infusion site pain
Investigations	blood pressure increased
Skin and subcutaneous tissue disorders	erythema
Vascular disorders	thrombophlebitis (predominantly, infusion-site thrombophlebitis)

Other Studies with Postoperative Nausea and Vomiting

In well-controlled clinical studies in patients receiving general balanced anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron intravenously.

Adverse reactions were reported in approximately 4% of patients treated with 40 mg aprepitant compared with approximately 6% of patients treated with 4 mg ondansetron intravenously.

In patients treated with aprepitant, increased ALT (1.1%) was seen at a greater incidence than with ondansetron (1.0%). The following additional adverse reactions were observed in patients treated with aprepitant at an incidence <1% and greater than with ondansetron.

Table 9: Adverse Reactions (incidence <1%) in patients receiving Aprepitant 40 mg with a greater incidence in the Aprepitant group relative to ondansetron
Psychiatric disorders	insomnia
Nervous system disorders	dysarthria, hypoesthesia, sensory disturbance
Eye disorders	miosis, visual acuity reduced
Cardiac disorders	bradycardia
Respiratory, thoracic and mediastinal disorders	dyspnea, wheezing
Gastrointestinal disorders	abdominal pain upper, bowel sounds abnormal, dry mouth, nausea, stomach discomfort

In addition, two serious adverse reactions were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of subileus.

Other Studies

Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria.

Immune system disorders: hypersensitivity reactions including anaphylactic reactions.

Drug Interactions

Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant.

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9.

Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4, and does not induce CYP3A4. Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.

The following information was derived from data with oral aprepitant, two studies conducted with fosaprepitant and oral midazolam, and one study conducted with fosaprepitant and dexamethasone.

Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents

CYP3A4 Substrates:

Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications (4)].

5-HT3 antagonists:

In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids:

Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-24hr of dexamethasone, administered as a single 8 mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg intravenous on Day 1.

An oral aprepitant regimen of 125 mg on Day 1, and 80 mg/day on Days 2 through 5, coadministered with 20 mg oral dexamethasone on Day 1 and 8 mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant.

Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant.

Chemotherapeutic agents:

Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions (5.1)].

Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions (5.1)].

Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment.

The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant.

Midazolam:

Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”).

Table 10: Pharmacokinetic Interaction Data for Aprepitant/Fosaprepitant and Coadministered Midazolam
Dose of fosaprepitant/ aprepitant	Dose of Midazolam	Observed Drug Interactions
fosaprepitant 150 mg on Day 1	oral 2 mg on Days 1 and 4	AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4
fosaprepitant 100 mg on Day 1	oral 2 mg	oral midazolam AUC ↑ 1.6-fold
oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5	oral 2 mg SD on Days 1 and 5	oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5
oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3	intravenous 2 mg prior to 3-day regimen of aprepitant and on Days 4, 8 and 15	intravenous midazolam AUC ↑ 25 % on Day 4, AUC ↓ 19 % on Day 8 and AUC ↓ 4 % on Day 15
oral aprepitant 125 mg	intravenous 2 mg given 1 hour after aprepitant	intravenous midazolam AUC ↑ 1.5-fold

A difference of less than 2-fold increase of midazolam AUC was not considered clinically important.

The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant.

CYP2C9 Substrates (Warfarin, Tolbutamide):

Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle.

Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15.

Effect of Other Agents on the Pharmacokinetics of Aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy.

Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of