Eltrombopag

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. Do not take more than one dose of eltrombopag in one day.

Eltrombopag may cause serious side effects. See “Drug Precautions”.

The most common side effects of eltrombopag are:

• nausea
• diarrhea
• upper respiratory tract infection; symptoms may include runny nose, stuffy nose, and sneezing
• vomiting
• muscle aches
• urinary tract infections; symptoms may include frequent or urgent need to urinate, low fever in some people, pain or burning with urination
• pain or swelling (inflammation) in your throat or mouth (oropharyngeal pain and pharyngitis)
• abnormal liver function tests
• abnormal skin sensations such as tingling, itching, or burning
• back pain
• ‘flu’ symptoms (influenza); symptoms may include fever, headache, tiredness, cough, sore throat, and body aches
• rash

These are not all the possible side effects of eltrombopag. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects.

• Store at room temperature between 59˚F to 86˚F (15˚C to 30˚C).
• Keep eltrombopag and all medicines out of the reach of children.

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

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

• Importance of understanding that treatment can only be prescribed by a clinician registered with the PROMACTA CARES program; all ITP patients receiving eltrombopag must be enrolled in the PROMACTA CARES 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.)

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:

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• body aches or pain
• chills or fever
• cough
• difficulty with breathing
• headache
• loss of voice
• pale skin
• rapid weight gain
• runny nose
• sore throat
• tingling of the hands or feet
• troubled breathing with exertion
• unusual tiredness or weakness
• unusual weight gain or loss
• yellow eyes or skin

• Bladder pain
• blindness
• blurred or decreased vision
• bruising
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• diarrhea
• general feeling of discomfort or illness
• hoarseness
• joint pain
• lower back or side pain
• muscle aches and pains
• nausea
• pinpoint red spots on the skin
• redness of the eye
• shivering
• sweating
• tender, swollen glands in the neck
• trouble sleeping
• trouble swallowing
• voice changes
• vomiting

• Chest pain
• pain, redness, or swelling in the legs or arms

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:

• Decreased appetite
• difficulty with moving
• hair loss or thinning of the hair
• itching skin
• lack or loss of strength
• muscle aching or cramping
• muscle pains or stiffness
• swollen joints

• Acid or sour stomach
• back pain
• belching
• bone pain
• dry mouth
• heartburn
• indigestion
• rash
• stomach discomfort, upset, or pain

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.

• Colony Stimulating Factor
• Hematopoietic Agent
• Thrombopoietic Agent

Plasma eltrombopag apparent clearance following oral administration (CL/F) increased with increasing body weight. East Asian pediatric patients with ITP had approximately 43% higher plasma eltrombopag AUC(0-τ) values compared with non-East Asian patients.

Note: Do not use eltrombopag to normalize platelet counts.

Chronic immune (idiopathic) thrombocytopenia (ITP): Note: Use the lowest dose to achieve and maintain platelet count ≥50,000/mm3 as needed to reduce the risk of bleeding. Discontinue if platelet count does not respond to a level that avoids clinically important bleeding after 4 weeks at the maximum of 75 mg/day.

Children 1 to 5 years: Oral: Initial: 25 mg once daily; dose should be titrated based on platelet response (no dosage adjustment required for patients of East Asian ancestry). Maximum dose: 75 mg/day.

Children ≥6 years and Adolescents: Oral: Refer to adult dosing

Applies to eltrombopag: oral powder for reconstitution, oral tablet

General

The most common side effects reported in ITP patients have included nausea, diarrhea, upper respiratory tract infection, vomiting, increased ALT, myalgia, urinary tract infection, oropharyngeal pain, increased AST, pharyngitis, back pain, influenza, paresthesia, and rash.

The most common side effects reported in thrombocytopenic patients with chronic hepatitis C have included anemia, pyrexia, fatigue, headache, nausea, diarrhea, decreased appetite, influenza-like illness, asthenia, insomnia, cough, pruritus, chills, myalgia, alopecia, and peripheral edema.[Ref]

Cardiovascular

Common (1% to 10%): Deep vein thrombosis, edema, palpitations, peripheral edema, prolonged QT interval on ECG, thrombotic/thromboembolic events
Uncommon (0.1% to 1%): Acute myocardial infarction, cardiovascular disorder, chest pain, cyanosis, embolism, flushing, hematoma, hot flush, hypertension, sinus tachycardia, superficial thrombophlebitis, tachycardia[Ref]

Hepatic

Common (1% to 10%): Abnormal hepatic function, ascites, hepatic failure, hyperbilirubinemia, increased ALT or AST, increased blood alkaline phosphatase, increased blood bilirubin levels, jaundice, portal vein thrombosis, drug-induced liver injury
Uncommon (0.1% to 1%): Cholestasis, hepatic lesion, hepatitis[Ref]

In clinical trials, hepatic decompensation (ascites, hepatic encephalopathy, variceal hemorrhage, spontaneous bacterial peritonitis) was reported more commonly in chronic HCV patients with cirrhosis treated with eltrombopag compared to placebo.[Ref]

Hematologic

Very common (10% or more): Anemia
Common (1% to 10%): Decreased hemoglobin, decreased neutrophil count, decreased white blood cell count, hemolytic anemia, increased INR, lymphopenia, prolonged activated partial thromboplastin time
Uncommon (0.1% to 1%): Anisocytosis, eosinophilia, increased hemoglobin, increased band neutrophil count, increased platelet cell counts, leukocytosis, myelocytosis, presence of myelocytes, thrombocytopenia[Ref]

In clinical studies, hemorrhage was the most common serious adverse reaction and most hemorrhagic reactions followed discontinuation of eltrombopag.[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea, nausea
Common (1% to 10%): Abdominal discomfort, abdominal distension, abdominal pain, aphthous stomatitis, constipation, dry mouth, dyspepsia, dysgeusia, esophageal varices hemorrhage, esophageal varices, gastritis, gastroenteritis,stomatitis, gastroesophageal reflux disease, hemorrhoids, toothache, upper abdominal pain, vomiting
Uncommon (0.1% to 1%): Abdominal tenderness, discolored feces, flatulence, food poisoning, frequent bowel movements, gingival bleeding, glossodynia, hematemesis, hemorrhoids, mouth hemorrhage, oral discomfort[Ref]

Dermatologic

Very common (10% or more): Alopecia, pruritus
Common (1% to 10%): Dry skin, eczema, erythema, generalized pruritus, hyperhidrosis, night sweats, pruritic rash, rash, skin lesion
Uncommon (0.1% to 1%): Cold sweat, contusion, dermatosis, ecchymosis, inflammation of wound, melanosis, petechia, pigmentation disorder, skin discoloration, skin exfoliation, swelling face, sunburn, urticaria[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection
Uncommon (0.1% to 1%): Dysuria, leukocyturia, nocturia, proteinuria[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Hypersensitivity[Ref]

Immunologic

Very common (10% or more): Influenza-like illness
Common (1% to 10%): Influenza, oral herpes[Ref]

Metabolic

Very common (10% or more): Decreased appetite
Common (1% to 10%): Abnormal loss of weight, decreased blood albumin, hyperglycemia, increased blood glucose
Uncommon (0.1% to 10%): Gout, hypocalcemia, hypokalemia, increased appetite, increased blood albumin, increased blood uric acid, increased total protein, increased weight[Ref]

Musculoskeletal

Very common (10% or more): Myalgia
Common (1% to 10%): Arthralgia, back pain, bone pain, muscle spasm, musculoskeletal pain, pain in extremity
Uncommon (0.1% to 1%): Muscular weakness, sensation of heaviness[Ref]

Nervous system

Very common (10% or more): Headache
Common (1% to 10%): Dizziness, hepatic encephalopathy, lethargy, memory impairment, paresthesia
Uncommon (0.1% to 1%): Balance disorder, cerebral infarction, dysesthesia, hemiparesis, hypoesthesia, migraine, migraine with aura, peripheral neuropathy, peripheral sensory neuropathy, somnolence, speech disorder, toxic neuropathy, tremor, vascular headache[Ref]

Ocular

Common (1% to 10%): Cataract, dry eye, ocular icterus, retinal exudates, retinal hemorrhage
Uncommon (0.1% to 1%): Abnormal visual acuity tests, astigmatism, blepharitis, blurred vision, conjunctival hemorrhage, cortical cataract, eye pain, increased lacrimation, keratoconjunctivitis sicca, lenticular opacities, retinal hemorrhage, retinal pigment epitheliopathy, reduced visual acuity, visual impairment,[Ref]

Oncologic

Common (1% to 10%): Malignant hepatic neoplasm
Uncommon (0.1% to 1%): Rectosigmoid cancer[Ref]

Psychiatric

Very common (10% or more): Insomnia
Common (1% to 10%): Agitation, anxiety, confusional state, depression, disturbance in attention, sleep disorder
Uncommon (0.1% to 1%): Altered mood, apathy, tearfulness[Ref]

Renal

Uncommon (0.1% to 1%): Increased blood creatinine, increased blood urea, increased urine pH, increased urine protein/creatinine ratio, lupus nephritis, renal failure[Ref]

Respiratory

Very common (10% or more): Cough (up to 23%), upper respiratory tract infection (up to 17%), nasopharyngitis (up to 12%), rhinorrhea (up to 12%)
Common (1% to 10%): Bronchitis, dyspnea, exertional dyspnea, oropharyngeal pain, pharyngitis, productive cough, pulmonary embolism, upper respiratory tract infection, rhinitis, oropharyngeal pain
Uncommon (0.1% to 1%): Epistaxis, nasal discomfort, oropharyngeal blistering, pneumonia, pulmonary infarction, sinusitis, sinus disorder, sleep apnea syndrome, tonsillitis[Ref]

Other

Very common (10% or more): Asthenia, chills, fatigue, pyrexia
Common (1% to 10%): Chest discomfort, irritability, malaise, non-cardiac chest pain, pain
Uncommon (0.1% to 1%): Ear pain, feeling hot, feeling jittery, ill-defined disorder, mucosal inflammation, pyrexia, sensation of foreign body, vertigo, vessel puncture site hemorrhage[Ref]

Local

Common (1% to 10%): Injection site rash/pruritus, injection site reaction[Ref]

Some side effects of eltrombopag may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Initial dose: 50 mg orally once a day; increase daily dose if necessary in increments of 50 mg every two weeks

Patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean):
Initial dose: 25 mg orally once a day; increase to 50 mg once a day after 2 weeks if necessary, then increase daily dose in increments of 50 mg every 2 weeks

Maintenance dose: The lowest dose to achieve and maintain a platelet count between 50 to 200 x 10(9)/L as necessary
Maximum dose: 150 mg orally once a day

Duration:
-Patients who achieve trilineage response, including transfusion independence lasting at least 8 weeks: Eltrombopag dose may be reduced by 50% and discontinued if counts remain stable after 8 weeks at the reduced dose.
-Treatment should be discontinued if no hematologic response is observed after 16 weeks of therapy.
-Consider treatment discontinuation if new cytogenetic abnormalities are observed.

Comments:
-Treatment should be restarted at the previous effective dose if platelet counts fall to below 30 x 10(9)/L, hemoglobin falls to less than 9 g/dL, or ANC falls to less than 0.5 x 10(9)/L.

Use: Treatment of severe aplastic anemia in patients who have had an insufficient response to immunosuppressive therapy.

1 TO 5 YEARS:
Initial dose: 25 mg orally once a day

6 YEARS OR OLDER:
Initial dose: 50 mg orally once a day

Patients of East Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean):
Initial dose: 25 mg orally once a day

Maintenance dose: The lowest dose to achieve and maintain a platelet count between 50 to 200 x 10(9)/L as necessary to reduce the risk of bleeding.
Maximum dose: 75 mg orally once a day

Duration: Treatment should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of therapy at the maximum daily dose.

Comments:
-Monitor CBC with differentials, including platelet counts, every week until the platelet count is stable, followed by monthly thereafter. Monitoring should continue every week for at least 4 weeks following treatment discontinuation.
-Platelet counts generally increase within 1 to 2 weeks after starting therapy and decrease within 1 to 2 weeks after treatment discontinuation.

Use: Treatment of thrombocytopenia in patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

US BOXED WARNINGS:
-RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH CHRONIC HEPATITIS C: In patients with chronic hepatitis C, eltrombopag in combination with interferon and ribavirin may increase the risk of hepatic decompensation.
-RISK OF HEPATOTOXICITY: This drug may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

Safety and efficacy have not been established in patients younger than 1 year with ITP. Safety and efficacy have not been established in patients younger than 18 years with thrombocytopenia associated with chronic hepatitis C and severe aplastic anemia.

Consult WARNINGS section for dosing related precautions.