Eltrombopag Olamine

Registered South African indications:

• Thrombocytopenia in adult patients with chronic idiopathic (immune) thrombocytopenic purpura (ITP)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Moderate to severe hepatic impairment (Chronic HCV associated thrombocytopenia)
• Hepatic impairment (Thrombocytopenia in adult patients with chronic ITP and SAA)
• Elderly
• Low albumin levels
• Myelodysplastic syndromes
• Known risk to thromboembolism
• Bleeding following discontinuation of eltrombopag
• Bone marrow reticulin formation
• Bone marrow fibrosis
• Cytogenetic abnormalities
• Myelodysplastic syndrome (MDS)

Forms avail. in SA and covered in this monograph: tab

Thrombocytopenia in adult patients with chronic idiopathic (immune) thrombocytopenic purpura (ITP) 
-Who have had insufficient response to corticosteroids, immunoglobulin or splenectomy

• Oral (tab): Initial: 50mg, dly (Asian ancestry: Initial: 25mg, dly); Maintenance: Adjust dose to achieve and maintain a platelet count  ≥50 000/μl; Max: 75mg/24hrs(see additional prescribing points for dose adjustments of eltrombopag in ITP patients)

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Dosing regimens must be individualised based on the patient’s platelet counts

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Use the lowest effective dosing regimen to maintain platelet counts, as clinically indicated

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In most patients, measurable elevations in platelet counts take 1 - 2 weeks

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Should only be used in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding

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Should not be used in an attempt to normalise platelet counts

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Chronic hepatitis C virus (HCV) associated thrombocytopenia
-Where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy

• Oral (tab): Initial: 25mg, dly; Titrate by 25mg at intervals of 2 weeks; Maintenance: Adjust dose to achieve and maintain a platelet count of between 50 000-75 000/μl; Max: 100mg/24hrs(see additional prescribing points for dose adjustments of eltrombopag in HCV patients during antiviral therapy)

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No dosage adjustment is necessary for HCV patients of East Asian ancestry

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Platelet counts should be monitored every week prior to starting antiviral therapy  

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On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose adjustments should be avoided  

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Platelet counts should be monitored weekly during antiviral therapy until a stable platelet count is achieved

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Full blood counts including platelet counts and peripheral blood smears should be obtained monthly thereafter

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Acquired severe aplastic anaemia (SAA)
-When patients are either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation

• Oral (tab): Initial: 50mg, dly (Asian ancestry: Initial: 25mg, dly); Titrate by 50mg at intervals of 2 weeks; Maintenance: Adjust dose to achieve and maintain a platelet count ≥50 000/μl; Max: 150mg/24hrs(see additional prescribing points for dose adjustments of eltrombopag in patients with severe aplastic anaemia)

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The treatment should not be initiated when the patients has existing cytogenetic abnormalities of chromosome 7

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Haematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks after starting eltrombopag  

Not registered for use in South Africa for children

Pregnancy

• Caution
• There are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Eltrombopag is not recommended during pregnancy
• Eltrombopag is not recommended in women of childbearing potential not using contraception

Breastfeeding

• Caution; not recommended
• It is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have shown that eltrombopag is likely secreted into milk; therefore a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to continue/abstain from eltrombopag therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

• Fertility was not affected in male or female rats at exposures that were comparable to those in humans. However, the risk for humans cannot be ruled out

Renal Impairment

• Caution; no dose adjustment recommended

Hepatic Impairment

Thrombocytopenia in adult patients with chronic ITP

• Caution; dose adjustment recommended
  Initial: 25mg, dly; 3 weeks should be observed before increasing the dose
  Not recommended when Child-Pugh score ≥5 unless the expected benefit outweighs the identified risk of portal venous thrombosis

Chronic HCV associated thrombocytopenia

• Mild (Child-Pugh score ≤6): No dose adjustment recommended 
• Moderate to severe (Child-Pugh >6): Caution; dose adjustment recommended
  Initial: 25mg, dly; 2 weeks should be observed before increasing the dose

Acquired severe aplastic anaemia (SAA)

• Caution; dose adjustment recommended
• Initial: 25mg, dly; 2 weeks should be observed before increasing the dose

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Sleep disorder
• Depression
• Apathy
• Mood altered
• Tearfulness
• Paraesthesia
• Hypoaesthesia
• Somnolence
• Migraine
• Migraine with aura
• Tremor
• Dysaesthesia
• Hemiparesis
• Neuropathy peripheral
• Peripheral sensory neuropathy
• Speech disorder
• Toxic neuropathy
• Vascular headache
• Asthenia
• Jittery

Cardiovascular Disorders

• Tachycardia
• Fatal thromboembolic events
• Acute myocardial infarction
• Cardiovascular disorder
• Cyanosis
• Sinus tachycardia
• Electrocardiogram QT prolonged
• Deep vein thrombosis
• Embolism
• Hot flush
• Thrombophlebitis superficial
• Flushing
• Haematoma
• Chest pain

Respiratory Disorders

• Nasopharyngitis
• Rhinitis
• Pharyngitis
• Influenza
• Pneumonia
• Sinusitis
• Tonsilitis
• Respiratory tract infection
• Cough
• Oropharyngeal pain
• Rhinorrhoea
• Pulmonary embolism
• Pulmonary infarction
• Nasal discomfort
• Oropharyngeal blistering
• Oropharyngeal pain
• Sinus disorder
• Sleep apnoea syndrome

Gastrointestinal Disorders

• Gingivitis
• Anorexia
• Decreased appetite 
• Nausea and vomiting
• Diarrhoea
• Mouth ulceration
• Toothache
• Dry mouth
• Abdominal pain
• Glossodynia
• Mouth haemorrhage
• Abdominal tenderness
• Discoloured faeces
• Flatulence
• Food poisoning
• Frequent bowel movements
• Haematemesis
• Oral discomfort
• Oral herpes

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Hyperbilirubinaemia
• Fatal hepatic decompensation
• Abnormal hepatic function
• Cholestasis
• Hepatic lesion
• Hepatitis
• Drug-induced liver injury
• Hepatotoxicity

Genitourinary Disorders

• Renal failure
• Acute kidney injury
• Leukocyturia
• Lupus nephritis
• Nocturia
• Proteinuria
• Increased urea
• Increased creatinine
• Increased urine protein/creatinine ratio
• Menorrhagia
• Increased urine pH

Endocrine and Metabolic Disorders

• Cold sweat
• Hypokalaemia
• Gout
• Feeling hot
• Hypocalcaemia
• Increased blood uric acid

Musculoskeletal Disorders

• Myalgia
• Muscle spasm
• Musculoskeletal pain
• Bone pain
• Back pain
• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Skin infection
• Rash
• Alopecia
• Hyperhidrosis
• Generalised pruritus
• Urticaria
• Dermatosis
• Petechiae
• Erythema
• Melanosis
• Pigmentation disorder
• Skin discolouration
• Skin exfoliation
• Sunburn

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Rectosigmoid cancer
• Anaemia
• Anisocytosis
• Eosinophilia
• Progression of myelodysplastic syndrome (MDS) to acute myeloid leukaemia (AML)
• Haemolytic anaemia
• Leukocytosis
• Myelocytosis
• Thrombocytopenia
• Increased haemoglobin
• Increased band neutrophil count
• Decreased haemoglobin
• Myelocyte present
• Increased platelet count
• Decreased white blood cell count
• Increased albumin
• Decreased albumin
• Increased alkaline phosphatase
• Increased protein total
• Pyrexia

Sensory Disorders

• Dry eye
• Vision blurred
• Lenticular opacities
• Astigmatism
• Cataract cortical
• Eye pain
• Increased lacrimation
• Retinal haemorrhage
• Retinal pigment epitheliopathy
• Reduced visual acuity
• Visual impairment
• Abnormal visual acuity tests
• Blepharitis
• Keratoconjunctivitis sicca
• Ear pain
• Vertigo
• Balance disorder

• HMG CoA reductase inhibitors
• OATP1B1 substrates
• BCRP substrates
• CYP450 substrates
• HCV protease inhibitors
• Ciclosporin
• Polyvalent cations
• Lopinavir/Ritonavir
• CYP1A2 and CYP2C8 inhibitors
• CYP1A2 and CYP2C8 inducers
• Corticosteroids
• Danazol
• Azathioprine
• Intravenous immunoglobulin
• Anti-D immunoglobulin
• Ribavirin
• Interferon
• Directly acting antivirals

• Hepatic function
• Full blood count with differential
• Platelet count

Dose adjustments of eltrombopag in ITP patients

Platelet count	Dose adjustment or response
<50 000/μl (following at least 2 weeks of therapy)	Increase dose by 25mg, dly; Max: 75mg/24hrs
≥ 200 000 - ≤ 400 000/μl	Decrease the daily dose by 25mg; Wait 2 weeks to assess the effects of this and any subsequent dose adjustments
> 400 000/μl	Stop eltrombopag; increase the frequency of platelet monitoring to twice weekly; Once the platelet count is <150 000/μl, re-initiate therapy at a lower daily dose

The standard dose adjustment, either decrease or increase, would be 25 mg once daily. However, in a few patients, a combination of different tablet strengths on different days may be required.

After any eltrombopag dose adjustment, platelet counts should be monitored at least weekly for 2 to 3 weeks. Wait for at least 2 weeks to see the effect of any dose adjustment on the patient's platelet response prior to considering another dose adjustment

Discontinuation: Treatment with eltrombopag should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after four weeks of eltrombopag therapy at 75 mg once daily.

Dose adjustments of eltrombopag in HCV patients during antiviral therapy

Platelet count	Dose adjustment or response
<50 000/µl following at least 2 weeks of therapy	Increase daily dose by 25mg; Max: 100 mg/24hrs
≥50 000/µl - ≤100 000/µl	Use the lowest dose of eltrombopag as necessary to avoid dose reductions of peginterferon
>100 000/µl - ≤150 000/µl	Decrease daily dose by 25mg; Wait 2 weeks to assess the effects of this and any subsequent dose adjustments Note: On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose reductions should be avoided
>150,000/µl	Stop eltrombopag; Increase the frequency of platelet monitoring to twice weekly; Once the platelet count is ≤100,000/µl, reinitiate therapy at a daily dose reduced by 25 mg Note: For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating dosing at 25 mg every other day

Discontinuation: If after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral therapy is not achieved, eltrombopag should be discontinued.

Eltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise justified. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation.

Dose adjustments of eltrombopag in patients with severe aplastic anaemia

Clinical haematology and liver tests should be monitored regularly throughout therapy with eltrombopag and the dosage regimen of eltrombopag modified based on platelet counts as the table below;

Platelet count	Dose adjustment or response
<50 000/µl following at least 2 weeks of therapy	Increase daily dose by 50 mg; Max: 150 mg/24hrs For patients taking 25mg once daily, increase the dose to 50 mg daily before increasing the dose amount by 50 mg
≥50 000/µl - ≤150 000/µl	Use the lowest dose of eltrombopag to maintain platelet counts
>150 000/µl - ≤250 000/µl	Decrease the daily dose by 50mg; Wait 2 weeks to assess the effects of this and any subsequent dose adjustments
>250,000/µl	Stop eltrombopag; for at least one week; Once the platelet count is ≤100,000/µl, reinitiate therapy at a daily dose reduced by 50mg

Tapering for tri-lineage (white blood cells, red blood cells, and platelets) responders
For patients who achieve a tri-lineage response, including transfusion independence, lasting at least 8 weeks: The dose of eltrombopag may be reduced by 50%.

If counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued and blood counts monitored. If platelet counts drop to <30,000/µl, haemoglobin drops to <9g/dl or absolute neutrophil count (ANC) <0.5 x 10⁹/l, eltrombopag may be reinitiated at the previously effective dose.

Discontinuation: If no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapy should be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of eltrombopag is appropriate. Excessive platelet count responses or important liver test abnormalities also necessitate discontinuation of eltrombopag.

Other

• Eltrombopag may interfere with laboratory tests
• A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin

Food interaction

• Administration with a high-calcium meal (e.g. a meal that included dairy products) = significantly reduced plasma eltrombopag
• Administration with a standard high-calorie (e.g. a high-fat breakfast, included dairy products) = reduced plasma eltrombopag mean maximum concentration by 65%
• Administration with a high-calcium, moderate-fat and moderate-calorie meal = reduced plasma eltrombopag mean maximum concentration by 79%
• Administration with food low in calcium (including fruit, lean ham, beef and unfortified fruit juice, unfortified soya milk and unfortified grain) = did not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content

Pharmacokinetics

• Elimination half-life (t_1/2) in healthy individuals: 21-32 hours
• Elimination half-life (t_1/2) in patients with ITP: 26-35 hours

Prescription

• Eltrombopag treatment should be initiated by and remain under the supervision of a physician who is experienced in the treatment of haematological diseases or the management of chronic hepatitis C and its complications
• Eltrombopag dosing requirements must be individualised based on the patient's platelet counts

Loss of response to eltrombopag

• A loss of response or failure to maintain a platelet response with eltrombopag treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin

Eltrombopag is a thrombopoietin (TPO) nonpeptide agonist which increases platelet counts by binding to and activating the human TPO receptor. Eltrombopag activates intracellular signal transduction pathways inducing proliferation and differentiation from bone marrow progenitor cells.

Tablet 25mg 

Revolade (Novartis) originator

Tablet 50mg

Revolade (Novartis) originator