Revolade Special Precautions

The effectiveness and safety of REVOLADE have not been established for use in other thrombocytopenic conditions including chemotherapy-induced thrombocytopenia and myelodysplastic syndromes (MDS).
REVOLADE should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain optimal interferon-based therapy.
The safety and efficacy of REVOLADE have not been established in combination with direct acting antiviral agents approved for treatment of chronic hepatitis C genotype 1 infection.
Hepatotoxicity: REVOLADE administration can cause hepatobiliary laboratory abnormalities, severe hepatotoxicity, and potentially fatal liver injury.
Clinical data: In clinical studies of adult and paediatric patients (aged 1 to 17 years) with chronic ITP who received REVOLADE, increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and indirect (unconjugated) bilirubin were observed (see Adverse Reactions).
These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate impaired liver function. In the two placebo controlled Phase III studies in adults with chronic ITP, adverse events of ALT increase were reported in 5.7 % and 4.0 % of eltrombopag and placebo treated patients respectively. In two placebo-controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT ≥ 3 times the upper limit of normal (x ULN) was reported in 4.7 % and 0 % of the eltrombopag and placebo groups, respectively.
In two controlled clinical studies in thrombocytopenic patients with HCV, ALT or AST ≥ 3 x ULN were reported in 34 % and 38 % of the REVOLADE and placebo groups, respectively. REVOLADE administration in combination with peginterferon/ribavirin therapy is associated with indirect hyperbilirubinaemia. Overall, total bilirubin ≥ 1.5 x ULN was reported in 76 % and 50 % of the REVOLADE and placebo groups, respectively.
In a single-arm open-label clinical study in definitive immunosuppressive therapy-naïve SAA patients who received REVOLADE concurrently with h-ATG and ciclosporin, ALT or AST >3 x ULN with total bilirubin >1.5 x ULN was reported in 43.5% (40/92) of patients. None of these elevations resulted in discontinuation.
In the single-arm phase II monotherapy study in patients with refractory SAA, concurrent ALT or AST >3 x ULN with total bilirubin >1.5 x ULN were reported in 5 % of patients. Total bilirubin >1.5 x ULN occurred in 14 % of patients.
Dosage adjustment: In patients with ITP, HCV, and refractory SAA, serum ALT, AST and bilirubin should be monitored prior to initiation of REVOLADE, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinemia. If bilirubin is elevated, fractionation should be performed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, stabilize, or return to baseline levels. REVOLADE should be discontinued if ALT levels increase to ≥ 3 x ULN in patients with normal liver function or ≥ 3 x baseline (or > 5 x ULN, whichever is the lower) in patients with elevations in transaminases before treatment and are: progressive, or persistent for ≥ 4 weeks, or accompanied by increased direct bilirubin, or accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.
In the first-line setting of severe aplastic anaemia, ALT, AST, and bilirubin should be measured prior to initiation of REVOLADE. During treatment, increases in ALT levels should be managed as recommended in Table 14.
Caution should be exercised when administering REVOLADE to patients with hepatic disease. In ITP and refractory SAA patients, a lower starting dose of REVOLADE should be used when administering to patients with hepatic impairment (see Dosage & Administration).
Severe liver injury: Isolated cases of severe liver injury were identified in clinical studies. The elevation of liver laboratory values improved or resolved following REVOLADE interruption or discontinuation. No cases of severe liver injury related to REVOLADE were identified in a clinical study in patients with definitive immunosuppressive therapy-naïve SAA or refractory SAA, however the number of exposed patients in these indications was limited. As the highest authorized dose is administered to patients in SAA indication (150 mg/day) and due to the nature of the reaction, drug induced liver injury might be expected in this patient's population.
If the potential benefit for reinitiating REVOLADE treatment is considered to outweigh the risk for hepatotoxicity, then cautiously reintroduce REVOLADE and measure serum liver tests weekly during the dose adjusted phase. If liver test abnormalities persist, worsen or recur, then permanently discontinue REVOLADE.
Hepatic decompensation in patients with chronic HCV (concomitant use with interferons): Chronic HCV patients with liver cirrhosis may be at risk for hepatic decompensation, some with fatal outcomes, when receiving REVOLADE and alpha interferon therapy. In the two controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) occurred more frequently in the REVOLADE arm (13 %) than in the placebo arm (7 %). In patients with albumin levels ≤ 35 g/L or with a MELD score ≥ 10 at baseline, there was a three-fold greater risk of hepatic decompensation and an increased risk of a fatal adverse event compared to those with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion achieving SVR compared with placebo were modest in these patients (especially for those with baseline albumin ≤ 35 g/L) compared with the group overall. REVOLADE should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation. The respective interferon product information for discontinuation criteria should be referred to. REVOLADE should be terminated if antiviral therapy is discontinued for hepatic decompensation.
Thrombotic/Thromboembolic Complications: Platelet counts above the normal range present a theoretical risk for thrombotic/thromboembolic complications. In REVOLADE clinical studies in ITP thromboembolic events were observed at low and normal platelet counts.
Caution should be used when administering REVOLADE to patients with known risk factors for thromboembolism (e.g., advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity, smoking, Factor V Leiden, ATIII deficiency, and antiphospholipid syndrome). Platelet counts should be closely monitored and consideration given to reducing the dose or discontinuing REVOLADE treatment if the platelet count exceeds the target levels (see Dosage & Administration).
In adult ITP studies, thromboembolic/thrombotic events (TEEs) were observed in 42 out of 763 patients (5.5%). The TEE events included: embolism including pulmonary embolism, deep vein thrombosis, transient ischaemic attack, myocardial infarction, ischaemic stroke, and suspected prolonged reversible ischemic neurologic deficiency. Patients who had a prior history of thrombosis AND at least 2 additional proven risk factors for TEE were excluded from the pivotal studies and therefore the safety of the drug in such patients has not been established.
No cases of TEEs were identified in a clinical study in refractory SAA patients, however the number of exposed patients in this indication was limited. As the highest authorized dose is administered to patients in the SAA indication (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient's population.
In the two controlled Phase III studies in thrombocytopenic patients with HCV (n = 1439, safety population), 31 out of 955 patients (3 %) treated with REVOLADE experienced a TEE and 5 out of 484 patients (1 %) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (1 % in patients treated with REVOLADE versus < 1 % for placebo). No specific temporal relationship between start of treatment and occurrence of TEE was observed. The majority of TEEs resolved and did not lead to the discontinuation of antiviral therapy.
In a controlled study in thrombocytopenic patients with chronic liver disease (n = 288, safety population) undergoing elective invasive procedures, the risk of portal vein thrombosis was increased in patients treated with 75 mg REVOLADE once daily for 14 days. Six of 143 (4 %) adult patients with chronic liver disease receiving REVOLADE experienced TEEs (all of the portal venous system) and two out of 145 (1 %) patients and one within the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five REVOLADE patients with a TEE experienced the event within 14 days of completing REVOLADE dosing and at a platelet count above 200 x 10⁹/L.
REVOLADE is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease undergoing invasive procedures.
QT/QTc prolongation: A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically significant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of these QTc prolongation events is unknown.
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.
Bleeding following discontinuation of REVOLADE: Following discontinuation of REVOLADE in the ITP and HCV settings, platelet counts returned to baseline levels within 2 weeks in the majority of patients (see Pharmacology: Pharmacodynamics: Clinical trials under Actions), which increases the bleeding risk and in some cases may lead to bleeding. Platelet counts must be monitored weekly for 4 weeks following discontinuation of REVOLADE.
Risk of bone marrow fibrosis: Thrombopoietin receptor (TPO-R) agonists, including REVOLADE, may increase the risk for development or progression of reticulin fibres within the bone marrow. Analysis of the bone marrow biopsy data collected in the EXTEND (TRA105325) study (302 patients with chronic ITP who received eltrombopag treatment and were followed for up to 72 months or longer) did not suggest that REVOLADE is associated with clinically relevant increases in bone marrow reticulin or collagen fibres. Analysis of the bone marrow biopsy data collected from 159 patients in study TRA112940 (a longitudinal 2 year bone marrow study of eltrombopag in adults with chronic ITP) suggests that, for most chronic ITP patients, treatment with REVOLADE is not associated with clinically significant increases in bone marrow reticulin or collagen. Four patients in the TRA112940 study had bone marrow biopsies performed at > 14 days after the last dose of study medication to assess the reversibility in fibrosis after stopping REVOLADE. The bone marrow biopsies from half of them demonstrated a lower reticulin fibrosis grade when compared with prior biopsy results.
Prior to initiation of REVOLADE, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of REVOLADE, perform FBC with white blood cell count (WBC) differential monthly. If immature or dysplastic cells are observed, examine peripheral blood smears for new or worsening morphological abnormalities (e.g., teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with REVOLADE and consider a bone marrow biopsy, including staining for fibrosis. Cytogenetic analysis of the bone marrow sample for clonal abnormality should also be considered.
Biennial bone marrow examinations are recommended while patients are receiving eltrombopag treatment until the clinical significance of such findings can be elucidated.
This risk has not been well characterised in children.
Cytogenetic abnormalities: In study ELT112523, bone marrow aspirates were tested for cytogenetic abnormalities by the North American National Institute of Health (NIH). Consistent with the known occurrence of cytogenetic abnormalities in SAA, three out of forty-three patients had a cytogenetic abnormality present at baseline (7 %).
At the Primary Response Assessment, twelve to sixteen weeks after initiating REVOLADE treatment, eight patients (19 %) had a new cytogenetic abnormality detected after treatment. Of these eight patients, five patients (all non-responders) had cytogenetic abnormalities affecting the structure or number of chromosome 7. One patient subsequently developed fatal hypocellular MDS.
Malignancies and progression of malignancies: There is a theoretical concern that thrombopoietin-receptor (TPO-R) agonists may stimulate the progression of existing haematological malignancies such as MDS (see Pharmacology: Toxicology: Preclinical Safety Data: Carcinogenicity under Actions).
The effectiveness and safety of REVOLADE has not been established for the treatment of thrombocytopenia due to MDS. REVOLADE should not be used outside of clinical studies for the treatment of thrombocytopenia due to MDS.
There have been post-marketing cases describing appearance or progression of MDS in patients receiving REVOLADE. However, the information included in the post-marketing reports does not provide sufficient evidence to establish a causal relationship between treatment with REVOLADE and the appearance or worsening of MDS.
Cataracts: Treatment related cataracts were detected in rodents; an effect that was both dose- and time-dependent. Cataract formation was observed after 6 weeks of treatment at systemic exposure ≥ 6 times and 3 times that anticipated in humans in ITP at 75 mg/day and HCV patients at 100 mg/day, respectively (based on plasma AUC). This effect was also evident during long-term (2 years) treatment at systemic exposure 2-5 times the anticipated clinical exposure, with the no-effect-dose level being similar to or below the anticipated clinical exposure level. Cataract formation progressed even after the cessation of treatment. Cataracts have not been observed in dogs after 52 weeks of dosing at 3 times the anticipated clinical exposure in ITP patients at 75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on plasma AUC.
In the three controlled ITP clinical studies, cataracts developed or worsened in 15 (7 %) of patients who received 50 mg REVOLADE daily and 8 (7 %) placebo-group patients. Perform a baseline ocular examination prior to administration of REVOLADE and, during therapy with REVOLADE, regularly monitor patients for signs and symptoms of cataracts.
In the two controlled Phase III studies in thrombocytopenic patients with HCV receiving interferon based therapy (n = 1439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8 % of the REVOLADE group and 5 % of the placebo group.
Routine monitoring of patients for cataracts is recommended.
Interference with serological testing: Eltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum discoloration and interference with total bilirubin and creatinine testing have been reported in patients taking REVOLADE. If the laboratory results and clinical observations are inconsistent, evaluation of contemporaneous aminotransferase values may help in determining the validity of low total bilirubin levels in the presence of clinical jaundice and blood urea should be evaluated in the event of an unexpectedly high serum creatinine. Re-testing using another method may also help in determining the validity of the result.
Photosensitivity: Eltrombopag is phototoxic and photoclastogenic in vitro. In vitro photoclastogenic effects were observed only at drug concentrations that were cytotoxic (≥ 15 μg/mL) in the presence of high ultraviolet (UV) light exposures (700 mJ/cm²). There was no evidence of in vivo cutaneous phototoxicity in mice (10 times the human clinical exposure in ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at 100 mg/day based on AUC) or photo-ocular toxicity in mice or rats (up to 10 and 6 times the human clinical exposure in ITP patients at 75 mg/day and 5 and 3 times the human clinical exposure in HCV patients at 100 mg/day based on AUC). Furthermore, a clinical pharmacology study in 36 patients showed no evidence that photosensitivity was increased following administration of eltrombopag 75 mg once daily for six days. This was measured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled out since no specific preclinical study could be performed.
Use in hepatic impairment: REVOLADE should not be used in patients with hepatic impairment (Child-Pugh score ≥ 5) unless the expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is considered appropriate, caution should be exercised when administering REVOLADE to patients with hepatic impairment (see Dosage & Administration and Adverse Reactions).
Use in renal impairment: Patients with impaired renal function should use REVOLADE with caution and close monitoring, for example by testing serum creatinine and/or performing urine analysis (see Pharmacology: Pharmacokinetics: Special Patient Populations under Actions).
Effects on laboratory tests: Refer to Dosage & Administration and Precautions for information on effects on laboratory tests.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of REVOLADE on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated from the pharmacology of REVOLADE. The clinical status of the patient and the adverse event profile of REVOLADE should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills. The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
Use in Children: Refer to Dosage & Administration, Precautions, Adverse Reactions and Pharmacology: Pharmacokinetics under Actions for information on paediatric patients.
Use in the Elderly: Refer to Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions for information on elderly patients.