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Combination with direct-acting antiviral agents: Safety and efficacy have not been established in combination with direct-acting antiviral agents approved for treatment of chronic hepatitis C infection.
Risk of hepatotoxicity: Revolade administration can cause abnormal liver function and severe hepatotoxicity, which might be life-threatening (see Adverse Reactions).
In a single-arm open-label clinical trial in definitive immunosuppressive therapy-naïve SAA patients who received Revolade concurrently with h-ATG and cyclosporine, 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 refractory SAA study, concurrent ALT or AST >3 x ULN with total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients.
Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin should be measured prior to initiation of Revolade, every 2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. Revolade inhibits UGT1A1 and OATP1B1, which may lead to indirect hyperbilirubinaemia. 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, stabilise, or return to baseline levels. Revolade should be discontinued if ALT levels increase (≥3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or >5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) 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 anemia, 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 17.
Isolated cases of severe liver injury were identified in clinical trials. The elevation of liver laboratory values occurred approximately three months after initiation of Revolade. In all cases, the event resolved following Revolade discontinuation. No cases were identified from clinical trials in refractory SAA, however the number of exposed patients in this indication was limited. As the highest authorized dose is given 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.
Caution is required when administering Revolade to patients with hepatic disease. In ITP and SAA patients a lower starting dose of Revolade should be used. Close monitoring is required when administering to patients with hepatic impairment (see Dosage & Administration).
Hepatic decompensation (use with interferon): Hepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with low albumin levels (≤35 g/l) or with MELD score ≥10 at baseline.
Chronic HCV patients with liver cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 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 (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or with a MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the 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 summary of product characteristics should be referenced for discontinuation criteria. Revolade should be terminated if antiviral therapy is discontinued for hepatic decompensation.
Thrombotic/thromboembolic complications: In controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy (n=1,439), 38 out of 955 patients (4%) treated with Revolade and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Reported thrombotic/thromboembolic complications included both venous and arterial events. The majority of TEEs were non-serious and resolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with Revolade versus <1% for placebo). No specific temporal relationship between start of treatment and event of TEE were observed. Patients with low albumin levels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Revolade should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients should be closely monitored for signs and symptoms of TEE.
The risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated with 75 mg Revolade once daily for 2 weeks in preparation for invasive procedures. Six of 143 (4%) adult patients with CLD receiving Revolade experienced TEEs (all of the portal venous system) and 2 of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous system and one myocardial infarction). Five of the 6 patients treated with Revolade experienced the thrombotic complication at a platelet count >200,000/μl and within 30 days of the last dose of Revolade. Revolade is not indicated for the treatment of thrombocytopenia in patients with chronic liver disease in preparation for invasive procedures.
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 including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. 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). The risk-benefit balance should be considered in patients at risk of TEEs of any aetiology.
No case of TEE was identified from a clinical study in refractory SAA, however the risk of these events cannot be excluded in this patient population due to the limited number of exposed patients. As the highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of the reaction, TEEs might be expected in this patient population.
Revolade should not be used in ITP 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 is required when administering Revolade to patients with hepatic impairment (see Dosage & Administration and Adverse Reactions).
Bleeding following discontinuation of Revolade: Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with Revolade. Following discontinuation of Revolade, platelet counts return to baseline levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may lead to bleeding. This risk is increased if Revolade treatment is discontinued in the presence of anticoagulants or anti-platelet agents. It is recommended that, if treatment with Revolade is discontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following discontinuation of Revolade.
In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal cases, was reported following discontinuation of peginterferon, ribavirin, and Revolade. Following discontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinal bleeding.
Bone marrow reticulin formation and risk of bone marrow fibrosis: Revolade may increase the risk for development or progression of reticulin fibres within the bone marrow. The relevance of this finding, as with other thrombopoietin-receptor (TPO-R) agonists, has not been established yet.
Prior to initiation of Revolade, the peripheral blood smear should be examined closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable dose of Revolade, full blood count (FBC) with white blood cell count (WBC) differential should be performed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be examined 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), treatment with Revolade should be discontinued and a bone marrow biopsy considered, including staining for fibrosis.
Progression of existing myelodysplastic syndrome (MDS): There is a theoretical concern that TPO-R agonists may stimulate the progression of existing haematological malignancies such as MDS. TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is predominantly expressed on the surface of cells of the myeloid lineage.
In clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell counts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) were reported.
The diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion of other clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be excluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the course of the disease and treatment, particularly in patients over 60 years of age, those with systemic symptoms, or abnormal signs such as increased peripheral blast cells.
The effectiveness and safety of Revolade have 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.
Cytogenetic abnormalities and progression to MDS/AML in patients with SAA: Cytogenetic abnormalities are known to occur in SAA patients. It is not known whether Revolade increases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAA clinical study with Revolade with a starting dose of 50 mg/day (escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months.
In the phase II refractory SAA clinical study with Revolade at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of Revolade therapy and one patient had cytogenetic abnormality at Month 6.
In clinical studies with Revolade in SAA, 4% of patients (5/133) were diagnosed with MDS. The median time to diagnosis was 3 months from the start of Revolade treatment.
For SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone marrow examination with aspirations for cytogenetics is recommended prior to initiation of Revolade, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are detected, it must be evaluated whether continuation of Revolade is appropriate.
Ocular changes: Cataracts were observed in toxicology studies of Revolade in rodents (see Pharmacology: Toxicology: Preclinical safety data under Actions). In controlled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1,439), progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the Revolade group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have been reported in HCV patients receiving interferon, ribavirin and Revolade (2% of the Revolade group and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), under the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of patients is recommended.
QT/QTc prolongation: A QTc study in healthy volunteers dosed 150 mg Revolade 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 Revolade: A loss of response or failure to maintain a platelet response with Revolade treatment within the recommended dosing range should prompt a search for causative factors, including an increased bone marrow reticulin.
Interference with laboratory tests: Revolade is highly coloured and so has the potential to interfere with some laboratory tests. Serum discolouration and interference with total bilirubin and creatinine testing have been reported in patients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing using another method may help in determining the validity of the result.
Effects on ability to drive and use machines: Revolade has negligible influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of Revolade, including dizziness and lack of alertness, should be borne in mind when considering the patient's ability to perform tasks that require judgement, motor and cognitive skills.
Use in Children: The previously mentioned warnings and precautions for ITP also apply to the paediatric population.
