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The safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171) (see Pharmacology: Pharmacodynamics under Actions). PETIT2 (TRA115450) was a two-part, double-blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ◆ in Table 19. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea.
Thrombocytopenia with HCV infection in adult patients: ENABLE 1 (TPL103922 n=716, 715 treated with Revolade) and ENABLE 2 (TPL108390 n=805) were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=252). Patients are analysed according to the treatment received (total safety double-blind population, Revolade n=955 and placebo n=484). The most important serious adverse reactions identified were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included headache, anaemia, decreased appetite, cough, nausea, diarrhoea, hyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and oedema.
Definitive immunosuppressive therapy-naïve severe aplastic anemia in adult and paediatric patients: The safety of Revolade administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine to patients with severe aplastic anemia who had not received prior definitive immunosuppressive therapy (i.e., ATG therapy, alemtuzumab, or high dose cyclophosphamide) was evaluated in a single-arm, sequential cohort study (see Clinical studies). A total of 154 patients were enrolled and 153 were dosed in this study, of which 92 patients were enrolled to the cohort where Revolade, h-ATG, and cyclosporine were initiated concurrently at the recommended dose and schedule (Cohort 3 regimen): Revolade up to 150 mg once daily on Day 1 to Month 6 (D1-M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a hematologic response at 6 months. The median duration of exposure to Revolade in this cohort was 183 days with 83.7% of patients exposed for >12 weeks. Adverse drug reactions for the first-line SAA study population (N=92) are shown in Table 21.
The most common adverse drug reactions occurring in at least 10% of patients were alanine aminotransferase increased, aspartate aminotransferase increased, and blood bilirubin increased (including ocular icterus).
Refractory severe aplastic anaemia in adult patients: The safety of Revolade in refractory severe aplastic anaemia was assessed in a single-arm, open-label study (N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (16%) were treated for >1 year (see Pharmacology: Pharmacodynamics under Actions). The most common adverse reactions occurring in at least 10% of patients included headache, dizziness, cough, oropharyngeal pain, rhinorrhoea, nausea, diarrhoea, abdominal pain, transaminases increased, arthralgia, pain in extremity, muscle spasms, fatigue and pyrexia.
List of adverse reactions: The adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV studies (N=1,520), the definitive immunosuppressive therapy-naïve SAA (first-line SAA) study population (N=92), the SAA studies (N=43) and post-marketing reports are listed as follows by MedDRA system organ class and by frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); not known (cannot be estimated from the available data). (See Tables 19, 20 and 21.)
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Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageThe only adverse drug reaction associated with Revolade reported in definitive immunosuppressive therapy-naïve SAA patients not previously reported in the refractory SAA study population is skin discolouration including skin hyperpigmentation (5.4%). In definitive immunosuppressive therapy-naïve SAA patients, blood bilirubin increased was reported more frequently (17.4%) than in the refractory SAA study population.
New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the Revolade D1-M6 cohort were 15.2% and 2.2% for AST, 26.4% and 4.3% for ALT, and 12.1% and 1.1% for bilirubin, respectively.
Paediatric patients: The safety assessment of Revolade in definitive immunosuppressive therapy-naïve paediatric SAA patients 2 to 17 years old is based on 37 patients enrolled in the single-arm, sequential cohort study: 2 patients aged 2 to 5 years, 12 patients aged 6 to 11 years, and 23 patients aged 12 to 17 years (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). The safety profile in paediatric patients was consistent with the safety profile observed in the overall population. (See Table 22.)
Click on icon to see table/diagram/imageDescription of selected adverse reactions: Thrombotic/thromboembolic events (TEEs): In 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving Revolade (n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction (n=2), cerebral infarction (n=2), embolism (n=1) (see Precautions).
In a placebo-controlled study (n=288, Safety population), following 2 weeks' treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving Revolade experienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group experienced 3 TEEs. Five of the 6 patients treated with Revolade experienced the TEE at a platelet count >200 000/μl.
No specific risk factors were identified in those patients who experienced a TEE with the exception of platelet counts ≥200 000/μl (see Precautions).
In controlled studies in thrombocytopenic patients with HCV (n=1,439), 38 out of 955 patients (4%) treated with Revolade experienced a TEE and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with Revolade versus <1% for placebo) (see Precautions). 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.
Hepatic decompensation (use with interferon): Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the Revolade arm (11%) than in the placebo arm (6%). In patients with low albumin levels (≤35 g/l) or 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. 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 (see Precautions).
Hepatotoxicity: In the controlled clinical studies in chronic ITP with Revolade, increases in serum ALT, AST and bilirubin were observed (see Precautions).
These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in adults with chronic ITP, 1 patient in the placebo group and 1 patient in the Revolade group experienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT ≥3 x ULN was reported in 4.7% and 0% of the Revolade and placebo groups, respectively.
In 2 controlled clinical studies in patients with HCV, ALT or AST ≥3 x ULN was reported in 34% and 38% of the Revolade and placebo groups, respectively. Most patients receiving Revolade in combination with peginterferon/ribavirin therapy will experience indirect hyperbilirubinaemia. Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the Revolade and placebo groups, respectively.
In the single-arm phase II monotherapy refractory SAA study, 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.
Thrombocytopenia following discontinuation of treatment: In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8% and 8% of the Revolade and placebo groups, respectively (see Precautions).
Increased bone marrow reticulin: Across the programme, no patients had evidence of clinically relevant bone marrow abnormalities or clinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, Revolade treatment was discontinued due to bone marrow reticulin (see Precautions).
Cytogenetic abnormalities: In the single-arm study in patients with definitive immunosuppressive therapy-naïve SAA, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. In the entire study across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality, 7 patients had the loss of chromosome 7, six of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13, which is considered a good prognostic factor in aplastic anemia; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. In the Revolade D1-M6 cohort, 7 patients had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7, occurring within 6.1 months. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with Revolade.
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.
Haematologic malignancies: In the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following treatment with Revolade, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and 1/62 (2%) patient has been diagnosed with MDS or AML in each study.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed.
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