Revolade Adverse Reactions

Summary of the safety profile: Chronic ITP Studies in adult and paediatric patients: Adults: The safety and efficacy of REVOLADE was assessed in adult patients using pooled double-blind, placebo controlled studies (TRA102537 RAISE and TRA100773A and B), and TRA113765 in which 403 patients were exposed to REVOLADE and 179 to placebo, in addition to data from completed open label studies TRA108057 (REPEAT), TRA105325 (EXTEND), and TRA112940. Patients received study medication for up to 8 years (in EXTEND).
The most common adverse drug reactions (≥10%) for REVOLADE were diarrhoea, nausea, increased alanine aminotransferase and back pain.
Adverse drug reactions for the adult ITP study population are shown in Table 17.
Paediatrics: The safety and efficacy of REVOLADE in paediatric patients (aged 1 to 17 years) with previously treated chronic ITP have been demonstrated in two studies. PETIT 2 (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 1 (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. Adverse drug reactions in the adult ITP study population (Table 17) may also occur in the pediatric ITP population.
The most common additional adverse drug reactions (≥10%) for REVOLADE were upper respiratory tract infection, pyrexia, abdominal pain, nasopharyngitis and cough. Additional adverse drug reactions occurring in the paediatric adult ITP study population are shown in Table 18.
Thrombocytopenia in patients with HCV infection in adult patients: The safety of REVOLADE was assessed in adult patients, in two controlled studies, including data from patients who initially received REVOLADE in the pre-antiviral treatment phase and were later randomized to the placebo arm. ENABLE 1 (TPL103922, n=716) and ENABLE 2 (TPL108390, n=805) were randomized, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of REVOLADE in thrombocytopenic subjects with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies, the safety population consisted of all randomized subjects who received double-blind study drug during Part 2 of ENABLE 1 (REVOLADE treatment n = 449, placebo n = 232) and ENABLE 2 (REVOLADE treatment n = 506, placebo n = 252). Subjects are analysed according to the treatment received (total safety double-blind population, REVOLADE n = 955 and placebo n = 484).
The most common adverse drug reactions (>10%) for REVOLADE were anaemia, pyrexia, fatigue, headache, nausea, influenza like illness, diarrhea, decreased appetite, asthenia, pruritus, cough, chills, and myalgia.
The adverse reactions identified in the HCV study populations are presented in Table 19.
Definitive immunosuppressive therapy-naïve severe aplastic anaemia in adult and paediatric patients: The safety of REVOLADE administered in combination with horse antithymocyte globulin (h-ATG) and ciclosporin to patients with severe aplastic anaemia 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 Pharmacology: Pharmacodynamics: Clinical trials under Actions). 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 ciclosporin were initiated concurrently at the recommended dose and schedule (the trial's 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 ciclosporin for 6 months, followed by low dose of ciclosporin (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. A summary of the safety profile is provided as follows (see Definitive immunosuppressive therapy-naïve SAA population as follows).
The most common adverse drug reactions (>10%) for REVOLADE 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 12 patients (28 %) were treated for > 6 months and 9 patients (21 %) were treated for > 1 year. The adverse reactions identified in the SAA study population are presented in Table 20 and Table 21.
The most common adverse drug reactions (>10%) for REVOLADE were nausea, fatigue, cough, headache, diarrhoea, pain in extremity, dizziness, oropharyngeal pain, pyrexia, rhinorrhoea, abdominal pain, transaminases increased, arthralgia and muscle spasms.
The most undesirable reactions associated with REVOLADE in ITP, HCV and SAA were mild to moderate in severity, early in onset and rarely treatment limiting.
Tabulated summary of reactions from clinical studies: Adverse reactions from clinical studies are listed as follows by MedDRA body 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 in 10; Common ≥ 1 in 100 and < 1 in 10; Uncommon ≥ 1 in 1,000 and < 1 in 100; Rare ≥ 1 in 10,000 and < 1 in 1,000.
TRA102537 (RAISE): In the RAISE study, 197 patients were randomised 2:1, REVOLADE (n=135) to placebo (n=62). Patients received study medication for up to 6 months. See Table 16.
TRA100773B: In this study, 114 patients were randomised and treated for up to 42 days with either placebo (n = 38) or REVOLADE (n = 76). (See Tables 16 and 17.)

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In 3 controlled and 2 uncontrolled clinical studies, among adult chronic ITP patients receiving REVOLADE (n = 446), 17 subjects 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). (See Tables 18, 19 and 20.)

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In the single-arm, open-label study in SAA, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported, including 5 patients who had changes in chromosome 7 (see Precautions).
Definitive immunosuppressive therapy-naïve SAA population: The adverse drug reaction associated with REVOLADE reported in the definitive immunosuppressive therapy-naïve SAA patients are summarised in Table 21. In definitive immunosuppressive therapy-naïve SAA patients, blood bilirubin increase (very common) was reported more frequently than in the refractory SAA study population (common, see Table 20). (See Table 21.)

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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 the 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. The safety profile in paediatric patients was consistent with the safety profile observed in the overall population.
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 anaemia; 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 out of 92 (7.6%) 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.
Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been reported during post-approval use of REVOLADE (see Table 22). These include spontaneous case reports as well as serious adverse events from registries, investigator sponsored studies, clinical pharmacology studies and exploratory studies in unapproved indications. Because they are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. (See Table 22.)

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Reporting suspected adverse effects: Reporting suspected adverse reactions after registration 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.