Tibsovo Adverse Reactions

Newly diagnosed acute myeloid leukaemia in combination with azacitidine: Summary of the safety profile: The most common adverse reactions were vomiting (40%), neutropenia (31%), thrombocytopenia (28%), electrocardiogram QT prolonged (21%), insomnia (19%).
The most common serious adverse reactions were differentiation syndrome (8%) and thrombocytopenia (3%).
In patients treated with ivosidenib in combination with azacitidine, the frequency of discontinuation of ivosidenib due to adverse reactions was 6%. Adverse reactions leading to discontinuation were electrocardiogram QT prolonged (1%), insomnia (1%), neutropenia (1%) and thrombocytopenia (1%).
The frequency of dose interruption of ivosidenib due to adverse reactions was 35%. The most common adverse reactions leading to dose interruption were neutropenia (24%), electrocardiogram QT prolonged (7%), thrombocytopenia (7%), leukopenia (4%) and differentiation syndrome (3%).
The frequency of dose reduction of ivosidenib due to adverse reactions was 19%. Adverse reactions leading to dose reduction were electrocardiogram QT prolonged (10%), neutropenia (8%) and thrombocytopenia (1%).
Tabulated list of adverse reactions: The frequencies of adverse reactions are based on Study AG120-C-009 which included 72 patients with newly diagnosed AML randomised to and treated with ivosidenib (500 mg daily) in combination with azacitidine. The median duration of treatment with Tibsovo was 8 months (range 0.1 to 40.0 months). The adverse reaction frequencies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than ivosidenib, such as the disease, other medicinal products or unrelated causes.
Frequencies are defined as: 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); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. (See Table 4.)

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Previously treated, locally advanced or metastatic cholangiocarcinoma: Summary of the safety profile: The most common adverse reactions were fatigue (43%), nausea (42%), abdominal pain (35%), diarrhoea (35%), decreased appetite (24%), ascites (23%), vomiting (23%), anaemia (19%) and rash (15%).
The most common serious adverse reactions were ascites (2%), hyperbilirubinemia (2%), and jaundice cholestatic (2%).
In patients treated with ivosidenib, the frequency of treatment discontinuation due to adverse reactions was 2%. Adverse reactions leading to discontinuation were ascites (1%) and hyperbilirubinemia (1%).
The frequency of dose interruption of ivosidenib due to adverse reactions was 16%. The most common adverse reactions leading to dose interruption were hyperbilirubinemia (3%), alanine aminotransferase increased (3%), aspartate aminotransferase increased (3%), ascites (2%) and fatigue (2%).
The frequency of dose reduction of ivosidenib due to adverse reactions was 4%. Adverse reactions leading to dose reduction were electrocardiogram QT prolonged (3%) and neuropathy peripheral (1%).
Tabulated list of adverse reactions: The frequencies of adverse reactions are based on Study AG120-C-005 which included 123 patients with previously treated, locally advanced or metastatic cholangiocarcinoma, randomised to and treated with 500 mg ivosidenib once daily. The median duration of treatment with Tibsovo was 2.8 months (range 0.1 to 45.1 months; mean (standard deviation [SD]) 6.7 (8.2) months).
The adverse reaction frequencies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have other causes than ivosidenib, such as the disease, other medicinal products or unrelated causes.
Frequencies are defined as: 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); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. (See Table 5.)

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Description of selected adverse reactions: Differentiation syndrome in patients with acute myeloid leukaemia (see Dosage & Administration and Precautions): In study AG120-C-009, in the 72 patients with newly diagnosed AML treated with Tibsovo in combination with azacitidine, 14% experienced differentiation syndrome. No patient discontinued ivosidenib treatment due to differentiation syndrome and dose interruptions (3%) to manage signs/symptoms were required in a minority of patients. Of the 10 patients who experienced differentiation syndrome, all recovered after treatment or after dose interruption of Tibsovo. The median time to onset of differentiation syndrome was 20 days. Differentiation syndrome occurred as early as 3 days and up to 46 days after treatment initiation during combination therapy.
QTc interval prolongation (see Dosage & Administration, Precautions and Interactions): In Study AG120-C-009, in the 72 patients with newly diagnosed AML treated with ivosidenib in combination with azacitidine, electrocardiogram QT prolonged was reported in 21%; 11% experienced Grade 3 or higher reactions. Based on the analysis of the ECGs, 15% of patients treated with ivosidenib in combination with azacitidine, who had at least one post-baseline ECG assessment, were found to have a QTc interval ˃500 msec, 24% had an increase from baseline QTc ˃60 msec. One percent (1%) of patients discontinued ivosidenib treatment due to electrocardiogram QT prolonged, dose interruption and reduction were required in 7% and 10% of patients, respectively. The median time to onset of QT prolongation in patients treated with ivosidenib was 29 days. Electrocardiogram QT prolonged occurred as early as 1 day and up to 18 months after treatment initiation.
In Study AG120-C-005, in the 123 patients with locally advanced or metastatic cholangiocarcinoma treated with ivosidenib monotherapy, electrocardiogram QT prolonged was reported in 10%; 2% experienced Grade 3 or higher reactions. Based on the analysis of the ECGs, 2% of patients had a QTc interval ˃500 msec and 5% QTc interval prolongation ˃60 msec from baseline. Dose reduction to manage signs/symptoms was required in 3% of patients. The median time to onset of QT prolongation in patients treated with ivosidenib monotherapy was 28 days. Electrocardiogram QT prolonged occurred as early as 1 day and up to 23 months after treatment initiation.
Special populations: Hepatic impairment: The safety and efficacy of ivosidenib have not been established in patients with moderate and severe hepatic impairment (Child-Pugh classes B and C). A trend to a higher incidence of adverse reactions was observed in patients with mild hepatic impairment (Child-Pugh class A) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
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 in Appendix V.