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Safety profile

TIBSOVO (ivosidenib tablets) safety profile

The most common adverse reactions (≥15%) in patients with advanced mIDH1 cholangiocarcinoma (CCA) were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash.1

Adverse reactions reported in ≥10% of patients receiving TIBSOVO1

  TIBSOVO (500 mg daily)
n=123		 Placebo
n=59
Body system
Adverse reaction		 All grades
n (%) 		Grade ≥3
n (%) 		All grades
n (%) 		Grade ≥3
n (%)
General disorders and administration site conditions
Fatiguea 53 (43) 4 (3) 18 (31) 3 (5)
Gastrointestinal disorders
Nausea 51 (41) 3 (2) 17 (29) 1 (2)
Diarrhea 43 (35) 0 10 (17) 0
Abdominal painb 43 (35) 3 (2) 13 (22) 2 (3)
Ascites 28 (23) 11 (9) 9 (15) 4 (7)
Vomitingc 28 (23) 3 (2) 12 (20) 0
Respiratory, thoracic, and mediastinal disorders
Coughd 33 (27) 0 5 (9) 0
Metabolism and nutrition disorders
Decreased appetite 30 (24) 2 (2) 11 (19) 0
Blood and lymphatic system disorders
Anemia 22 (18) 8 (7) 3 (5) 0
Skin and subcutaneous tissue disorders
Rashe 19 (15) 1 (1) 4 (7) 0
Nervous system disorders
Headache 16 (13) 0 4 (7) 0
Neuropathy peripheralf 13 (11) 0 0 0
Investigations
Electrocardiogram QT prolonged 12 (10) 2 (2) 2 (3) 0

a Grouped term includes asthenia and fatigue.

b Grouped term includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, epigastric discomfort, abdominal tenderness, and gastrointestinal pain.

c Grouped term includes vomiting and retching.

d Grouped term includes cough and productive cough.

e Grouped term includes rash, rash maculo-papular, erythema, rash macular, dermatitis exfoliative generalized, drug eruption, and drug hypersensitivity.

f Grouped term includes neuropathy peripheral, peripheral sensory neuropathy, and paraesthesia.

Selected laboratory abnormalities reported in ≥10% of patients receiving TIBSOVO1,g

  TIBSOVO (500 mg daily)
n=123		 Placebo
n=59
Parameter All grades
n (%) 		Grade ≥3
n (%) 		All grades
n (%) 		Grade ≥3
n (%)
Aspartate aminotransferanse increased 41 (34) 5 (4) 14 (24) 1 (2)
Bilirubin increased 36 (30) 15 (13) 11 (19) 2 (3)
Hemoglobin decreased 48 (40) 8 (7) 14 (25) 0

gLaboratory abnormality is defined as new or worsened by at least one grade from baseline, or baseline is unknown.1

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Dose modifications

Dose modifications1

Dose reductions, interruptions, and discontinuations due to adverse events1
  • Dose interruptions due to adverse reactions occurred in 29% of patients treated with TIBSOVO
    • The most common (>2%) adverse reactions leading to dose interruption were hyperbilirubinemia, alanine aminotransferase increased, aspartate aminotransferase increased, ascites, and fatigue
  • Dose reductions of TIBSOVO due to an adverse reaction occurred in 4.1% of patients
    • Adverse reactions leading to dose reduction were electrocardiogram QT prolonged (3.3%) and neuropathy peripheral (0.8%)
  • TIBSOVO was permanently discontinued in 7% of patients
    • The most common adverse reaction leading to permanent discontinuation was acute kidney injury (1.6%)
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Dose intensity

In the ClarIDHy trial, median relative dose intensity was 100% across all patients2

  • Relative dose intensity is the amount of medication taken over a specific period of time in relation to what was prescribedh
  • There were few occurrences of missed dose modifications, indicating excellent overall compliance

hRelative Dose Intensity (%) was calculated as: [Actual Dose Intensity] / [Planned Dose Intensity]. Planned Dose Intensity (mg/day) is the total daily dose assigned at the study entry, which was 500 mg QD.

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Warnings & precautions

Warnings and precautions1

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

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Learn about TIBSOVO dosing

References: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022. 2. Data on file. Servier Pharmaceuticals LLC.

 

TIBSOVO® (ivosidenib tablets) was studied in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial—one of the largest clinical trials to date of a targeted therapy in cholangiocarcinoma1-3

cca-efficacy-modal cca-efficacy-modal

CCA, cholangiocarcinoma; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IDH1, isocitrate dehydrogenase-1; mIDH1, mutated IDH1; NGS, next-generation sequencing; QD, once a day; RECIST, Response Evaluation Criteria in Solid Tumors.

References: 1. Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2022. 2. Data on file. Servier Pharmaceuticals LLC. 3. Zhu AX, Macarulla T, Javle MM, et al. Final results from the ClarIDHy Phase III study of ivosidenib versus placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 (IDH1) mutation. EMJ Oncol. 2021;9(suppl 2):2-5. doi:10.1200/JCO.2021.39.3_suppl.266

TIBSOVO® was studied in a patient population reflective of that seen in a clinical practice1,2

Selected baseline demographics and disease characteristics (N=185)1

  TIBSOVO
(n=124)		 Placebo
(n=61)
Demographics
Median age, years (min, max) 61 (33,80) 63 (40,83)
Sex
Male 36% 40%
Female 65% 61%
Race
White 57% 57%
Asian 12% 13%
Black 0.8% 1.6%
Native Hawaiian/Other Pacific Islander 0.8% 0%
American Indian or Alaska Native 0.8% 0
Disease characteristics
Prior lines of therapy
1 prior line of therapy 53% 54%
2 prior lines of therapy 47% 46%
ECOG PS
0 40% 31%
1 60% 67%
IDH1 mutation
R132C 68% 74%
R132L 17% 12%
R132G 14% 10%
R132H 0% 3.3%
R132S 1.6% 1.6%
Cholangiocarcinoma type at initial diagnosis
Intrahepatic 90% 95%
Metastatic disease 93% 92%

ECOG PS: Eastern Cooperative Oncology Group Performance Status.

References: 1.  Tibsovo. Package insert. Servier Pharmaceuticals LLC; 2023. 2. Data on file. Servier Pharmaceuticals LLC.

 

Indication

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

  • In patients with cholangiocarcinoma, the most common adverse reactions (≥15%) were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. The most common laboratory abnormalities (≥10%) were hemoglobin decreased, aspartate aminotransferase increased, and bilirubin increased.

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Advise women not to breastfeed.

Please see Full Prescribing Information.

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Indication & Important Safety Information

INDICATION

TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (eg, anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.