TIBSOVO Film-coated tablet Ref.[109170] Active ingredients: Ivosidenib

Differentiation syndrome in patients with acute myeloid leukaemia

Differentiation syndrome has been reported following treatment with ivosidenib (see section 4.8). Differentiation syndrome may be life-threatening or fatal if not treated (see below and section 4.2). Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. Symptoms include: non-infectious leukocytosis, peripheral oedema, pyrexia, dyspnoea, pleural effusion, hypotension, hypoxia, pulmonary oedema, pneumonitis, pericardial effusion, rash, fluid overload, tumour lysis syndrome and creatinine increased.

Patients must be informed of signs and symptoms of differentiation syndrome, be advised to contact their physician immediately if these occur and the need to carry the Patient Alert Card with them at all times.

If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days.

If leukocytosis is observed, initiate treatment with hydroxycarbamide according to institutional standards of care and leukapheresis as clinically indicated (see section 4.5).

Taper corticosteroids and hydroxycarbamide only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxycarbamide treatment. Interrupt treatment with Tibsovo if severe signs/symptoms persist for more than 48 hours after the initiation of systemic corticosteroids and resume treatment at 500 mg ivosidenib once daily when the signs/symptoms are moderate or lower and upon improvement in the patient’s clinical condition.

QTc interval prolongation

QTc interval prolongation has been reported following treatment with ivosidenib (see section 4.8). An ECG must be performed prior to treatment initiation, at least weekly during the first 3 weeks of therapy and then monthly thereafter if the QTc interval remains ≤ 480 msec (see section 4.2). Any abnormalities should be managed promptly (see section 4.2). In case of suggestive symptomatology, an ECG should be performed as clinically indicated. In case of severe vomiting and/or diarrhoea, an assessment of serum electrolytes abnormalities, especially hypokalaemia and magnesium, must be performed.

Patients should be informed of the risk of QT prolongation, its signs and symptoms (palpitation, dizziness, syncope or even cardiac arrest) and be advised to contact their physician immediately if these occur.

Concomitant administration of medicinal products known to prolong the QTc interval, or moderate or strong CYP3A4 inhibitors may increase the risk of QTc interval prolongation and should be avoided whenever possible during treatment with Tibsovo. Patients should be treated with caution and closely monitored for QTc interval prolongation if use of a suitable alternative is not possible. ECG should be performed prior to co-administration, weekly monitoring for at least 3 weeks and then as clinically indicated. The recommended dose of ivosidenib should be reduced to 250 mg once daily if use of moderate or strong CYP3A4 inhibitors cannot be avoided (see sections 4.2 and 4.5).

If administration of furosemide (an OAT3 substrate) is clinically indicated to manage signs/symptoms of differentiation syndrome, patients should be closely monitored for electrolyte imbalances and QTc interval prolongation.

Patients with congestive heart failure or electrolyte abnormalities should be monitored closely, with periodic monitoring of ECGs and electrolytes, during treatment with ivosidenib. Treatment with Tibsovo should be permanently discontinued if patients develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia (see section 4.2).

Ivosidenib should be used with caution in patients who have either albumin levels below the normal range or are underweight.

Severe renal impairment

The safety and efficacy of ivosidenib have not been established in patients with severe renal impairment (eGFR ˂30 mL/min/1.73 m²). Tibsovo should be used with caution in patients with severe renal impairment and this patient population should be closely monitored (see sections 4.2 and 5.2).

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). Tibsovo should be used with caution in patients with moderate and severe hepatic impairment and this patient population should be closely monitored (see sections 4.2 and 5.2).

Tibsovo should be used with caution in patients with mild hepatic impairment (Child-Pugh class A) (see section 4.8).

CYP3A4 substrates

Ivosidenib induces CYP3A4 and it may, therefore, decrease systemic exposure to CYP3A4 substrates. Patients should be monitored for loss of antifungal efficacy if use of itraconazole or ketoconazole cannot be avoided (see section 4.5).

Women of childbearing potential/contraception

Women of childbearing potential should have a pregnancy test prior to starting treatment with Tibsovo and should avoid becoming pregnant during therapy (see section 4.6).

Women of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment with Tibsovo and for at least 1 month after the last dose.

Ivosidenib may decrease the systemic concentrations of hormonal contraceptives and, therefore, concomitant use of a barrier method of contraception is recommended (see sections 4.5 and 4.6).

Lactose intolerance

Tibsovo contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should avoid this medicinal product.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effect of other medicinal products on ivosidenib

Strong CYP3A4 inducers

Ivosidenib is a CYP3A4 substrate. Concomitant administration of strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum)) is expected to decrease plasma concentrations of ivosidenib and is contraindicated during treatment with Tibsovo (see section 4.3). Clinical studies evaluating the pharmacokinetics of ivosidenib in the presence of a CYP3A4 inducer have not been conducted.

Moderate or strong CYP3A4 inhibitors

In healthy subjects, administration of a single dose of 250 mg ivosidenib and 200 mg itraconazole once daily for 18 days increased the ivosidenib AUC by 169% (90% CI: 145, 195) with no change in C_max. Concomitant administration of moderate or strong CYP3A4 inhibitors increases plasma concentrations of ivosidenib. This may increase the risk of QTc interval prolongation and suitable alternatives that are not moderate or strong CYP3A4 inhibitors should be considered whenever possible during treatment with Tibsovo. Patients should be treated with caution and closely monitored for QTc interval prolongation if use of a suitable alternative is not possible. If use of moderate or strong CYP3A4 inhibitors cannot be avoided, the recommended dose of ivosidenib should be reduced to 250 mg once daily (see sections 4.2 and 4.4).

• Moderate CYP3A4 inhibitors include: aprepitant, ciclosporin, diltiazem, erythromycin, fluconazole, grapefruit and grapefruit juice, isavuconazole, verapamil.
• Strong CYP3A4 inhibitors include: clarithromycin, itraconazole, ketoconazole, posaconazole, ritonavir, voriconazole.

Medicinal products known to prolong the QTc interval

Concomitant administration of medicinal products known to prolong the QTc interval (e.g. anti-arrhythmics, fluoroquinolones, 5-HT₃ receptor antagonists, triazole antifungals) may increase the risk of QTc interval prolongation and should be avoided whenever possible during treatment with Tibsovo. Patients should be treated with caution and closely monitored for QTc interval prolongation if use of a suitable alternative is not possible (see sections 4.2 and 4.4).

Effect of ivosidenib on other medicinal products

Interactions with transporters

Ivosidenib inhibits P-gp and has the potential to induce P-gp. Therefore, it may alter systemic exposure to active substances that are predominantly transported by P-gp (e.g. dabigatran). Concomitant administration of dabigatran is contraindicated (see section 4.3).

Ivosidenib inhibits OAT3, organic anion-transporting polypeptide 1B1 (OATP1B1) and organic anion-transporting polypeptide 1B3 (OATP1B3). Therefore, it may increase systemic exposure to OAT3 or OATP1B1/1B3 substrates. Concomitant administration of OAT3 substrates (e.g. benzylpenicillin, furosemide) or sensitive OATP1B1/1B3 substrates (e.g. atorvastatin, pravastatin, rosuvastatin) should be avoided whenever possible during treatment with Tibsovo (see section 5.2). Patients should be treated with caution if use of a suitable alternative is not possible. If administration of furosemide is clinically indicated to manage signs/symptoms of differentiation syndrome, patients should be closely monitored for electrolyte imbalances and QTc interval prolongation.

Enzyme induction

Cytochrome P450 (CYP) enzymes

Ivosidenib induces CYP3A4, CYP2B6, CYP2C8, CYP2C9 and may induce CYP2C19. Therefore, it may decrease systemic exposure to substrates of these enzymes. Suitable alternatives that are not CYP3A4, CYP2B6, CYP2C8 or CYP2C9 substrates with a narrow therapeutic index, or CYP2C19 substrates should be considered during treatment with Tibsovo. Patients should be monitored for loss of substrate efficacy if use of such medicinal products cannot be avoided (see section 5.2).

• CYP3A4 substrates with a narrow therapeutic index include: alfentanil, ciclosporin, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus.
• CYP2B6 substrates with a narrow therapeutic index include: cyclophosphamide, ifosfamide, methadone.
• CYP2C8 substrates with a narrow therapeutic index include: paclitaxel, pioglitazone, repaglinide.
• CYP2C9 substrates with a narrow therapeutic index include: phenytoin, warfarin.
• CYP2C19 substrates include: omeprazole.

Itraconazole or ketoconazole should not be used concomitantly with Tibsovo due to the expected loss of antifungal efficacy.

Ivosidenib may decrease the systemic concentrations of hormonal contraceptives and, therefore, concomitant use of a barrier method of contraception is recommended for at least 1 month after the last dose (see sections 4.4 and 4.6).

Uridine diphosphate glucuronosyltransferases (UGTs)

Ivosidenib has the potential to induce UGTs and it may, therefore, decrease systemic exposure to substrates of these enzymes (e.g. lamotrigine, raltegravir). Suitable alternatives that are not UGT substrates should be considered during treatment with Tibsovo. Patients should be monitored for loss of UGT substrate efficacy if use of such medicinal products cannot be avoided (see section 5.2).

Women of childbearing potential/Contraception

Women of childbearing potential should have a pregnancy test prior to starting treatment with Tibsovo and should avoid becoming pregnant during therapy (see section 4.4).

Women of childbearing potential and males with female partners of childbearing potential should use effective contraception during treatment with Tibsovo and for at least 1 month after the last dose.

Ivosidenib may decrease the systemic concentrations of hormonal contraceptives and, therefore, concomitant use of an alternative contraceptive method such as barrier contraceptives is recommended (see sections 4.4 and 4.5).

Pregnancy

There are no adequate data on the use of ivosidenib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Tibsovo is not recommended for use during pregnancy and in women of childbearing potential not using effective contraception. Patients should be informed of the potential risk to the foetus if it is used during pregnancy or if a patient (or female partner of a treated male patient) becomes pregnant during treatment or during the one-month period after the last dose.

Breast-feeding

It is unknown whether ivosidenib and its metabolites are excreted in human milk. No studies in animals have been conducted to evaluate the excretion of ivosidenib and its metabolites in milk. A risk to the newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with Tibsovo and for at least 1 month after the last dose.

Fertility

There are no human data on the effect of ivosidenib on fertility. No fertility studies in animals have been conducted to evaluate the effect of ivosidenib. Undesirable effects on reproductive organs were observed in a 28-day repeat-dose toxicity study (see section 5.3). The clinical relevance of these effects is unknown.

Ivosidenib has minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported in some patients taking ivosidenib (see section 4.8) and should be considered when assessing a patient’s ability to drive or operate machines.

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.

Table 2. Adverse drug reactions reported in patients with newly diagnosed AML treated with ivosidenib in combination with azacitidine in clinical study AG120-C-009 (N=72):

¹ Grouped term includes vomiting and retching.

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.

Table 3. Adverse drug reactions reported in patients with locally advanced or metastatic cholangiocarcinoma treated with ivosidenib in clinical study AG120-C-005 (N=123):

¹ Grouped term includes rash, rash maculo-papular, erythema, rash macular, dermatitis exfoliative generalized, drug eruption, and drug hypersensitivity.

Description of selected adverse reactions

Differentiation syndrome in patients with acute myeloid leukaemia (see sections 4.2 and 4.4)

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 sections 4.2, 4.4 and 4.5)

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 sections 4.2 and 5.2.).

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.

Not applicable.