Ivosidenib

Ivosidenib is an inhibitor of the mutant isocitrate dehydrogenase-1 (IDH1) enzyme. Normal IDH1 converts isocitrate to alpha-ketoglutarate (α-KG). In cancers with an IDH1 R132 mutation, the enzyme gains a new activity and converts α-KG to the oncometabolite 2-hydroxyglutarate (2-HG), which blocks cellular differentiation and promotes tumour development in both haematologic and non-haematologic malignancies.

Mechanism of Action

• Mutant IDH1 inhibition: ivosidenib inhibits the mutant enzyme at much lower concentrations than the wild-type enzyme.
• Lower 2-HG: with 500 mg once daily, plasma 2-HG in patients with mutated IDH1 fell to levels close to those of healthy subjects. The mean reduction in 2-HG was 93.1% in bone marrow (haematological malignancies) and 82.2% in tumour biopsies (cholangiocarcinoma).
• Differentiation: in models of IDH1-mutated AML, ivosidenib induced myeloid differentiation. How it acts beyond lowering 2-HG and restoring differentiation is not fully understood across indications.
• QTc effect: a concentration-dependent QTc prolongation of about 17.2 msec at steady-state peak concentration with 500 mg once daily was predicted in 173 patients with AML and observed in 101 patients with cholangiocarcinoma.

Pharmacokinetics

• Absorption: the median time to peak concentration is about 2 hours after a single 500 mg dose. At steady state with 500 mg daily, the mean peak concentration was 6,145 ng/mL in newly diagnosed AML with azacitidine and 4,799 ng/mL in cholangiocarcinoma. Over one month the accumulation was about 1.6-fold for AUC and 1.2-fold for peak concentration in AML, and about 1.5-fold and 1.2-fold in cholangiocarcinoma; steady state is reached within 14 days. A high-fat meal raised the peak concentration by about 98% and the AUC by about 25% in healthy subjects.
• Distribution: the mean apparent volume of distribution at steady state is 3.20 L/kg in AML with azacitidine and 2.97 L/kg in cholangiocarcinoma. In vitro, 92–96% is bound to plasma proteins.
• Metabolism: mainly by oxidation, largely through CYP3A4, with minor N-dealkylation and hydrolysis; ivosidenib is the predominant component (over 92%) of plasma radioactivity in healthy subjects. It induces CYP3A4 (including its own metabolism), CYP2B6, CYP2C8 and CYP2C9, and may induce CYP2C19 and UGTs.
• Elimination: in healthy subjects 77% of a single oral dose was found in faeces (67% unchanged) and about 17% in urine (10% unchanged). At steady state the mean apparent clearance was 4.6 L/h with a mean terminal half-life of 98 hours in AML with azacitidine, and 6.1 L/h with 129 hours in cholangiocarcinoma.
• Special populations: see Administration and Dosage for kidney and liver impairment; a trend towards more adverse reactions was seen in mild hepatic impairment.

• Newly diagnosed AML, in combination with azacitidine: adults with newly diagnosed acute myeloid leukaemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive standard induction chemotherapy.
• Cholangiocarcinoma, as monotherapy: adults with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy.
• In both indications, an IDH1 R132 mutation must be confirmed with an appropriate diagnostic test before treatment (see Special Instructions).

• Hypersensitivity to the active substance or to any of the excipients.
• Concomitant use of strong CYP3A4 inducers or of dabigatran.
• Congenital long QT syndrome.
• Family history of sudden death or polymorphic ventricular arrhythmia.
• QT/QTc interval above 500 msec, regardless of the correction method.

In newly diagnosed AML (ivosidenib with azacitidine, 72 patients) the most common reactions were vomiting (40%), neutropenia (31%), thrombocytopenia (28%), QT prolongation on the ECG (21%) and insomnia (19%); the most common serious reactions were differentiation syndrome (8%) and thrombocytopenia (3%). In previously treated cholangiocarcinoma (ivosidenib alone, 123 patients) they 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 reactions were ascites, hyperbilirubinaemia and cholestatic jaundice (2% each). The frequencies count all-cause events, so some may have other causes such as the disease or other medicines.

Very common (≥1/10): in AML with azacitidine, differentiation syndrome, leukocytosis, thrombocytopenia, neutropenia, insomnia, headache, dizziness, vomiting (including retching), pain in an extremity, arthralgia, back pain and QT prolongation on the ECG; in cholangiocarcinoma, anaemia, decreased appetite, peripheral neuropathy, headache, ascites, diarrhoea, vomiting, nausea, abdominal pain, rash (a grouped term), fatigue, raised aspartate aminotransferase and raised blood bilirubin.

Common (≥1/100 to <1/10): in AML with azacitidine, leukopenia, peripheral neuropathy and oropharyngeal pain; in cholangiocarcinoma, cholestatic jaundice, hyperbilirubinaemia, falls, QT prolongation on the ECG, raised alanine aminotransferase, decreased white blood cell count and decreased platelet count.

The SmPC tables list no reactions in the less frequent categories.

Important reactions:

• Differentiation syndrome occurred in 14% of the 72 AML patients, at a median of 20 days after starting (as early as day 3 and up to day 46). No patient stopped ivosidenib because of it, and all 10 affected patients recovered after treatment or a dose interruption.
• QT prolongation on the ECG was reported in 21% of AML patients treated with azacitidine (11% grade 3 or higher), and 15% of those with a post-baseline ECG had a QTc interval above 500 msec; in cholangiocarcinoma it was reported in 10% (2% grade 3 or higher). The median time to onset was about 29 and 28 days, and it occurred from day 1 up to 18 and 23 months after starting.
• Treatment changes: because of adverse reactions, ivosidenib was stopped in 6%, interrupted in 35% and reduced in 19% of AML patients, and stopped in 2%, interrupted in 16% and reduced in 4% of cholangiocarcinoma patients.
• Hepatic impairment: a trend towards a higher incidence of adverse reactions was seen in mild impairment (Child-Pugh class A).

• Strong CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin, rifampicin, St John’s wort): expected to lower ivosidenib concentrations; contraindicated.
• Moderate or strong CYP3A4 inhibitors: itraconazole (200 mg daily for 18 days) raised the AUC of a single 250 mg ivosidenib dose by 169% in healthy subjects with no change in peak concentration. These inhibitors can increase the risk of QTc prolongation, so alternatives should be considered; if they cannot be avoided, reduce ivosidenib to 250 mg once daily and monitor the QTc interval. Moderate inhibitors include aprepitant, ciclosporin, diltiazem, erythromycin, fluconazole, grapefruit and grapefruit juice, isavuconazole, verapamil and atazanavir; strong inhibitors include clarithromycin, itraconazole, ketoconazole, posaconazole, ritonavir and voriconazole.
• QTc-prolonging medicines (for example anti-arrhythmics, fluoroquinolones, 5-HT3 receptor antagonists, triazole antifungals): avoid where possible; if there is no alternative, monitor the QTc interval closely.
• Dabigatran and other P-gp substrates: ivosidenib inhibits P-gp and may also induce it. Dabigatran is contraindicated.
• OAT3 and OATP1B1/1B3 substrates: ivosidenib inhibits these transporters and may raise exposure to OAT3 substrates (benzylpenicillin, furosemide) and sensitive OATP1B1/1B3 substrates (atorvastatin, pravastatin, rosuvastatin). Avoid where possible; use caution if no alternative exists. If furosemide is needed to manage differentiation syndrome, monitor electrolytes and the QTc interval.
• CYP and UGT induction: ivosidenib induces CYP3A4, CYP2B6, CYP2C8 and CYP2C9 and may induce CYP2C19 and UGTs, lowering exposure to their substrates. Suitable alternatives should be considered, and loss of efficacy monitored, for narrow-therapeutic-index substrates such as alfentanil, fentanyl, ciclosporin, everolimus, pimozide, quinidine, sirolimus, tacrolimus, atazanavir (CYP3A4); cyclophosphamide, ifosfamide, methadone (CYP2B6); paclitaxel, pioglitazone, repaglinide (CYP2C8); phenytoin, warfarin (CYP2C9); and for omeprazole (CYP2C19) and UGT substrates such as lamotrigine and raltegravir.
• Itraconazole and ketoconazole should not be used with Tibsovo because their antifungal efficacy is expected to be lost.
• Hormonal contraceptives: concentrations may fall; a barrier method is recommended for at least 1 month after the last dose.
• Food: a high-fat meal raises exposure, so nothing is eaten for 2 hours before and 1 hour after the tablets. Grapefruit and grapefruit juice must be avoided.

Treatment should be started under the supervision of physicians experienced in the use of anti-cancer medicinal products. Before taking Tibsovo, patients must have confirmation of an IDH1 R132 mutation using an appropriate diagnostic test. The tablets are taken once daily at about the same time each day, swallowed whole with water, with nothing to eat for 2 hours before and through 1 hour after the dose. Patients should not swallow the silica gel desiccant found in the tablet bottle.

Recommended Dose

• Acute myeloid leukaemia: 500 mg (2 × 250 mg tablets) orally once daily on days 1–28 of each cycle, started on cycle 1 day 1 together with azacitidine 75 mg/m² of body surface area, given intravenously or subcutaneously once daily on days 1–7 of each 28-day cycle. The first azacitidine cycle is given at 100% of the dose. Treatment for a minimum of 6 cycles is recommended and continues until disease progression or until it is no longer tolerated. Azacitidine is dosed according to its own product information.
• Cholangiocarcinoma: 500 mg (2 × 250 mg tablets) orally once daily, continued until disease progression or until it is no longer tolerated.

Monitoring Before and During Treatment

• An ECG must be performed before starting. The heart-rate-corrected QT interval (QTc) should be below 450 msec before starting; if the QT is abnormal, the benefit/risk of starting should be thoroughly reassessed. With QTc prolongation between 480 msec and 500 msec, starting should remain exceptional and be accompanied by close monitoring.
• ECGs are repeated at least weekly during the first 3 weeks and then monthly if the QTc interval remains 480 msec or less, and whenever symptoms suggest a problem. QTc abnormalities should be managed promptly; the SmPC gives the dose modifications for QTc prolongation and other adverse reactions in its dose-modification table.

Dose Adjustments

• Moderate or strong CYP3A4 inhibitors that cannot be avoided: reduce to 250 mg once daily, with an ECG before co-administration, weekly monitoring for at least 3 weeks and then as clinically indicated.
• Differentiation syndrome: interrupt Tibsovo if severe signs or symptoms persist for more than 48 hours after systemic corticosteroids were started, and resume at 500 mg once daily when they are moderate or lower and the clinical condition has improved.
• QTc prolongation with signs or symptoms of life-threatening arrhythmia: discontinue permanently.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years or older; there are no data for patients aged 85 years or older.
• Renal impairment: no adjustment in mild (eGFR 60 to below 90 mL/min/1.73 m²) or moderate (eGFR 30 to below 60) impairment. No dose has been determined for severe impairment (eGFR below 30): use with caution and monitor closely.
• Hepatic impairment: no adjustment in mild impairment (Child-Pugh class A). No dose has been determined for moderate or severe impairment (Child-Pugh classes B and C): use with caution and monitor closely.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

If a dose is missed or not taken at the usual time, the tablets should be taken as soon as possible within 12 hours of the missed dose; two doses should not be taken within 12 hours. The tablets are taken as usual the next day. If a dose is vomited, replacement tablets should not be taken; the tablets are taken as usual the next day.

IDH1 R132 Mutation Required

Before taking Tibsovo, patients must have confirmation of an IDH1 R132 mutation using an appropriate diagnostic test.

Differentiation Syndrome in Acute Myeloid Leukaemia

Differentiation syndrome has been reported with ivosidenib. It may be life-threatening or fatal if not treated, and 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 increased creatinine.

• Patients must be informed of the signs and symptoms, advised to contact their physician immediately if they occur, and told to carry the Patient Alert Card with them at all times.
• If differentiation syndrome is suspected, systemic corticosteroids are given and haemodynamic monitoring is started, continuing until the symptoms resolve and for a minimum of 3 days.
• If leukocytosis is observed, treatment with hydroxycarbamide is started according to institutional standards of care, with leukapheresis as clinically indicated.
• Corticosteroids and hydroxycarbamide are tapered only after the symptoms have resolved; symptoms may return if they are stopped too early.
• Tibsovo is interrupted if severe signs or symptoms persist for more than 48 hours after systemic corticosteroids were started, and resumed at 500 mg once daily when they are moderate or lower and the patient’s clinical condition has improved.

QTc Interval Prolongation

• QTc prolongation has been reported. Patients should be informed of its signs and symptoms (palpitation, dizziness, syncope or even cardiac arrest) and advised to contact their physician immediately if they occur.
• In severe vomiting and/or diarrhoea, serum electrolytes, especially potassium and magnesium, must be assessed.
• Medicines known to prolong the QTc interval, and moderate or strong CYP3A4 inhibitors, can add to the risk and should be avoided whenever possible; if there is no suitable alternative, patients are treated with caution and closely monitored.
• Patients with congestive heart failure or electrolyte abnormalities need close monitoring, with periodic ECGs and electrolyte checks. Ivosidenib should be used with caution in patients with albumin below the normal range or who are underweight.
• Treatment must be permanently discontinued if QTc prolongation occurs with signs or symptoms of life-threatening arrhythmia.

Kidney and Liver Impairment

Safety and efficacy have not been established in severe renal impairment (eGFR below 30 mL/min/1.73 m²) or in moderate and severe hepatic impairment (Child-Pugh classes B and C); Tibsovo should be used with caution and patients closely monitored. Caution is also advised in mild hepatic impairment (Child-Pugh class A).

CYP3A4 Substrates

Ivosidenib induces CYP3A4 and may lower exposure to CYP3A4 substrates. Patients should be monitored for loss of antifungal efficacy if itraconazole or ketoconazole cannot be avoided.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential should have a pregnancy test before starting and avoid becoming pregnant during treatment. Women of childbearing potential, and men with female partners of childbearing potential, should use effective contraception during treatment and for at least 1 month after the last dose. Because ivosidenib may lower the concentrations of hormonal contraceptives, an alternative method such as barrier contraception is recommended.
• Pregnancy: there are no adequate data in pregnant women, and animal studies showed reproductive toxicity. Tibsovo is not recommended in pregnancy or in women of childbearing potential not using effective contraception. Patients should be told of the potential risk to the foetus if pregnancy occurs during treatment or in the month after the last dose.
• Breastfeeding: it is unknown whether ivosidenib or its metabolites pass into human milk, and a risk to the newborn or infant cannot be excluded. Breastfeeding should be discontinued during treatment and for at least 1 month after the last dose.
• Fertility: there are no human data and no animal fertility studies.

Lactose and Sodium

Each tablet contains 9.5 mg of lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should avoid Tibsovo. Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially ‘sodium-free’.

Effect on Driving

Ivosidenib has a minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported and should be considered when assessing a patient’s ability to drive or operate machines.

Tibsovo needs no special temperature storage conditions. Keep the bottle tightly closed to protect the tablets from moisture. The tablets come in a high-density polyethylene bottle with a child-resistant polypropylene closure and an induction-sealed liner. Each bottle holds 60 film-coated tablets and a silica gel desiccant in a canister, which must not be swallowed.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on restricted medical prescription (Annex II B of the marketing authorisation); treatment is started under the supervision of physicians experienced in anti-cancer medicinal products. Tibsovo is taken at home as film-coated tablets, so it is supplied to the patient or to the treating clinic on prescription.