Tibsovo^® ▼ (ivosidenib)

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Prescribing Information  

Refer to Summary of Product Characteristics (SPC) before prescribing.  

Presentation: Film-coated tablets, 250mg ivosidenib.

Indication: Treatment in combination with azacitidine of adult patients with newly diagnosed acute myeloid leukaemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive standard induction chemotherapy. Treatment (monotherapy) of adult patients with locally advanced or metastatic cholangiocarcinoma (CCA) with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy.

Dosage and Administration: Treatment should be initiated under the supervision of the physicians experienced in the use of anti-cancer medicinal products. Before treatment initiation, patients must have confirmation of an IDH1 R132 mutation using an appropriate diagnostic test, in addition an electrocardiogram complete blood count and blood chemistry should be performed. Posology: AML: recommended dose is 500 mg ivosidenib (2 x 250 mg tablets) taken orally once daily. Ivosidenib should be started on Cycle 1 Day 1 in combination with azacitidine at 75 mg/m 2 of body surface area, intravenously or subcutaneously, once daily on Days 1-7 of each 28-day cycle. The first treatment cycle of azacitidine should be given at 100% of the dose. It is recommended that patients be treated for a minimum of 6 cycles. For the posology and method of administration of azacitidine, please refer to the full product information for azacitidine. Treatment should be continued until disease progression or until treatment is no longer tolerated by the patient. CCA: recommended dose is 500 mg ivosidenib (2 x 250 mg tablets) taken orally once daily. Treatment should be continued until disease progression or until treatment is no longer tolerated by the patient. Dose adjustments: If a dose is missed or not taken at the usual time, the tablets should be taken as soon as possible within 12 hours after the missed dose. Two doses should not be taken within 12 hours. The tablets should be taken as usual the following day. If a dose is vomited, replacement tablets should not be taken. The tablets should be taken as usual the following day. Consult SPC for dose modifications for concomitant administration of moderate or strong CYP3A4 inhibitors and for adverse reactions.Administration: tablets are taken once daily at about the same time each day. Patients should not eat anything for 2 hours before and through 1 hour after taking the tablets. The tablets should be swallowed whole with water. Patients should be advised to avoid grapefruit and grapefruit juice during treatment. Renal impairment: No dose adjustment is required in patients with mild (eGFR ≥ 60 to ˂ 90 mL/min/1.73 m 2 ) or moderate (eGFR ≥ 30 to ˂ 60 mL/min/1.73 m 2 ) renal impairment. A recommended dose has not been determined for patients with severe renal impairment (eGFR ˂ 30 mL/min/1.73 m 2 ). Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. A recommended dose has not been determined for patients with moderate and severe hepatic impairment. Elderly: ≥ 65 years - No adjustment of starting dose. >85 years - Limited data. See SPC for dose modifications and management recommendations for adverse reactions.

Contraindications: Hypersensitivity to the active substance or to any of the excipients. Concomitant administration of strong CYP3A4 inducers or dabigatran. Congenital long QT syndrome. Familial history of sudden death or polymorphic ventricular arrhythmia. QT/QTc interval > 500 msec, regardless of the correction method.

Warnings and Precautions: Differentiation syndrome in patients with AML: Rapid proliferation and differentiation of myeloid cells. It may be life-threatening or fatal if not treated, symptoms include: non-infectious leucocytosis, 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. Consult SPC for management of differentiation syndrome. QTc interval prolongation: 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. Patients should be informed of the risk of QT prolongation, its signs and symptoms (palpitation, dizziness, syncope or even cardiac arrest). 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. 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. Patients with congestive heart failure or electrolyte abnormalities should be monitored closely, with periodic monitoring of ECGs and electrolytes. Tibsovo should be used with caution in patients who have either albumin levels below the normal range or are underweight. Severe renal impairment: Tibsovo should albumin levels below the normal range or are underweight. Severe renal impairment: Tibsovo should be used with caution in patients with severe renal impairment and this patient population should be closely monitored. Hepatic impairment: Tibsovo should be used with caution in patients with moderate and severe hepatic impairment (Child-Pugh classes B and C). and this patient population should be closely monitored. Tibsovo should be used with caution in patients with mild hepatic impairment (Child-Pugh class A). 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. Lactose intolerance: contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption should avoid use. Sodium content: contains less than 1 mmol sodium (23 mg) per tablet considered as “sodium-free”.

Interaction: 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. Concomitant administration of moderate (aprepitant, ciclosporin, diltiazem, erythromycin, fluconazole, grapefruit and grapefruit juice, isavuconazole, verapamil) or strong (clarithromycin, itraconazole, ketoconazole, posaconazole, ritonavir, voriconazole) CYP3A4 inhibitors increases plasma concentrations of ivosidenib and may increase the risk of QTc prolongation. Concomitant administration of medicinal products known to prolong the QTc interval (e.g. antiarrhythmics, fluoroquinolones, 5HT3 receptor antagonists, triazole antifungals) may increase the risk of QTc interval prolongation and should be avoided whenever possible during treatment with ivosidenib. Patients should be treated with caution and closely monitored for QTc interval prolongation if use of a suitable alternative is not possible. The recommended dose of ivosidenib should be reduced to 250 mg once daily if use of strong CYP3A4 inhibitors cannot be avoided (see sections 4.2 and 4.5 of the SPC).

Interaction of ivosidenib on other medicinal products: Ivosidenib inhibits P-gp and has the potential to induce P-gp, so it may alter systemic exposure to active substances that are predominantly transported by P-gp (eg. Dabigatran). Ivosidenib inhibits OAT3, organic anion-transporting polypeptide 1B1 (OATP1B1) and organic anion-transporting polypeptide 1B3 (OATP1B3), so it may increase systemic exposure to OAT3 (e.g. benzylpenicillin, furosemide) or OATP1B1/1B3 substrates (e.g. atorvastatin, pravastatin, rosuvastatin). 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. Ivosidenib induces CYP3A4, CYP2B6, CYP2C8, CYP2C9 and may induce CYP2C19, so it may decrease systemic exposure to substrates of these enzymes (eg. alfentanil, ciclosporin, everolimus, fentanyl, pimozide, quinidine, sirolimus, tacrolimus are substrates of CYP3A4. cyclophosphamide, ifosfamide, methadone are substrates of CYP2B6. paclitaxel, pioglitazone, repaglinide, substrates of CYP2C8. phenytoin, warfarin are substrates of CYP2C9. Omeprazole is substrates of CYP2C19). Patients should be monitored for loss of substrate efficacy if use of such medicinal products cannot be avoided. 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 a concomitant use of a barrier method of contraception is recommended for at least 1month after the last dose. Ivosidenib has the potential to induce UGTs and it may, therefore, decrease systemic exposure to substrates of these enzymes (e.g. lamotrigine, raltegravir). Patients should be monitored for loss of UGT substrate efficacy if use of such medicinal products cannot be avoided.

Fertility, pregnancy and Lactation: Contraception: Women of childbearing potential should have a pregnancy test prior to starting treatment with Tibsovo. 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. Concomitant use of a barrier method of contraception is recommended. Pregnancy: Tibsovo is not recommended for use during pregnancy and in women of childbearing potential not using effective contraception. Breast-feeding: should be discontinued during treatment with Tibsovo and for at least 1 month after the last dose.

Side Effects: Newly diagnosed acute myeloid leukaemia in combination with azacitidine. The most common serious adverse reactions were differentiation syndrome (8%) and thrombocytopenia (3%). Very common: Differentiation syndrome, leukocytosis, thrombocytopenia, neutropenia, insomnia, headache, dizziness, vomiting, pain in extremity, arthralgia, back pain, electrocardiogram QT prolonged. Common: leukopenia, neuropathy peripheral, oropharyngeal pain. Previously treated, locally advanced or metastatic cholangiocarcinoma. The most common serious adverse reactions were ascites (2%), hyperbilirubinemia (2%), and jaundice cholestatic (2%). Very common: anaemia, decrease appetite, neuropathy peripheral, headache, ascites, diarrhoea, vomiting, nausea, abdominal pain, rash, fatigue, aspartate aminotransferase increased, blood bilirubin increased. Common: jaundice cholestatic, hyperbilirubinemia, fall, electrocardiogram QT prolonged, alanine aminotransferase increased, white blood cell count decreased, platelet count decreased.

NHS Price Pack of 60 tablets: £12,500 (hospital only). Legal Category: POM. NI Product Licence Numbers: EU/1/23/1728/001 GB Product Licence Numbers: PLGB 05815/0120 Further Information: Servier Laboratories Ltd., Sefton Park, Stoke Poges, SL2 4JS, Tel (01753) 666409. Date of Revision: August 2023.