Ivosidenib

Ivosidenib is an oral targeted anticancer medicine belonging to the class of isocitrate dehydrogenase 1 (IDH1) inhibitors. It is used to treat selected cancers that carry a susceptible mutation in the IDH1 gene, including certain forms of acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), and cholangiocarcinoma, depending on the applicable regulatory approval. Mutated IDH1 can produce an abnormal substance called D-2-hydroxyglutarate, which interferes with normal cell maturation and contributes to cancer development. Ivosidenib blocks the activity of the mutated enzyme, reduces production of this substance, and may help cancer cells resume more normal maturation or limit disease progression. The medicine is taken by mouth as tablets and is prescribed following appropriate molecular testing to confirm the relevant IDH1 mutation. Depending on the indication, it may be used alone or in combination with another anticancer medicine, such as azacitidine. Treatment is generally continued while clinical benefit persists and adverse effects remain manageable. Important risks include differentiation syndrome, changes in heart rhythm associated with QT prolongation, and other potentially serious complications. Clinical assessment, blood tests, electrocardiograms when indicated, and review of concomitant medicines are essential during treatment. Ivosidenib should be prescribed and monitored by a healthcare professional experienced in cancer treatment.

Ivosidenib was developed as a precision oncology treatment targeting mutated IDH1, an enzyme involved in cellular metabolism. Mutations in this enzyme can lead to abnormal accumulation of D-2-hydroxyglutarate, which contributes to disrupted cellular differentiation and cancer biology. By inhibiting mutant IDH1, ivosidenib addresses a specific molecular abnormality rather than broadly targeting rapidly dividing cells. The United States Food and Drug Administration (FDA) first approved ivosidenib in 2018 for selected adults with IDH1-mutated acute myeloid leukaemia. Subsequent FDA approvals expanded its use to additional AML settings, locally advanced or metastatic IDH1-mutated cholangiocarcinoma, and relapsed or refractory IDH1-mutated myelodysplastic syndromes. In the European Union, Tibsovo received marketing authorisation on 4 May 2023 for newly diagnosed IDH1-mutated AML in combination with azacitidine in adults unsuitable for standard induction chemotherapy and for previously treated IDH1-mutated advanced or metastatic cholangiocarcinoma. Regulatory indications vary by country and may change over time. Clinical evidence has included studies evaluating remission, duration of response, transfusion independence, and disease progression in genetically selected patient populations.

Ivosidenib is used for selected cancers with a susceptible IDH1 mutation, confirmed using an appropriate diagnostic test. In the United States, approved uses include newly diagnosed AML in adults aged 75 years or older, or those with comorbidities that prevent intensive induction chemotherapy, in combination with azacitidine or as monotherapy; selected adults with relapsed or refractory AML; adults with relapsed or refractory IDH1-mutated MDS; and adults with locally advanced or metastatic IDH1-mutated cholangiocarcinoma previously treated with systemic therapy. European Union indications include combination treatment with azacitidine for newly diagnosed AML in adults unsuitable for standard induction chemotherapy and single-agent treatment for previously treated advanced or metastatic IDH1-mutated cholangiocarcinoma. The medicine is not appropriate for every patient with these cancers, because treatment eligibility depends on the mutation, disease status, previous therapy, clinical condition, and local regulatory guidance. Ivosidenib may be used alone or with azacitidine according to the specific indication. It should not be substituted for another treatment without specialist review.

Ivosidenib is supplied as oral tablets. The commonly recommended adult dose is 500 mg once daily, although the prescribed regimen must follow the current product information for the relevant indication and country. For AML treated with azacitidine, ivosidenib is generally taken continuously in combination with azacitidine administered according to its treatment-cycle schedule. For other approved indications, it is usually taken daily as a single agent. Tablets may generally be taken with or without food, but high-fat meals should be avoided because they can increase drug exposure. Tablets should be swallowed according to the product instructions and should not be altered without professional advice. Treatment may continue until disease progression, unacceptable toxicity, or another clinical reason for discontinuation. Dose interruption or reduction may be necessary for certain adverse effects or interactions. Patients should follow the instructions for missed doses and vomiting provided by their healthcare team rather than taking extra doses independently. Regular assessment of blood counts, biochemical parameters, heart rhythm, and treatment response is important.

Common adverse effects of ivosidenib can include fatigue, nausea, diarrhoea, vomiting, reduced appetite, abdominal discomfort, cough, muscle or joint pain, swelling, and changes in blood counts, depending on the cancer being treated and whether another medicine is given concurrently. Some patients may develop abnormal liver-related blood tests or changes in electrolyte levels. In patients with AML or MDS, symptoms and laboratory abnormalities may also reflect the underlying disease or accompanying treatment. Side effects vary between individuals and may change during therapy. Patients should report persistent vomiting or diarrhoea, worsening fatigue, reduced oral intake, new swelling, or other symptoms that interfere with daily activities. Supportive treatment, laboratory monitoring, or a clinician-directed dose adjustment may help manage some adverse effects. Patients should not stop or change the dose without discussing it with their treating specialist, except when instructed to seek urgent medical care.

Important risks associated with ivosidenib include differentiation syndrome, QT interval prolongation, and potentially serious complications related to changes in blood counts or the underlying cancer. Differentiation syndrome can cause fever, breathlessness, low oxygen levels, fluid retention, rapid weight gain, swelling, low blood pressure, or kidney dysfunction. It may be life-threatening and requires prompt assessment and treatment. QT prolongation can increase the risk of serious abnormal heart rhythms, particularly when electrolyte abnormalities or interacting medicines are present. Electrocardiograms and electrolyte measurements may be required before and during treatment. Other serious effects can include severe infection, bleeding related to low blood counts, and neurological complications such as Guillain–Barré syndrome reported in prescribing information. New breathing difficulties, unexplained fever, rapid swelling, fainting, palpitations, or new weakness or tingling require urgent medical evaluation. Depending on the adverse event, treatment may need to be interrupted, reduced, or discontinued under specialist supervision.

Before starting ivosidenib, the healthcare team should confirm the relevant IDH1 mutation using an appropriate validated test and review the patient's medical history, current medicines, cardiac risk factors, and baseline laboratory results. Particular care is required in patients with a history of prolonged QT interval, arrhythmias, electrolyte disturbances, or medicines that may prolong the QT interval. Strong CYP3A4 inhibitors can increase ivosidenib exposure and may require additional monitoring or dose adjustment, while strong CYP3A4 inducers can reduce exposure and should generally be avoided. Ivosidenib can also affect the metabolism of certain other medicines, so a complete medication review is important, including prescription drugs, non-prescription products, and herbal preparations. Potassium and magnesium abnormalities should be corrected when present. Patients with significant liver or kidney impairment may require closer assessment because evidence and dosing recommendations can vary. Pregnancy and breastfeeding require specialist counselling because of potential harm to a developing baby and limited safety information. Patients should discuss contraception and reproductive plans with their healthcare team.

Confirm the exact indication, disease status, and IDH1 mutation before dispensing or prescribing ivosidenib. Check that the dose and combination regimen match the current approved product information for the patient's country. Review all concomitant medicines for CYP3A4 interactions and QT-prolonging effects, and assess baseline cardiac history, electrocardiogram findings, potassium, magnesium, blood counts, and relevant biochemical parameters. Repeat electrocardiograms and laboratory tests at the intervals recommended in the prescribing information and whenever symptoms or medication changes raise concern. Counsel patients and caregivers about the early warning signs of differentiation syndrome, including fever, breathlessness, swelling, and rapid weight gain, and explain when emergency assessment is needed. Reinforce consistent daily administration, avoidance of high-fat meals, and the correct response to missed doses. Monitor treatment response and toxicity in coordination with the oncology team, especially when azacitidine is used concurrently. Pharmacists should check for new prescriptions and over-the-counter products at each review and reinforce adherence, safe storage, and prompt reporting of new symptoms.