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Ivosidenib – Uses, Dosage, Side Effects, Interaction – Rxharun

Ivosidenib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Ivosidenib is a reversible inhibitor of IDH1 which is non-competitive with respect to the cofactor NADH. It binds to many different 132-substituted IDH1 mutants as well as the wild-type enzyme. It is considered to be a slow-binder of the wild-type enzyme and binds to mutant enzymes at lower concentrations, both of which may contribute to its selectivity. Ivosidenib has not been observed to inhibit any form of IDH2 at micromolar concentrations.

Many cancers undergo missense mutations of their IDH1 gene leading to the substitution of arginine 132 residues of the IDH1 enzyme [A35629. This substitution leads to reduced production of the normal carboxylic acid cycle metabolite α-ketoglutarate (α-KG) in favor of a new metabolite, D-2-hydroxyglutarate (D-2HG) which reaches levels of 50-100 fold that of wild type cells. D-2HG is a weak competitor to α-KG, inhibiting aKG-dependent dioxygenases, and is present. These dioxygenases include several histone demethylases. This leads to hypermethylation of histones, a dominant feature of AML, which is associated with less expression of cell-differentiation genes. Furthermore, methylation-sensitive insulators can no longer regulate the activation of oncogenes when histones are hypermethylated. In AML this hypermethylation is known to disrupt hematopoietic differentiation. Ivosidenib reduces the production of D-2HG, relieving the inhibition of histone demethylases and restoring normal methylation conditions. This restores cell differentiation and oncogene regulation leading to the regression of cancer.

Indications

  • Ivosidenib is an orally available small-molecule inhibitor of isocitrate dehydrogenase 2 which is used as an antineoplastic agent in the treatment of selected cases of acute myeloid leukemia (AML).
  • Ivosidenib is approved for use in the treatment of relapsed or refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test.
  • Treatment of all conditions included in the category of malignant neoplasms (except central nervous system tumors, hematopoietic and lymphoid tissue neoplasms), Treatment of malignant neoplasms of the central nervous system
  • Treatment of acute myeloid leukemia. Locally Advanced or Metastatic Cholangiocarcinoma in adults who have been previously treated.
  • Ivosidenib is indicated for people with acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma.
  • Ivosidenib is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of patients with a susceptible IDH1 mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) in combination azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.[rx] Relapsed or refractory AML in adults.[rx]
  • Acute Myeloid Leukemia
  • Locally Advanced Cholangiocarcinoma
  • Metastatic Cholangiocarcinoma
  • Refractory Acute Myeloid Leukemia (AML)
  • Relapsed Acute Myelogenous Leukemia (AML)

Use in Cancer

Ivosidenib is approved to treat adults whose cancer has a certain mutation in the IDH1 gene, including:

  • Acute myeloid leukemia (AML). It is used:
    • Alone or with azacitidine in patients with newly-diagnosed cancer who are aged 75 years and older or who, due to health problems, cannot receive intensive induction chemotherapy.
    • When cancer has come back or has not gotten better after previous treatment.
  • Cholangiocarcinoma (bile duct cancer) has spread. It is used in adults whose cancer has been treated.

Ivosidenib is also being studied in the treatment of other types of cancer.

Contraindications

  • low amount of magnesium in the blood
  • low amount of calcium in the blood
  • low amount of potassium in the blood
  • Guillain-Barre syndrome
  • torsades de pointes, a type of abnormal heart rhythm
  • prolonged QT interval on EKG
  • chronic heart failure
  • abnormal EKG with QT changes from birth
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: 250 mg

Acute Myeloid Leukemia

  • 500 mg orally once daily until disease progression or unacceptable toxicity; for patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Select patients for the treatment of AML based on the presence of IDH1 mutations in the blood or bone marrow. Patients without IDH1 mutations at diagnosis should be retested at relapse because a mutation in IDH1 may emerge during therapy and at relapse.
  • For the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

Acute Myeloid Leukemia

75 years or older:

  • 500 mg orally once daily until disease progression or unacceptable toxicity; for patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.
  • For the treatment of adult patients with newly-diagnosed AML with a susceptible IDH1 mutation as detected by an FDA-approved test who are 75 years older or who have comorbidities that preclude the use of intensive induction chemotherapy.

Renal Dose Adjustments

  • Mild (CrCl 60 to less than 90 mL/min) or moderate (CrCl 30 to less than 60 mL/min): No adjustment is recommended.
  • Severe renal impairment (CrCl less than 30 mL/min): Data not available

Liver Dose Adjustments

  • Mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] and aspartate aminotransferase [AST] greater than ULN or total bilirubin 1 to 1.5 x ULN and any AST): No adjustment recommended.
  • Moderate hepatic impairment (total bilirubin 1.5 to 3.0 x ULN and any value for AST), or severe hepatic impairment (total bilirubin greater than 3 x ULN and any value for AST): Data not available

Dose Adjustments

DIFFERENTIATION SYNDROME:

  • If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days.
  • Interrupt therapy if severe signs and/or symptoms persist for more than 48 hours after initiation of systemic corticosteroids. Resume therapy when signs and symptoms improve to Grade 2 or less.

NONINFECTIOUS LEUKOCYTOSIS (white blood cell [WBC] count greater than 25 x 10(9)/L or an absolute increase in total WBC of greater than 15 x 10(9)/L from baseline):

  • Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated.
  • Taper hydroxyurea only after leukocytosis improves or resolves.
  • Interrupt therapy if leukocytosis is not improved with hydroxyurea, and then resume therapy at 500 mg daily when leukocytosis has resolved.

QTC INTERVAL GREATER THAN 480 MSEC TO 500 MSEC:

  • Monitor and supplement electrolyte levels as clinically indicated.
  • Review and adjust concomitant medications with known QTc interval-prolonging effects.
  • Interrupt therapy.
  • Restart therapy at 500 mg once daily after the QTc interval returns to less or equal to 480 msec.
  • Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation.

QTC INTERVAL GREATER THAN 500 MSEC:

  • Monitor and supplement electrolyte levels as clinically indicated.
  • Review and adjust concomitant medications with known QTc interval-prolonging effects.
  • Interrupt therapy.
  • Resume therapy at a reduced dose of 250 mg once daily when the QTc interval returns to within 30 msec of baseline or less than or equal to 480 msec.
  • Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation.
  • Consider re-escalating the dose to 500 mg daily if an alternative etiology for QTc prolongation can be identified.

QTC INTERVAL PROLONGATION WITH SIGNS/SYMPTOMS OF LIFE-THREATENING ARRHYTHMIA:

  • Discontinue therapy permanently.

GUILLAIN-BARRE SYNDROME:

  • Discontinue therapy permanently.

OTHER GRADE 3 OR HIGHER TOXICITY CONSIDERED TO BE RELATED TO TREATMENT:

  • Interrupt therapy until toxicity resolves to Grade 2 or lower.
  • Resume therapy at 250 mg once daily; may increase to 500 mg once daily if toxicities resolve to Grade 1 or lower.
  • If Grade 3 or higher toxicity recurs, discontinue therapy.

DOSE MODIFICATION FOR USE WITH STRONG CYP450 3A4 INHIBITORS

  • If a strong CYP450 3A4 inhibitor must be coadministered, reduce the dose of this drug to 250 mg once daily.
  • If the strong CYP450 3A4 inhibitor is discontinued, increase the dose of this drug (after at least 5 half-lives of the strong CYP450 3A4 inhibitor) to the recommended dose of 500 mg once daily.

Administration advice:

  • This drug may be taken with or without food; however, it should not be administered with a high-fat meal because of an increase in drug concentration.
  • Do not split or crush tablets.
  • Administer this drug at about the same time each day.
  • If a dose is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.
  • If a dose is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.
  • Assess blood counts and blood chemistries prior to the initiation of therapy, at least once weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy.
  • Monitor blood creatine phosphokinase weekly for the first month of therapy.
  • Monitor electrocardiograms (ECGs) at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy. Manage any abnormalities promptly.

Side Effects

The Most Common

  • headache
  • fatigue
  • joint or muscle pain
  • diarrhea
  • constipation
  • vomiting
  • nausea
  • decreased appetite
  • mouth pain and ulcers
  • stomach pain
  • difficulty falling asleep or staying asleep
  • dizziness, lightheadedness, or fainting
  • weakness or tingling sensation in legs, arms, or upper body; numbness and pain on one side or both sides of the body; changes in your ability to see, touch, hear, or taste; burning or prickling sensation; or difficulty breathing
  • chest pain

More common

  • Black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • blurred vision
  • burning, tingling, numbness or pain in the hands, arms, feet, or legs
  • chest pain or tightness
  • chills
  • confusion
  • cough
  • decreased urination
  • difficult or labored breathing
  • difficulty in moving
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • eye pain
  • fainting
  • fever
  • general feeling of illness
  • headache
  • irregular heartbeat, recurrent
  • joint pain, stiffness, or swelling
  • lower back, side, or stomach pain
  • muscle ache, cramps, pain, or stiffness
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • rapid weight gain
  • rash
  • the sensation of pins and needles
  • sore throat
  • sores, ulcers, or white spots on the lips, tongue, or inside the mouth
  • stabbing pain
  • swelling of your arms, feet, or lower legs
  • unusual bleeding or bruising
  • unusual tiredness or weakness

Rare

  • Inability to move the arms and legs
  • sudden numbness and weakness in the arms and legs
  • Cracked lips
  • decreased appetite
  • diarrhea
  • difficulty in swallowing
  • nausea
  • vomiting
  • decreased urination;
  • rapid weight gain; or
  • swelling in your arms or legs.
  • fast or pounding heartbeats, fluttering in your chest, shortness of breath, sudden dizziness (like you might pass out);
  • jaundice (yellowing of the skin or eyes);
  • fluid build-up around the stomach–rapid weight gain, stomach pain and bloating, trouble breathing while lying down;
  • low red blood cells (anemia)–pale skin, tiredness, feeling light-headed or short of breath, cold hands and feet;
  • high white blood cell counts–fever, weakness, not feeling well, bleeding or bruising, nausea, loss of appetite, weight loss; or
  • nervous system problems–numbness, pain, tingling, weakness, burning or prickly feeling, vision or hearing problems, trouble breathing.

Drug Interactions

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on animal embryo-fetal toxicity studies, TIBSOVO may cause fetal harm when administered to a pregnant woman. There are no available data on TIBSOVO use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal
embryo-fetal toxicity studies, oral administration of ivosidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 2 times the steady-state clinical exposure based on the AUC at the recommended
human dose (see Data). If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus.

Lactation

There are no data on the presence of ivosidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Why is this medication prescribed?

Ivosidenib is used to treat a certain type of acute myeloid leukemia (AML; a type of cancer that begins in the white blood cells) that has returned or that has not improved after previous treatment(s). Ivosidenib is also used alone or in combination with azacitidine (Onureg) to treat a certain type of AML in some adults older than 75 years of age as a first treatment. Ivosidenib is also used in adults who have already received previous treatment(s) to treat a certain type of cholangiocarcinoma (bile duct cancer) that has spread to nearby tissues or other parts of the body. Ivosidenib is in a class of medications called IDH1 inhibitors. It works by slowing or stopping the growth of cancer cells.

How should this medicine be used?

Ivosidenib comes as a tablet to take by mouth. It is usually taken with or without food once daily. Do not take it with high-fat food such as eggs, butter, whole-milk dairy products (such as whole milk, cheese, and yogurt), fried foods, or fast food. Take ivosidenib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ivosidenib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them. If you vomit after taking ivosidenib, do not take another dose. Continue your regular dosing schedule.

Your doctor may reduce your dose or temporarily or permanently stop your treatment with ivosidenib depending on your response to treatment or any side effects that you experience. Talk to your doctor about how you are feeling during your treatment. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking ivosidenib,

  • tell your doctor and pharmacist if you are allergic to ivosidenib, any other medications, or any of the ingredients in ivosidenib tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you or anyone in your family has or has ever had a prolonged QT interval (a condition that increases the risk of developing an irregular heartbeat that may cause fainting or sudden death); if you have or have ever had a slow or irregular heartbeat, heart failure, or other heart problems; low blood levels of sodium, potassium, calcium, or magnesium; nervous system problems; liver disease, including cirrhosis; or if you are receiving dialysis treatments or if you have or ever had kidney disease.
  • tell your doctor if you are pregnant or plan to become pregnant, or are breastfeeding. You should know that ivosidenib may decrease the effectiveness of hormonal contraceptives (birth control pills, patches, rings, or injections) while you are taking this medication. Talk to your doctor about using another form of birth control. If you become pregnant while taking ivosidenib, call your doctor immediately. Ivosidenib may cause fetal harm.
  • tell your doctor if are breastfeeding. Do not breastfeed during your treatment with ivosidenib and for 1 month after your final dose.

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet. Make sure you drink plenty of water or other fluids every day while you are taking ivosidenib.

What should I do if I forget a dose?

If your next dose is due in 12 hours or more, take the missed dose as soon as you remember it. However, if the next dose will be taken in less than 12 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

References

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