Enasidenib is an oral, targeted inhibitor of mutated isocitrate dehydrogenase 2 (IDH2) enzymes. IDH2 mutations can lead to the production of an abnormal metabolite known as 2-hydroxyglutarate (2-HG). This aberrant metabolite has been associated with the promotion of leukemogenesis (formation of leukemia). By inhibiting the mutated IDH2, enasidenib reduces the levels of 2-HG, potentially leading to the differentiation of malignant cells.

Enasidenib (IDHIFA) is an oral, small-molecule, allosteric inhibitor of mutated IDH2 proteins that is used in the treatment of patients with relapsed or refractory acute myeloid leukemia who have a genetic mutation of the isocitrate dehydrogenase 2 gene. Unlike other chemotherapeutic agents, it is not a cytotoxic drug and acts as a differentiating agent.

Enasidenib Uses:

• Acute myeloid leukemia (relapsed/refractory):
  • Enasidenib is used in patients of relapsed/refractory acute myeloid leukemia (AML) with detected isocitrate dehydrogenase-2 (IDH2) mutation by an approved test.

Enasidenib (IDHIFA) Dose in Adults

Note:

• Before starting Enasidenib, make sure to check if there's an IDH2 mutation in the blood or bone marrow.
• The medicine might make some people feel like throwing up, so take anti-sickness medicine before using it to avoid nausea and vomiting.

Enasidenib (IDHIFA) Dose in the treatment of relapsed or refractory acute myeloid leukemia: 

• For treating Acute Myeloid Leukemia (AML) that has come back or doesn't respond to other treatments, Enasidenib is taken by mouth as a pill.
• The usual dose is 100 milligrams once every day.
• You keep taking it until your leukemia gets worse, or you can't handle the side effects. Doctors usually suggest taking it for at least 6 months to see if it helps.
• If you accidentally miss a dose, or if you throw up after taking it, take it as soon as you remember on the same day. Then, go back to your regular schedule the next day.

Use in Children:

Not indicated.

Enasidenib (IDHIFA) Pregnancy Risk Category: N

• Using enasidenib when pregnant might harm the baby, based on how it works and tests on animals.
• Women who could become pregnant should take a pregnancy test before starting the medicine.
• Women should use reliable birth control while taking this drug and for at least a month after the last pill.
• Men taking this drug who have partners that might get pregnant should also use reliable birth control during treatment and for a month after.
• Animal tests suggest that enasidenib might make it harder for both men and women to have children.

Use Enasidenib while breastfeeding

• We don't know if enasidenib gets into breast milk.
• The company that makes it says not to breastfeed while taking it and for at least a month after the last dose.

Enasidenib (IDHIFA) Dose in Kidney disease:

If your kidneys filter 30 mL/minute or more:

• The drug company hasn't given special dose instructions, and this kidney function doesn't majorly affect how the drug works.

If your kidneys filter less than 30 mL/minute:

• The drug company still hasn't given special dose instructions.

Enasidenib (IDHIFA) Dose in Liver disease:

Before starting the treatment, if you have liver issues:

• Mild Liver Problem: If your bilirubin (a liver enzyme) levels are normal but your AST (another liver enzyme) is high, or if your bilirubin is a bit elevated (1 to 1.5 times the normal limit) with any AST level, the drug company says you don't need to change the dose. This level of liver problem doesn't really change how the drug works in your body.
• Moderate to Severe Liver Problem: If your bilirubin is more than 1.5 times but less than 3 times the normal limit (moderate) or more than 3 times the normal limit (severe) with any AST level, the drug company still doesn't give special dosing instructions.

If you have liver problems while on the treatment:

If your bilirubin goes over 3 times the normal limit and stays that way for 2 weeks or more, but you don't have other liver problems:

• Decrease your dose to 50 mg daily.
• If your bilirubin levels get better (less than 2 times the normal limit), you can go back to taking 100 mg daily.

Common Side Effects of Enasidenib (IDHIFA):

• Endocrine & Metabolic:
  • Decreased Serum Calcium
  • Decreased Serum Potassium
• Gastrointestinal:
  • Nausea
  • Diarrhea
  • Decreased Appetite
  • Vomiting
  • Dysgeusia
• Hematologic & Oncologic:
  • Abnormal Phosphorus Levels
  • Differentiation Syndrome
  • Leukocytosis
• Hepatic:
  • Increased Serum Bilirubin

Less Common Side Effects Of Enasidenib (IDHIFA):

• Hematologic & Oncologic:
  • Tumor Lysis Syndrome
• Respiratory:
  • Acute Respiratory Distress
  • Pulmonary Edema

Contraindications to Enasidenib (IDHIFA):

The drug company doesn't list any reasons you shouldn't take enasidenib in the U.S. label.

However, in Canada, if you're allergic to enasidenib or anything in the pill, you shouldn't take it.

Warnings and precautions

Differentiation syndrome: [US Boxed Warning]

• Some people taking enasidenib have had a serious problem called differentiation syndrome. This can be deadly if not caught and treated.
• Signs of this problem include: fever, trouble breathing, lung issues, fluid around the lungs or heart, sudden weight gain or swelling, swollen glands, bone pain, and problems with the liver, kidneys, or other organs.
• If you think you have these symptoms, you need to get treatment right away. Usually, doctors will give steroids like dexamethasone. Monitoring your body's response in a hospital is a good idea, especially if you have lung or kidney problems.
• This syndrome can happen quickly (as soon as 10 days) or take a while (up to 5 months) after starting the drug.
• If you're showing serious symptoms, like needing a breathing tube or if your kidneys aren't working well for over 2 days even after starting steroids, you should stop taking enasidenib. You can start again once you're better.

Inadequate electrolyte levels:

• Some people taking the medicine have had low levels of certain minerals in their blood.
• This includes low calcium, low potassium, and low phosphate.

Hematologic effects

• The medicine can sometimes cause a quick increase in white blood cells, even without an infection.
• This is because it can make blood cells grow quickly.
• If this happens, another medicine called hydroxyurea might be needed.
• Also, you might need to stop taking enasidenib for a while.

Hepatotoxicity

• Taking enasidenib can increase bilirubin levels in the blood, which is a sign of liver issues.
• However, most people with this issue didn't show other major liver problems.
• The medicine might affect how bilirubin is processed in the body.
• If high bilirubin levels continue, a lower dose of the medicine might be needed.

Toxicity to the GI:

• Enasidenib can upset the stomach.
• It might make some people feel like throwing up.
• To help prevent this, you can take medicine to stop nausea before starting enasidenib.
• Some people also reported feeling sick, throwing up, having diarrhea, not feeling hungry, or having a change in how things taste.

Tumor lysis syndrome

• Enasidenib can sometimes cause a problem where cancer cells break down too quickly, called tumor lysis syndrome.
• This can affect the body's salt balance and kidney function.

Monitoring parameters:

• IDH2 mutation status: Make sure it's present before starting.
• Blood tests:
  • Check blood counts and chemistry before starting and then every 2 weeks for the first 3 months.
  • Test liver and kidney function.
• Pregnancy test: For women who could become pregnant, take a test before starting treatment.

Watching Out for Side Effects:

• Differentiation Syndrome: Look for signs like:
  • Fever
  • Cough
  • Trouble breathing
  • Bone pain
  • Quick weight gain
  • Swelling
  • Swollen glands
• Tumor Lysis Syndrome: Be alert for signs.

Other:

• Taking the Medicine: Keep track to make sure the medicine is taken as directed.

How to administer Enasidenib (IDHIFA)?

Feeling Sick: Enasidenib might make you feel like throwing up.

• Tip: Take anti-sickness medicine before starting to help prevent this.

How to Take the Pill:

• Take it by mouth once a day.
• You can take it with or without food, but try to take it around the same time every day.
• Drink it down with a full glass of water.
• Important: Don't break or crush the pill. Swallow it whole.

Mechanism of action of Enasidenib (IDHIFA):

• Enasidenib is a tiny molecule that stops the activity of an enzyme called isocitrate dehydrogenase 2 (IDH2).
• It mainly targets the mutant forms of IDH2, like R140Q, R172S, and R172K. It's much more effective against these mutant forms compared to the normal, or "wildtype," enzyme.
• When it blocks these mutant IDH2 versions, it lowers the levels of a substance called 2-hydroxyglutarate (2-HG).
• This helps in two ways:
  • It reduces abnormal changes in how genes are marked in cells (histone hypermethylation).
  • It helps cells mature properly (myeloid differentiation).
• Additionally, enasidenib helps decrease the number of immature blast cells and increases the number of mature myeloid cells in the body. This is important because having too many immature cells can be a problem in conditions like leukemia.

Distribution:

• After it enters the body, it spreads out and occupies a space equivalent to 55.8 liters (like a medium-sized barrel).

Binding:

• Enasidenib (the main drug) sticks to proteins in the blood 98.5% of the time.
• AGI-16903 (its breakdown product) sticks to proteins 96.6% of the time.

Breaking Down:

• The drug mainly gets broken down in the liver.
• Many enzymes help with this, including several CYP enzymes and UGT enzymes.
• Its breakdown product, AGI-16903, also gets further broken down by some of these enzymes.

How Much Gets In:

• When you take a 100 mg dose, about 57% of it gets into the bloodstream.

How Long It Stays:

• It takes about 137 hours (almost 6 days) for half of the drug to leave the body.

When It Peaks:

• The highest amount of the drug in the blood is seen 4 hours after taking it.

Getting Rid of It:

• Most of it (89%) leaves the body through feces (poop). Out of this, 34% goes out unchanged.
• A smaller amount (11%) is removed in urine (pee). Less than 1% of this is the unchanged drug.

International Brand Names of Enasidenib:

• IDHIFA

Enasidenib Brand Names in Pakistan:

Not available.