Ixazomib is an oral proteasome inhibitor that was approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma. Proteasomes are cellular complexes that break down proteins; by inhibiting their action, ixazomib can disrupt the growth and survival of myeloma cells.

Ixazomib (Ninlaro) is the first orally available proteasome inhibitor that is used to treat patients with multiple myeloma.

Ixazomib (Ninlaro) Indications:

• Multiple myeloma:
  • Used in the treatment of multiple myeloma (combined with lenalidomide and dexamethasone)
  • Patients should who have received at least one prior chemotherapy

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Ixazomib (Ninlaro) Dose in Adults:

Note: Following are the pre-requisites

• Make sure the white blood cell count is at least 1,000/mm³.
• The platelet count should be at least 75,000/mm³.
• Any other health problems should be minor or at their normal level, unless the doctor thinks it's okay.

Ixazomib (Ninlaro) Dose in the treatment of Multiple myeloma:

Regular Dose:

• Take 4 mg by mouth once a week on days 1, 8, and 15 of a 4-week cycle.
• This is combined with two other drugs: lenalidomide and dexamethasone.
• Keep taking it until the disease gets worse or side effects become too much.

If You Forget a Dose:

• Only take the missed dose if it's more than 3 days until your next scheduled dose.
• If it's less than 3 days until your next dose, skip the missed one. Don't take double the dose to make up for it.
• If you throw up after taking it, don't take another one. Just wait for the next scheduled dose.

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Ixazomib (Ninlaro) use in children:

Not indicated.

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Pregnancy Risk Category: Not assigned

• Based on how ixazomib works and tests on animals, taking it while pregnant might harm the baby.
• If you can have children, men and women both need to use reliable birth control during treatment and for 3 months after the last dose.
• Women on birth control pills or other hormonal methods should also use a second type, like condoms.
• When treating multiple myeloma, ixazomib is used with two other drugs: lenalidomide and dexamethasone. Lenalidomide should never be taken during pregnancy; it's dangerous for the baby. Make sure to check its specific safety information.

Use of Ixazomib while breastfeeding

• We don't know if ixazomib gets into breast milk.
• Because it might harm a breastfeeding baby, the company that makes it suggests not breastfeeding while on the treatment and for 3 months after the last dose.

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Ixazomib (Ninlaro) Dose in Kidney Disease:

Measuring Kidney Function:

• The International Myeloma Working Group (IMWG) suggests using the CKD-EPI equation as the first choice, or the MDRD formula if needed, to check kidney function in multiple myeloma patients whose creatinine levels are steady.

Dosing Ixazomib Based on Kidney Function:

• If the kidney function (CrCl) is 30 mL/minute or more: Ixazomib, combined with lenalidomide and dexamethasone, can be used safely.
• If the kidney function (CrCl) is less than 30 mL/minute or if the patient has End Stage Renal Disease (ESRD) and needs dialysis: Start with a lower dose of 3 mg on days 1, 8, and 15 of a 4-week cycle. Note: Ixazomib doesn't get removed by dialysis, so you can take it anytime, regardless of when dialysis is done.

If There Are Kidney Problems During Treatment:

• If there's a severe kidney problem (Grade 3 or 4): Stop taking ixazomib until the problem gets better, going back to normal or just a minor issue. If ixazomib caused the problem, when restarting, use a lower dose.

Ixazomib (Ninlaro) Dose in Liver disease:

Dosing Ixazomib Based on Liver Function Before Starting Treatment:

• Mild Liver Problems: If your bilirubin (a liver enzyme) levels are a little high but still within the normal range, or a bit more than the normal range, you can take the usual dose of ixazomib.
• Moderate or Severe Liver Problems: If your bilirubin levels are significantly high (more than 1.5 times the upper normal limit), start with a lower dose of 3 mg on days 1, 8, and 15 of a 4-week cycle.

If There Are Liver Problems During Treatment:

• If there's a severe liver problem (Grade 3 or 4): Stop taking ixazomib until the liver issue improves, either going back to normal or becoming just a minor problem. If ixazomib caused the liver problem, when you start taking it again, use a lower dose.

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Adverse reaction percentages reported as part of a combination regimen with lenalidomide and dexamethasone.

Common Side Effects of Ixazomib (Ninlaro):

• Cardiovascular:
  • Peripheral Edema
• Central Nervous System:
  • Peripheral Neuropathy
  • Peripheral Sensory Neuropathy
• Dermatologic:
  • Skin Rash
• Gastrointestinal:
  • Diarrhea
  • Constipation
  • Nausea
  • Vomiting
• Hematologic & Oncologic:
  • Thrombocytopenia
  • Neutropenia
• Neuromuscular & Skeletal:
  • Back Pain
• Ophthalmic:
  • Eye Disease
• Respiratory:
  • Upper Respiratory Tract Infection

Less Common Side Effects Of Ixazomib (Ninlaro):

• Hepatic:
  • Hepatic Insufficiency
• Infection:
  • Herpes Zoster
• Ophthalmic:
  • Blurred Vision
  • Conjunctivitis
  • Xerophthalmia

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Contraindication to Ixazomib Include:

Manufacturer's General Instructions:

• No specific conditions where you shouldn't take ixazomib are mentioned.

Instructions for Canada:

• Don't take ixazomib if you're allergic to it or any of its ingredients. (This warning is specifically in Canadian guidelines and not in the U.S. ones.)

Warnings and precautions

Bone Marrow Issues with Ixazomib:

• In studies, people sometimes had low levels of white blood cells (neutropenia) and platelets (thrombocytopenia). Severe cases were also noticed.
• The lowest platelet counts usually happened between days 14-21 of the treatment cycle but returned to normal by the start of the next cycle.
• Check platelet counts at least once a month while on the drug. During the first 3 cycles, it might be good to check even more often.
• If counts get too low, you might need to stop the drug temporarily, lower the dose, or get a platelet transfusion.
• Also, keep an eye on white blood cell counts. If they get too low, adjustments in the drug dose or a break in treatment might be needed.

Skin Reactions with Ixazomib:

• Some people using ixazomib had skin rashes. Most rashes were mild or moderate (grade 1 or 2).
• A few people had more severe rashes (grade 3).
• The common types of rashes were maculopapular and macular rashes.
• Keep an eye on your skin for any issues, and if there's a problem, supportive care or changes in the drug doses might help, especially if the rash is grade 2 or higher.

Stomach and Gut Problems with Ixazomib:

• Some people experienced diarrhea, constipation, feeling sick (nausea), and throwing up (vomiting).
• To help with these issues, medicines to stop diarrhea or vomiting might be needed, along with other supportive care.
• If the symptoms are severe (grade 3 or 4), a change in the drug dose is suggested.

Liver Issues with Ixazomib:

• In studies, some rare cases showed the drug can cause liver problems. This includes liver damage, fat buildup in the liver, and different types of hepatitis.
• It's essential to check liver health often while on this drug.
• If liver problems become severe (grade 3 or 4), the amount of the drug taken might need to change.

Risk of Shingles with Ixazomib:

• Some people using ixazomib got shingles (herpes zoster).
• Taking preventive antiviral medicine can lower the chances of getting shingles.
• It's a good idea to think about taking this preventive medicine when on ixazomib to reduce the risk of shingles coming back.

Swelling in the Hands or Feet with Ixazomib:

• About 1 in 4 people using ixazomib had swelling in their hands or feet, but it was usually mild or moderate.
• If this happens, check for possible reasons for the swelling and give the right care to help.
• If the swelling is severe (grade 3 or 4), the amounts of dexamethasone and/or ixazomib you're taking might need to change.

Nerve Problems with Ixazomib:

• Some people using ixazomib had nerve problems, but these were mostly mild or moderate.
• The most common nerve issue felt was in sensation, like tingling or numbness. Problems with movement due to nerve issues were rare.
• Keep a close eye on any signs of nerve problems. If they happen, the amount of ixazomib and/or lenalidomide you're taking might need to change, or you might need to stop the treatment.

Liver Problems and Ixazomib:

• If you have serious liver problems, you should start with a lower dose of ixazomib. This is because the drug can affect the liver more in such cases.

Kidney Problems and Ixazomib:

• If your kidneys aren't working well (with CrCl less than 30 mL/minute) or you need dialysis, start with a lower dose of ixazomib. This is because the drug can stay in the body longer in these situations.
• The other medicine, lenalidomide, might also need a lower dose if you're taking it together with ixazomib.

Ixazomib: Drug Interaction

Risk Factor C (Monitor therapy)
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Ivosidenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Risk Factor D (Consider therapy modification)
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects).
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely.
Estrogen Derivatives (Contraceptive)	Ixazomib may decrease the serum concentration of Estrogen Derivatives (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of estrogen derivative contraceptives. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of Ixazomib.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Progestins (Contraceptive)	Ixazomib may decrease the serum concentration of Progestins (Contraceptive). More specifically, use of ixazomib with dexamethasone may decrease the serum concentrations of contraceptive progestins. Management: Patients of childbearing potential should use a nonhormonal barrier contraceptive during and 90 days following ixazomib treatment.
St John's Wort	May decrease the serum concentration of Ixazomib.

 

Monitoring parameters:

Platelet Counts:

• Check at least once a month. Especially during the first 3 cycles, you might want to check more often.

Blood Count:

• Check the full blood count as needed, including a breakdown of different types of blood cells.

Kidney and Liver:

• Keep an eye on how the kidney and liver are working using tests.

Stomach and Skin Issues:

• Watch for signs of stomach problems (like diarrhea or nausea) and skin reactions (like rashes).

Nerve and Swelling Problems:

• Be alert for nerve issues (like tingling or numbness) and swelling in the hands or feet.

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How to administer Ixazomib (Ninlaro)?

• Take it on the same day each week, around the same time.
• Eat your meal either 1 hour before or wait 2 hours after eating to take the pill.
• Just swallow the pill as it is. Don't break, chew, or open it.
• Be careful not to let what's inside the pill touch your skin or eyes.
  • If it gets on your skin, wash it off well with soap.
  • If it gets in your eyes, rinse them out with lots of water.

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Mechanism of action of Ixazomib (Ninlaro):

• Ixazomib acts on proteasomes, which are like the cell's recycling centers for proteins.
• It mainly blocks one part of the proteasome, called the beta 5 subunit.
• By doing this, it disrupts the cell's normal processes, stopping cell growth and causing the cell to self-destruct.

Absorption:

• Eating a high-fat meal before taking it can lower its absorption by up to 28%.

Spread in the Body:

• It can spread across a large volume (543 liters).

Binding:

• About 99% of it attaches to proteins in the blood.

Processing (Metabolism):

• The liver processes it, using several enzymes. No single enzyme does most of the work, but many might be involved, including CYP3A4, 1A2, and others.

Effectiveness in Entering the Body (Bioavailability):

• 58% of the drug reaches the bloodstream after you take it.

How Long it Stays (Half-life):

• It takes about 9.5 days for half of the drug to leave your body.

Peak Level:

• The highest drug level in the blood is reached about 1 hour after taking it.

Getting Rid of the Drug:

• Most of it (62%) goes out in urine, but only a tiny bit (less than 3.5%) is in its original form.
• Some of it (22%) goes out with feces.

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International Brands of Ixazomib:

• Ninlaro

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Ixazomib Brands Names in Pakistan:

Not available.