EMEDZ.NET

Ibritumomab tiuxetan (Zevalin) - Indications, Dosing, Side effects

Ibritumomab tiuxetan is a radiolabeled monoclonal antibody used in the treatment of certain types of non-Hodgkin's lymphoma (NHL). Specifically, it's a CD20-directed radiotherapeutic antibody.

Ibritumomab tiuxetan (Zevalin) is a monoclonal antibody that is linked with a radioactive isotope Yttrium-90 (Y90). The monoclonal antibody acts as a vehicle for the radioactive isotope to reach the target site.

Ibritumomab tiuxetan (Zevalin) Uses:

Non-Hodgkin lymphoma:
- Used for treatment of relapsed or refractory, low-grade or follicular B-cell no Hodgkin lymphoma (NHL)
- Also used to treat previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy

Ibritumomab tiuxetan (Zevalin) Dose in Adults:

Note:

Before each time you get rituximab, take a pain reliever called acetaminophen (650 mg) and an allergy medicine called diphenhydramine (50 mg).
After you finish your first round of chemotherapy, wait at least 6 weeks but not more than 12 weeks before starting this treatment.
Make sure your platelet count (a type of blood cell) is at least 150,000 per tiny drop of blood before you start.

Ibritumomab tiuxetan (Zevalin) Dose in the treatment of non-Hodgkin lymphoma:

In the treatment of Non-Hodgkin lymphoma using Ibritumomab tiuxetan (Zevalin regimen), the doses and steps are as follows:

Step 1 - Day 1:

You will receive a medication called Rituximab through a vein (intravenous or IV).
At first, it will be given at a slow rate of 50 mg per hour. If there are no problems like allergies or reactions, the rate can be increased by 50 mg per hour every half an hour, up to a maximum of 400 mg per hour.
If there is a severe reaction, the Rituximab infusion will be stopped and the treatment plan might be discontinued. For less severe reactions, the infusion might be slowed down or paused. It can be resumed at a slower rate if symptoms improve.

Step 2 - Day 7, 8, or 9:

You will receive another dose of Rituximab through a vein.
This time, it starts at a rate of 100 mg per hour (or 50 mg per hour if you had reactions during the first infusion). If there are no problems, the rate can be increased by 100 mg per hour every half an hour, up to a maximum of 400 mg per hour (or 50 mg per hour increments if you started at 50 mg per hour).

Step 3 - Within 4 hours of finishing Rituximab on Day 1:

You will receive Y-90 Ibritumomab through a vein.
The dose depends on your platelet count:
- If your platelet count is at least 150,000 cells per mm³: You will get 0.4 mCi/kg (14.8 MBq/kg) of your actual body weight over 10 minutes. The maximum dose is 32 mCi (1184 MBq).
- If your platelet count is between 100,000 and 149,000 cells per mm³ (for patients with relapsed or refractory disease): You will get 0.3 mCi/kg (11.1 MBq/kg) of your actual body weight over 10 minutes. The maximum dose is 32 mCi (1184 MBq).
- If your platelet count is below 100,000 cells per mm³: You should not receive this treatment.

Important Note:

The maximum dose of Y-90 Ibritumomab you can receive is 32 mCi (1184 MBq), regardless of your body weight.

This treatment plan combines Rituximab and Y-90 Ibritumomab to target and treat non-Hodgkin lymphoma. It's given in carefully controlled steps, and the doses vary based on factors like your platelet count.

Use in Children:

Not indicated.

Ibritumomab tiuxetan (Zevalin) Pregnancy Risk Category: D

Ibritumomab tiuxetan (labeled with Y-90) is a radiolabeled drug, which means it gives off radiation. This can be harmful to an unborn baby if given to a pregnant woman. Given below are the risks and precautions related to pregnancy:

Risk to the Fetus: Due to its radioactivity, Y-90 ibritumomab can harm an unborn baby, especially if given during pregnancy.
Transfer to the Fetus: Ibritumomab tiuxetan is a type of humanized monoclonal antibody, which is known as IgG. How much of this antibody passes to the fetus through the placenta depends on the type of IgG and how far along the pregnancy is. The transfer of this antibody generally increases as the pregnancy goes on. The lowest transfer would occur during the early stage of pregnancy when organs are forming.
Pregnancy Testing: Before starting the treatment, it's important to check if the patient is pregnant to avoid potential harm to the baby.
Avoiding Pregnancy: Women who can become pregnant should make sure they don't conceive during their treatment with ibritumomab tiuxetan.
Contraception: Both women who can become pregnant and men with such partners should use effective birth control methods during the treatment. This precaution should continue for at least 12 months after the last dose of the drug.

In summary, if you or someone you know is considering treatment with ibritumomab tiuxetan, it's crucial to be aware of its potential risks to an unborn child and take necessary precautions.

Ibritumomab Tiuxetan is used during breastfeeding

Ibritumomab tiuxetan might end up in breast milk because similar substances (immunoglobulins) are often found in milk.
We're not entirely sure if it does, but to be safe, the company that makes the drug suggests that if you're nursing, you should stop breastfeeding during the treatment and for 6 months after the treatment ends.
This is to prevent any potential harm to the baby.

Ibritumomab tiuxetan (Zevalin) Dose in Kidney Disease:

No dosage adjustments provided in the manufacturer's labeling.

Ibritumomab tiuxetan (Zevalin) Dose in Liver disease:

No dosage adjustments provided in the manufacturer's labeling.

Common Side Effects of Ibritumomab tiuxetan (Zevalin):

Central Nervous System:
- Fatigue
Gastrointestinal:
- Nausea
- Abdominal Pain
- Diarrhea
Hematologic & Oncologic:
- Thrombocytopenia
- Neutropenia
- Anemia
- Leukopenia
- Lymphocytopenia
- Metastases
Infection:
- Infection
Neuromuscular & Skeletal:
- Weakness
Respiratory:
- Nasopharyngitis
- Cough

Less Common Side Effects Of Ibritumomab tiuxetan (Zevalin):

Cardiovascular:
- Hypertension
Central Nervous System:
- Dizziness
Dermatologic:
- Night Sweats
- Pruritus
- Skin Rash
Gastrointestinal:
- Anorexia
Genitourinary:
- Urinary Tract Infection
Hematologic & Oncologic:
- Petechia
- Bruise
- Severe Cytopenia
Immunologic:
- Antibody Development
Neuromuscular & Skeletal:
- Myalgia
Respiratory:
- Bronchitis
- Flu-Like Symptoms
- Rhinitis
- Pharyngolaryngeal Pain
- Sinusitis
- Epistaxis
Miscellaneous:
- Fever
- Biodistribution Altered

Contraindications to Ibritumomab tiuxetan (Zevalin):

According to the manufacturer, there are no specific reasons to avoid using ibritumomab tiuxetan.

In Canada, they mention a few reasons why someone shouldn't use it:

If you've ever had a severe allergic reaction (like anaphylaxis) to ibritumomab tiuxetan, mouse proteins, or any part of the medicine, including yttrium chloride and rituximab.
If you're pregnant.
If you're breastfeeding.

So, if you're in Canada and any of the above applies to you, you shouldn't use ibritumomab tiuxetan.

Warnings and precautions

Suppression of bone marrow: [US Boxed Warning]

This is a warning about a potential side effect of the treatment.
Bone marrow makes important cells like platelets and neutrophils, which help with clotting and fighting infections.
Some patients might experience reduced production of these cells, leading to low counts in the blood (cytopenias).
This can happen more often, last longer, and be severe.
It's not recommended for patients with:
- A lot of lymphoma cells in their bone marrow (≥25% involvement),
- Weak bone marrow from previous strong treatments or low counts (platelets <100,000 or neutrophils <1,500),
- Failed stem cell collection before.
In studies, the lowest counts of platelets, neutrophils, and hemoglobin happened around 49 to 53 days, 61 to 62 days, and 68 to 69 days respectively after treatment.
Low counts might last over 12 weeks.
It took around 13 to 14 days for platelet recovery and 12 to 15 days for neutrophil recovery.
People with slightly low platelets at the start (100,000 to 149,000) might get more severe neutropenia and thrombocytopenia.
Bleeding can happen due to low platelets; avoid medicines affecting clotting or platelets.
Regularly check blood counts and platelets, usually weekly until things get better or as needed.
Watch out for problems from low counts (like infections or bleeding) for about 3 months after treatment.

Cutaneous or mucocutaneous reactions: [US-Bound Warning]

There's a warning about serious skin reactions from the treatment.
Some people have experienced severe skin issues, and in some cases, they have died from these reactions.
If someone starts having these severe skin problems, stop the treatment right away.
These skin problems can include conditions like erythema multiforme, Stevens-Johnson syndrome, and others that might cause skin to blister, peel, or form painful rashes.
These skin reactions can start a few days to 4 months after getting the treatment.

Radiation necrosis/extravasation:

Sometimes, the medication might accidentally leak out of the vein during the infusion. This is called extravasation.
If this happens, the area might become red and could develop an ulcer (a sore).
Keep a close eye on where the infusion is given, and if there are signs of a leak, like redness or pain, stop the infusion right away. If needed, the infusion can be restarted in another arm or leg.
In one case, a patient developed redness and a sore some time after the medication leaked out. This damage was due to the radiation from the drug and is known as radiation necrosis.

In short, it's crucial to monitor the site where the drug is given for any issues and to act quickly if there are any signs of a problem.

Infusion reactions: [US Boxed Warning]

There's a warning that the rituximab part of the treatment can cause severe, sometimes deadly, reactions during infusion.
If someone has a serious reaction while getting the drug, the infusion should be stopped right away and the entire treatment plan discontinued.
Some people have died from reactions to rituximab, and these deaths were often linked to issues like severe breathing problems, low oxygen levels, heart problems, or irregular heartbeats.
Most of these severe reactions (80%) happened the first time someone received rituximab.
Because of these risks, the drug should be given somewhere that's ready to handle emergencies.
Most of these reactions happen shortly after the infusion starts (within 30 to 120 minutes).
Other symptoms can include low blood pressure, swelling, breathing issues, and skin reactions like hives.
If the reactions are not as severe, slowing down or pausing the infusion might help.

In short, while getting rituximab, it's vital to monitor for any signs of a reaction, and medical professionals should be ready to respond quickly if something goes wrong.

Radiation injury

After getting the treatment, some people have experienced radiation damage to their tissues. This can happen up to a month later.
This damage often shows up in or around the areas where the lymphoma (cancer) is present.

In short, after the treatment, it's important to monitor for any signs of radiation damage, especially near areas affected by the lymphoma.

Secondary malignancies

The radiation from the treatment might cause other types of cancer to develop.
Some people have gotten new cancers like acute myelogenous leukemia (a type of blood cancer) or myelodysplastic syndrome (a bone marrow disorder) after the treatment.
On average, these new cancers showed up about 1.9 years after getting the ibritumomab treatment, but it ranged from as soon as 0.4 years to as long as 6.3 years later.

In short, after receiving ibritumomab treatment, there's a risk of developing other types of cancers in the future. It's crucial to stay vigilant and undergo regular check-ups.

Ibritumomab tiuxetan: Drug Interaction

Risk Factor C (Monitor therapy)
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.)	May enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding.
Anticoagulants	May enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding.
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.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Smallpox and Monkeypox Vaccine (Live)	Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live).
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
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.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Leflunomide	Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
Upadacitinib	Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib.
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live).

Monitoring parameters:

Regular Blood Checks

Do a complete blood count (CBC) with details and platelet counts:
- Every week until numbers get back to normal.
- Or when needed based on the patient's condition.
Before giving the medicine on day 7, 8, or 9, always check the platelet count.
Watch out for low blood counts (and problems they can cause) for up to 3 months after the treatment.

Checking for Hepatitis B

Before starting treatment, do these tests to check for Hepatitis B:
- Hepatitis B surface antigen (HBsAg).
- Hepatitis B core antibody (anti-HBc). Use a test that checks both IgG and IgM or just the IgG. Don't only use the IgM test.
If HBsAg is negative but anti-HBc is positive:
- Check for Hepatitis B reactivation by testing HBV DNA and ALT. Do this about every 3 months during treatment.

Other Monitoring

Watch for signs of active Hepatitis B:
- During treatment and for up to 12 months after it ends.
Check for allergic reactions related to the infusion:
- Usually, these happen within 30 to 120 minutes of getting the medicine.
During the ibritumomab infusion, make sure the medicine isn't leaking out of the vein.
Look out for severe skin reactions.

How to administer Ibritumomab tiuxetan?

Rituximab Infusion:

First, give rituximab slowly at 50 mg/hour.
If there's no bad reaction, increase the speed by 50 mg/hour every half-hour, but don't go over 400 mg/hour.
If there's a severe reaction, stop the infusion (also stop the whole ibritumomab treatment). If it's not as severe, slow down or pause the infusion. It can resume at half the previous speed when the patient feels better.
If no reaction happened in the first rituximab infusion, the next time you can start at 100 mg/hour and increase by 100 mg/hour every half-hour if tolerated.
If there was a reaction with the first rituximab infusion, start at 50 mg/hour and increase by 50 mg/hour every half-hour.

Y-90 Ibritumomab:

Give Y-90 ibritumomab within 4 hours after the rituximab infusion.
Inject it slowly over 10 minutes through a special filter placed between the syringe and the IV line.
Flush the line with at least 10 mL of normal saline after injecting.
Be careful to not let the medicine leak out of the vein (extravasation). Watch the site closely. If leakage happens, stop the infusion and restart it in another place.

Handling Precautions:

Y-90 ibritumomab is a radioactive substance. Use the right safety measures for handling and disposal.

Mechanism of action of Ibritumomab tiuxetan (Zevalin):

Ibritumomab is like a special delivery truck designed to target a specific type of cell called B lymphocytes, which can be found in both normal and sick cells.
It's paired with something called tiuxetan, which holds onto a radioactive substance, Yttrium-90 (Y90).
When combined, ibritumomab takes this radioactive substance directly to the targeted cells, even though it can also connect to similar cells in other body parts, including the intestines.
Once at its target, the radioactivity causes damage to those cells and their neighbors by producing harmful particles.

B Cell Recovery:

It takes about 12 weeks for B cells to start getting better.
Generally, within 9 months, they are back to normal levels.

Where It Goes:

The treatment goes to different parts of the body with lymphoid cells.
It also finds lymphoid nodules in organs like intestines, spleen, testes, and liver.

How It's Processed: