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:

• Prior to each rituximab infusion premedication should be done with oral acetaminophen 650 mg and oral diphenhydramine 50 mg.
• Following the 1st line, chemotherapy allow at least 6 weeks, but no more than 12 weeks before starting the treatment
• Before starting treatment regimen platelets should recover to ≥150,000/mm³.

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

• Ibritumomab is administered only as part of the Zevalin therapeutic regimen (a combined treatment regimen with rituximab).
• The regimen consists of two steps:

  • Day 1:

    • Rituximab: IV:
      • 250 mg/m² at an initial rate of 50 mg/hour. If there is no hypersensitivity or infusion-related event, the infusion should be increased in increments of 50 mg/hour every half an hour, to a maximum dose of 400 mg/hour.
      • If severe infusion reactions occur, stop rituximab, and discontinue regimen.
      • For less severe infusion reactions, the infusion should be temporarily slowed or interrupted and upon the improvement of symptoms, the infusion may be resumed at one-half the previous rate.

  • Day 7, 8, or 9 of treatment:

    • Rituximab: IV:
      • 250 mg/m² at an initial rate of 100 mg/hour (50 mg/hour if infusion-related events occurred with the day 1 infusion).
      • If there is no hypersensitivity or infusion-related event, the infusion should be increased in increments of 100 mg/hour every half an hour, to a maximum of 400 mg/hour, as tolerated (increase in 50 mg/hour increments every 30 minutes if initial infusion rate was 50 mg/hour).
    • Y-90 ibritumomab (within 4 hours after completion of the rituximab infusion): IV:
      • Platelet count ≥150,000 cells/mm³:
        • 0.4 mCi/kg (14.8 MBq/kg) actual body weight over 10 minutes;
        • The maximum dose: 32 mCi (1184 MBq)
      • Platelet count between 100,000 to 149,000 cells/mm³ (in relapsed or refractory patients):
        • 0.3 mCi/kg (11.1 MBq/kg) actual body weight over 10 minutes;
        • The maximum dose: 32 mCi (1184 MBq)
      • Platelet count <100,000 cells/mm³:
        • Do not administer
    • Maximum dose:
      • The  prescribed, measured and administered dose of Y-90 ibritumomab must not exceed 32 mCi (1184 MBq), irrespective of the patient's body weight

Use in Children:

Not indicated.

Ibritumomab tiuxetan (Zevalin) Pregnancy Risk Category: D

• Due to its radioactivity, Y-90 ibritumomab can cause harm to the fetus if given during pregnancy.
• Additionally, ibritumomab Tiuxetan (Humanized Monoclonal Antibody) (IgG) is also available.
• The potential placental transfer human IgG depends on the IgG subclass and the gestational year. It generally increases with each pregnancy.
• The lowest possible exposure is expected during the period of organogenesis.
• Before starting therapy, it is important to determine if you are pregnant.
• Women with reproductive potential should avoid tiuxetan pregnancy during treatment with ibritumomab.
• Effective contraception must be used during treatment as well as for at least 12 month following the last dose.
• This applies to male partners with female reproductive potential and females of reproductive capacity.

Ibritumomab Tiuxetan is used during breastfeeding

• It is unknown if breast milk contains ibritumomab.
• Many immunoglobulins can be found in milk so ibritumomab Tiuxetan should be excreted from breast milk
• Do not breastfeed during treatment or for six months afterward due to the possibility of serious side effects.

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):

• There are no contraindications in the labeling.

Canadian labeling:

• Patients with type I hypersensitivity, anaphylactic reactions to ibritumomab, murine proteins or any component of this formulation (yttrium chloride, rituximab) are contraindicated
• Pregnancy
• Breastfeeding

Warnings and precautions

• Suppression of bone marrow: [US Boxed Warning]

  • Common causes of severe, delayed, and prolonged cytopenias (thrombocytopenia, neutropenia) are:
  • Patients with lymphoma marrow involvement greater than 25%, patients with impaired bone marrow reserves (eg, prior myeloablative therapy, platelet count 100,000./mm3, neutrophil count >1,500/mm3, hypocellular cell marrow) and patients who have had stem cell collection failure prior to this procedure should not be given.
  • The median platelet, ANC and hemoglobin nadir for studies were respectively 49 to 53, 61 and 62, and 68 and 69 days.
  • The persistence of cytopenias can last beyond twelve weeks.
  • The median durations of thrombocytopenia, neutropenia, and ANC recovery were respectively 24 to 35 and 22 to 29, respectively.
  • Patients with mild baseline thrombocytopenia (100,000. to 149,000/mm3) might experience more severe neutropenia or thrombocytopenia.
  • Hemorrhage can occur from thrombocytopenia, which may cause hemorhage. Therefore, it is important to avoid the use of any medications that interfere with coagulation and platelet function.
  • CBC and platelets should both be checked weekly until they are fully recovered or as indicated by a physician.
  • For complications such as hemorhage or febrile neutropenia, strict monitoring should be performed for at least 3 months.

• Cutaneous or mucocutaneous reactions: [US-Bound Warning]

  • There have been reports of severe cutaneous and mucocutaneous skin reactions that led to fatalities.
  • Patients with severe cutaneous and mucocutaneous skin reactions should stop using any component of the therapeutic regimen, including Stevens-Johnson Syndrome, Stevens-Johnson Syndrome, toxic epidermal Necrolysis, bullous Dermatitis, exfoliative dermatitis, or erythema multiforme.
  • Infusions may cause symptoms within days or up to four months.

• Radiation necrosis/extravasation:

  • Extravasation has been associated with erythema and ulceration at the infusion site.
  • Monitor the infusion site.
  • Terminate infusion immediately if you feel the need to.
  • A case report of delayed erythema, and ulceration has been reported. It is described as radiation necrosis after yttrium 90 ibritumomab exavasation.

• Infusion reactions: [US Boxed Warning]

  • Infusion reactions that can be fatal may occur when the Rituximab component is used in the therapeutic regimen.
  • If you experience severe reactions to infusions, stop immediately and discontinue any therapeutic components.
  • Fatalities from rituximab injections were caused by hypoxia, acute respiratory distress syndrome, pulmonary infiltrates and cardiogenic shock. 80% of fatalities were due to the first rituximab injection.
  • You should be administered immediately in an area with access to resuscitative procedures.
  • Infusion reactions are most common with the first infusion (onset within 30-60 minutes).
  • Hypotension, angioedema and bronchospasm are some other possible reactions.
  • You can manage milder reactions by temporarily stopping or slowing down infusion.

• Radiation injury

  • Radiation injury that has been delayed (up to one month) in areas with lymphomatous involvement or close to it has occurred.

• Secondary malignancies

  • Radiation doses from therapeutic exposure can cause malignancies.
  • Secondary malignancies, such as acute myelogenous lymphoma and/or myelodysplastic disorder, have been also reported. The median time it took to diagnose secondary malignancy after ibritumomab was 1.9 years. There were a variety of 0.4-6.3 years.

Ibritumomab tiuxetan: Drug Interaction

Monitoring parameters:

• CBC with differentials and platelet counts every week until recovery has occurred or as clinically necessary.
• You must have a platelet count before day 7, 8 or 9.
• For up to three months, you should be monitored for cytopenias and related complications.

Hepatitis B screening recommendations (ASCO provisional Clinical Opinion Update [Hwang 2015]).:

• Before starting treatment, screen for hepatitis B virus infection (HBV).
• To screen for chronic or recurrent HBV infection, either a total anti HBc test (with both IgG/IgM) or an anti-HBc IgG (do not use anti HBc IgM because it may only confirm acute HBV infections).
• Monitor patients with HBsAg and anti-HBc negative status for HBV reactivation by HBV DNA testing every three months.
• Monitor for symptoms of active hepatitis B infection during and up to 12 months following treatment.
• Monitor for infusion-related allergic reaction (typically within 30 to 60 minutes of administration), extravasation during intramuscular infusion, and severe cutaneous or mucocutaneous reactions.

How to administer Ibritumomab tiuxetan?

Rituximab

• Initial doses of rituximab should not exceed 50 mg/hour.
• Infusion rates should be increased in increments of 50 mg/hour every 30 minutes to avoid hypersensitivity and other infusion-related events.
• Infusions should be stopped immediately for severe reactions (discontinue ibritumomab treatment). Less severe reactions can be managed by stopping or slowing down infusions.
• Infusions may be continued at half the rate of usual when there are no severe reactions. Patients with milder symptoms will likely experience a decrease in their need for continuous treatment.
• Infusion reactions can not occur in the initial rituximab injection. The rate can then be increased to 400 mg/hour at 30-minute intervals.
• Infusion reactions may occur after initial Rituximab infusion. Start at 50 mg/hour, increasing by 50 mg/hour every 30 minutes.

Y-90 Ibritumomab

• Within four hours after rituximab injection is completed, you can start. __S.9__
• Slowly inject the 0.22-micron low-protein binding in-line filter for 10 minutes. This filter is placed between the syringe port and infusion port. 
• The line should be flushed using at least 10mL of normal saline after injection.
• Extravasation should not be allowed and the infusion site must be monitored closely.
• Extravasation symptoms can be detected and treated immediately.

Mechanism of action of Ibritumomab tiuxetan (Zevalin):

• Ibritumomab, a monoclonal antibody that targets the CD20 antigen on pre-B lymphocytes and mature B lymphocytes (normal or malignant), is available.
• In vitro, Ibritumomab binding induces apoptosis of B lymphocytes. It is combined with the chelator tiuxetan which acts as a specific chelation spot for Yttrium 90 (Y90).
• Monoclonal antibodies act as a delivery system for radioactive isotopes to targeted cells.
• However, binding has been observed in lymphoid lymphoid nodules in large and small intestines as well as in lymphoid cells throughout your body.
• Beta-emission is the formation of free radicals in target cells. This causes cellular damage.

Duration:

• B cell began to recover in ~12 weeks and generally reach in normal range within 9 months

Distribution:

• To lymphoid cells throughout the body and in lymphoid nodules in organs such as the large and small intestines, spleen, testes, and liver

Metabolism:

• Has not been characterized;
• the product of yttrium-90 radioactive decay is zirconium-90 (nonradioactive)

Half-life elimination:

• Y-90 ibritumomab: 30 hours
• Yttrium-90 decays with a physical half-life of 64 hours

Excretion:

• A median of 7.2% of the radiolabeled activity was excreted in urine over 7 days

International Brands of Ibritumomab tiuxetan:

• Zevalin Y-90
• Zevalin
• Zevamab

Ibritumomab tiuxetan Brand Names in Pakistan:

No Brands Available in Pakistan.