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OFATUMUMAB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to CD20 molecule on normal B lymphocytes and on B-cell chronic lymphocytic leukemia, resulting in B-cell lysis. Ofatumumab is used to treat patients with chronic lymphocytic leukemia.

Specific Substances

    1) 2F2
    2) GSK-1841157
    3) HuMax-CD20
    4) Ofatumumabum
    5) CAS 679818-59-8

Available Forms Sources

    A) FORMS
    1) Ofatumumab is available in the United States as 20 mg/mL solution in 10 mL single-use vials (100 mg of ofatumumab in 5 mL of solution per vial) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) USES
    1) Ofatumumab is used to treat patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Overview

Laboratory Monitoring

    A) Monitor vital signs, serial CBC with differential, and ECG after significant overdose.
    B) Monitor patients for clinical signs of infection.
    C) Administration of ofatumumab may result in progressive multifocal leukoencephalopathy (PML), including fatal cases of PML. Observe patients for new-onset or changes in neurologic signs or symptoms and perform relevant diagnostic tests (eg, brain MRI, lumbar puncture).

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor patients for clinical signs of infection.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Neutropenia and anemia have been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) Decontamination is not necessary; ofatumumab is administered parenterally.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reactions, but this is rare.
    E) ANTIDOTE
    1) None
    F) MYELOSUPPRESSION
    1) For severe neutropenia, administer colony stimulating factor. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes OR sargramostim 250 mcg/m(2)/day IV over 4 hours.
    G) ACUTE ALLERGIC REACTION
    1) MILD to MODERATE effects: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE Effects: Administer oxygen, aggressive airway management may be necessary. Administer antihistamines, epinephrine, corticosteroids as needed. Treatment includes IV fluids and ECG monitoring.
    H) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Patients with significant overdose should be sent to a health care facility for evaluation and treated until symptoms resolve.
    2) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    3) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected ofatumumab overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) In studies, the mean volume of distribution ranged from 1.7 L to 5.1 L. The mean clearance was approximately 0.01 L/hr and the mean half-life was approximately 14 days (range 2.3 to 61.5 days).
    K) DIFFERENTIAL DIAGNOSIS
    1) Ofatumumab may be administered to cancer patients in combination with other antineoplastic agents. Includes other agents that may cause myelosuppression (eg, methotrexate).

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose and schedule is 12 doses administered (as an IV infusion) as follows: initial dose of 300 mg, followed one week later by 2000 mg weekly for 7 doses (doses 2 to 8), followed 4 weeks later by 2000 mg every 4 weeks for 4 doses (doses 9 to 12). Dosing schedule may be adjusted based on tolerance. PEDIATRIC: The safety and effectiveness of ofatumumab have not been established in pediatric patients.

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ofatumumab is used to treat patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.
    B) PHARMACOLOGY: Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to the CD20 molecule on normal B lymphocytes and on B-cell chronic lymphocytic leukemia, resulting in B-cell lysis.
    C) EPIDEMIOLOGY: Overdose is very rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (10% or greater): Rash, diarrhea, nausea, neutropenia, anemia, fatigue, pneumonia, cough, dyspnea, upper respiratory tract infection, bronchitis, and fever. The following adverse effects have also been reported following therapeutic doses of ofatumumab: Hypertension, hypotension, tachycardia, peripheral edema, urticaria, hyperhidrosis, obstruction of the small intestine, muscle spasm, back pain, insomnia, headache, nasopharyngitis, sinusitis, chills, sepsis, multifocal leukoencephalopathy (some fatal), and infusion reactions.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported.
    0.2.20) REPRODUCTIVE
    A) There are no adequate and well-controlled studies of ofatumumab use in pregnant women. In animal studies, there was no evidence of maternal toxicity or teratogenicity after ofatumumab administration during pregnancy at up to 2.4 times the recommended human dose.

Clinical Effects

Summary Of Exposure

    A) USES: Ofatumumab is used to treat patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.
    B) PHARMACOLOGY: Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to the CD20 molecule on normal B lymphocytes and on B-cell chronic lymphocytic leukemia, resulting in B-cell lysis.
    C) EPIDEMIOLOGY: Overdose is very rare.
    D) WITH THERAPEUTIC USE
    1) COMMON (10% or greater): Rash, diarrhea, nausea, neutropenia, anemia, fatigue, pneumonia, cough, dyspnea, upper respiratory tract infection, bronchitis, and fever. The following adverse effects have also been reported following therapeutic doses of ofatumumab: Hypertension, hypotension, tachycardia, peripheral edema, urticaria, hyperhidrosis, obstruction of the small intestine, muscle spasm, back pain, insomnia, headache, nasopharyngitis, sinusitis, chills, sepsis, multifocal leukoencephalopathy (some fatal), and infusion reactions.
    E) WITH POISONING/EXPOSURE
    1) TOXICITY: There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), pyrexia was reported in 20% (all grades) and 3% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, pyrexia was reported in 25% (all grades) and 5% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    2) CHILLS: In 2 open-label clinical studies, chills (all grades) were reported in 8% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 10% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Chills of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, hypertension (all grades) was reported in 5% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 8% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Hypertension of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, hypotension (all grades) was reported in 5% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 3% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Hypotension of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), tachycardia was reported in 5% (all grades) and less than 1% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, tachycardia was reported in 7% (all grades) and 2% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    D) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), peripheral edema was reported in 9% (all grades) and less than 1% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, peripheral edema was reported in 8% (all grades) and 2% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), pneumonia was reported in 23% (all grades) and 14% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, pneumonia was reported in 25% (all grades) and 15% (grade 3 or greater) of patients who received ofatumumab (n=59). Cases of pneumonia included pneumonia, lung infection, lobar pneumonia, and bronchopneumonia (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, cough (all grades) was reported in 19% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 19% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Cough of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    C) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), dyspnea was reported in 14% (all grades) and 2% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, dyspnea was reported in 19% (all grades) and 5% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    D) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, upper respiratory tract infection (all grades) was reported in 11% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 3% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Upper respiratory tract infection of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    E) BRONCHITIS
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), bronchitis was reported in 11% (all grades) and less than 1% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, bronchitis was reported in 19% (all grades) and 2% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    F) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, nasopharyngitis (all grades) was reported in 8% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 8% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Nasopharyngitis of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    G) SINUSITIS
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), sinusitis was reported in 5% (all grades) and 2% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, sinusitis was reported in 3% (all grades) and 2% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) Administration of ofatumumab may result in progressive multifocal leukoencephalopathy (PML), including fatal cases of PML (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, headache (all grades) was reported in 6% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 7% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Headache of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, fatigue (all grades) was reported in 15% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 15% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Fatigue of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, insomnia (all grades) was reported in 7% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 10% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Insomnia of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, diarrhea (all grades) was reported in 18% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 19% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Diarrhea of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, nausea (all grades) was reported in 11% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 12% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Nausea of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    C) INTESTINAL OBSTRUCTION
    1) WITH THERAPEUTIC USE
    a) Treatment with ofatumumab may result in obstruction of the small intestine (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In clinical studies of chronic lymphocytic leukemia (CLL) patients with normal baseline neutrophil counts, neutropenia of grade 3 or greater was reported in 42% (45 of 108) of patients treated with ofatumumab, with 18% (19 of 108) of patients developing grade 4 neutropenia. New-onset grade 4 neutropenia lasted over 2 weeks in some patients (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), anemia was reported in 16% (all grades) and 5% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, anemia was reported in 17% (all grades) and 8% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), rash, including macular and vesicular rash, was reported in 14% (all grades) and less than 1% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, rash was reported in 17% (all grades) and 2% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, urticaria (all grades) was reported in 8% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 5% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Urticaria of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    C) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, hyperhidrosis (all grades) was reported in 5% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 5% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Hyperhidrosis of grade 3 or greater was not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    D) COMPLICATION OF INFUSION
    1) WITH THERAPEUTIC USE
    a) Infusion reactions, manifesting as dyspnea, pulmonary edema, laryngeal edema, bronchospasm, flushing, hypertension, hypotension, cardiac ischemia or infarction, syncope, back pain, abdominal pain, rash, urticaria, pyrexia, and angioedema, have been reported with the administration of ofatumumab, most often with the first 2 infusions (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    b) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), infusion reactions were reported in 44% of patients on the first day of infusion with ofatumumab 300 mg, 29% of patients on the second day of infusion with ofatumumab 2000 mg, and in fewer patients with subsequent infusions (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) SPASM
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies, muscle spasms (all grades) were reported in 5% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who received ofatumumab (n=154) and 3% of patients with CLL refractory to fludarabine and alemtuzumab who received ofatumumab (n=59). Muscle spasms of grade 3 or greater were not observed in either group (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).
    B) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In 2 open-label clinical studies of patients with relapsed or refractory chronic lymphocytic leukemia (CLL), back pain was reported in 8% (all grades) and 1% (grade 3 or greater) of patients treated with ofatumumab (n=154). In patients with CLL refractory to fludarabine and alemtuzumab, back pain was reported in 12% (all grades) and 2% (grade 3 or greater) of patients who received ofatumumab (n=59) (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate and well-controlled studies of ofatumumab use in pregnant women. In animal studies, there was no evidence of maternal toxicity or teratogenicity after ofatumumab administration during pregnancy at up to 2.4 times the recommended human dose.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) In animal studies, there was no evidence of maternal toxicity or teratogenicity after the administration of ofatumumab at up to 2.4 times the recommended human dose during organogenesis (Prod Info ARZERRA(R) intravenous injection, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) There are no adequate and well-controlled studies of ofatumumab use in pregnant women (Prod Info ARZERRA(R) intravenous injection, 2016).
    B) RISK SUMMARY
    1) There are no data on the use of ofatumumab during pregnancy to inform a drug-associated risk. Avoid administering live vaccines to neonates or infants who were exposed to ofatumumab in utero until B-cell recovery occurs (Prod Info ARZERRA(R) intravenous injection, 2016).
    C) ANIMAL STUDIES
    1) There was no evidence of maternal toxicity after ofatumumab administration at doses up to 2.4 times the recommended human dose during organogenesis. Ofatumumab crossed the placenta while decreased spleen weights as well as the depletion of peripheral B cells were noted in exposed dam fetuses (Prod Info ARZERRA(R) intravenous injection, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether ofatumumab is excreted in human milk or absorbed systemically after ingestion. Because ofatumumab is an IgG kappa human monoclonal antibody and human IgG is known to be present in human milk, caution should be used when administering ofatumumab to breastfeeding women (Prod Info ARZERRA(R) intravenous injection, 2016).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) Long term studies have not been done on ofatumumab to evaluate its effect on fertility (Prod Info ARZERRA(R) intravenous injection, 2016).

Carcinogenicity

    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential with ofatumumab.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) In an animal toxicity study, there was no evidence of tumorigenic or unexpected mitogenic responses in cynomolgus monkey administered ofatumumab (up to 3.5 times the human dose) for 7 months (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Genotoxicity

    A) At the time of this review, no data were available to assess the genotoxic or mutagenic effects of ofatumumab.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, serial CBC with differential, and ECG after significant overdose.
    B) Monitor patients for clinical signs of infection.
    C) Administration of ofatumumab may result in progressive multifocal leukoencephalopathy (PML), including fatal cases of PML. Observe patients for new-onset or changes in neurologic signs or symptoms and perform relevant diagnostic tests (eg, brain MRI, lumbar puncture).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with significant overdose should be sent to a health care facility for evaluation and treatment.

Monitoring

    A) Monitor vital signs, serial CBC with differential, and ECG after significant overdose.
    B) Monitor patients for clinical signs of infection.
    C) Administration of ofatumumab may result in progressive multifocal leukoencephalopathy (PML), including fatal cases of PML. Observe patients for new-onset or changes in neurologic signs or symptoms and perform relevant diagnostic tests (eg, brain MRI, lumbar puncture).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not necessary; ofatumumab is administered parenterally.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) PLASMAPHERESIS
    1) Unbound ofatumumab could likely be removed with plasmapheresis, but there is not experience using this modality in treating overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose and schedule is 12 doses administered (as an IV infusion) as follows: initial dose of 300 mg, followed one week later by 2000 mg weekly for 7 doses (doses 2 to 8), followed 4 weeks later by 2000 mg every 4 weeks for 4 doses (doses 9 to 12). Dosing schedule may be adjusted based on tolerance. PEDIATRIC: The safety and effectiveness of ofatumumab have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) CHRONIC LYMPHOCYTIC LEUKEMIA
    1) The recommended dose and schedule is as follows: Initial IV dose of 300 mg, followed by 1000 mg one week later (day 8) and on Day 1 of each subsequent cycle for up to 12 cycles (minimum of 3 cycles). Each 28-day period is considered one treatment cycle (Prod Info ARZERRA intravenous injection solution, 2014).
    B) EXTENDED TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA
    1) The recommended dose and schedule is as follows: Initial IV dose of 300 mg (day 1), followed by 1000 mg one week later (day 8), followed by 1000 mg 7 weeks later, and then every 8 weeks thereafter up to a maximum of 2 years (Prod Info ARZERRA(R) intravenous injection, 2016).
    C) REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA
    1) The recommended dose and schedule is 12 doses administered (as an IV infusion) as follows: Initial dose of 300 mg, followed one week later by 2000 mg weekly for 7 doses (doses 2 to 8), followed 4 weeks later by 2000 mg every 4 weeks for 4 doses (doses 9 to 12) (Prod Info ARZERRA intravenous injection solution, 2014).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of ofatumumab have not been established in pediatric patients (Prod Info ARZERRA intravenous injection solution, 2014).

Maximum Tolerated Exposure

    A) A toxic dose has not been established.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ofatumumab is a human IgG1-kappa monoclonal antibody that binds specifically to both the small and large extracellular loops of the CD20 molecule, which is expressed on normal B lymphocytes and on B-cell chronic lymphocytic leukemia. In vitro, the Fab domain of ofatumumab binds to the CD20 molecule while the Fc domain mediates immune effector functions resulting in B-cell lysis. Complement-dependent and antibody-dependent, cell-mediated cytotoxicity are suggested mechanisms of cell lysis (Prod Info ARZERRA(TM) intravenous injection, solution, 2009).

Physicochemical

Physical Characteristics

    A) A clear to opalescent, colorless, liquid (Prod Info ARZERRA(R) IV injection, 2011)

Ph

    A) 5.5 (Prod Info ARZERRA(R) IV injection, 2011)

Molecular Weight

    A) approximately 149 kiloDaltons (Prod Info ARZERRA(R) IV injection, 2011)

References

General Bibliography

    1) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
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