Pronunciation
(oh fa TOOM yoo
mab)
Index Terms
HuMax-CD20
Dosage Forms
Excipient
information presented when available (limited, particularly for generics);
consult specific product labeling.
Concentrate,
Intravenous [preservative free]:
Arzerra: 100
mg/5 mL (5 mL); 1000 mg/50 mL (50 mL) [contains edetate disodium, mouse
(murine) and/or hamster protein, polysorbate 80]
SLIDESHOW
Leukemia Symptoms And Lessons: Is A Solution In Sight?
Brand Names:
U.S.
Arzerra
Pharmacologic
Category
Antineoplastic
Agent, Anti-CD20Antineoplastic
Agent, Monoclonal Antibody
Pharmacology
Ofatumumab is a
monoclonal antibody which binds specifically the extracellular (large and
small) loops of the CD20 molecule (which is expressed on normal B lymphocytes
and in B-cell CLL) resulting in potent complement-dependent cell lysis and
antibody-dependent cell-mediated toxicity in cells that overexpress CD20.
Distribution
Vdss:
6.1 L (following repeated infusions)
Half-Life
Elimination
17.6 days
(following repeated infusions)
Use: Labeled
Indications
Chronic
lymphocytic leukemia, previously untreated: Treatment of previously untreated
chronic lymphocytic leukemia (CLL) (in combination with chlorambucil) when
fludarabine-based therapy is considered inappropriate
Chronic
lymphocytic leukemia, relapsed: Treatment of relapsed CLL (in combination with
fludarabine and cyclophosphamide).
Chronic
lymphocytic leukemia, refractory: Treatment of CLL refractory to fludarabine and
alemtuzumab
Chronic
lymphocytic leukemia, extended treatment: Extended treatment of patients who
are in complete or partial response after at least two lines of therapy for
recurrent or progressive CLL
Contraindications
There are no
contraindications listed in the manufacturer's US labeling.
Canadian
labeling: Hypersensitivity
to ofatumumab or any component of the formulation; presence or history of
progressive multifocal leukoencephalopathy.
Dosing: Adult
Note: Premedicate
with acetaminophen, an antihistamine, and a corticosteroid 30 to 120 minutes
prior to treatment (see Premedication below).
Chronic
lymphocytic leukemia (CLL), previously untreated: IV: Cycle 1 (cycle is 28 days):
300 mg on day 1, followed by 1,000 mg on day 8; Subsequent cycles: 1,000 mg on
day 1 every 28 days; continue for at least 3 cycles until best response or a
maximum of 12 cycles (in combination with chlorambucil) (Hillmen 2015)
Premedication: Premedicate
with oral acetaminophen (1,000 mg) or equivalent, an oral or IV antihistamine
(eg, diphenhydramine 50 mg or cetirizine 10 mg orally or equivalent), and an IV
corticosteroid (prednisolone 50 mg or equivalent). Full dose corticosteroid is
recommended for the first 2 infusions; in the absence of infusion reaction ≥
grade 3, may reduce or omit corticosteroid dose for subsequent infusions.
CLL,
relapsed: IV: Cycle 1 (cycle is 28 days): 300 mg on day 1, followed by 1,000 mg on
day 8; Subsequent cycles: 1,000 mg on day 1 every 28 days; continue for a
maximum of 6 cycles (in combination with fludarabine and cyclophosphamide)
(Robak 2017)
Premedication: Premedicate
with oral acetaminophen (1,000 mg) or equivalent, an oral or IV antihistamine
(eg, diphenhydramine 50 mg or cetirizine 10 mg orally or equivalent), and an IV
corticosteroid (prednisolone 50 mg or equivalent). Full dose corticosteroid is
recommended for the first 2 infusions; in the absence of infusion reaction ≥
grade 3, may reduce or omit corticosteroid dose for subsequent infusions.
CLL, refractory: IV:
Initial dose: 300 mg on day 1, followed 1 week later by 2,000 mg once weekly
for 7 doses (doses 2 to 8), followed 4 weeks later by 2,000 mg once every 4
weeks for 4 doses (doses 9 to 12; for a total of 12 doses) (Wierda 2010)
Premedication: Premedicate
with oral acetaminophen (1,000 mg) or equivalent, an oral or IV antihistamine
(eg, diphenhydramine 50 mg or cetirizine 10 mg orally or equivalent), and an IV
corticosteroid (prednisolone 100 mg or equivalent). Full dose corticosteroid is
recommended for doses 1, 2, and 9; in the absence of infusion reaction ≥ grade
3, may reduce or omit corticosteroid dose for doses 3 to 8; may administer
reduced corticosteroid dose (ranging from half to full dose) with doses 10 to
12 if ≥ grade 3 reaction did not occur with dose 9.
CLL, extended
treatment: IV: 300 mg
on day 1, followed by 1,000 mg on day 8, followed by 1,000 mg 7 weeks later and
then every 8 weeks for up to a maximum of 2 years (van Oers 2015)
Premedication: Premedicate
with oral acetaminophen (1,000 mg) or equivalent, an oral or IV antihistamine
(eg, diphenhydramine 50 mg or cetirizine 10 mg orally or equivalent), and an IV
corticosteroid (prednisolone 50 mg or equivalent). Full dose corticosteroid is
recommended for the first 2 infusions; in the absence of infusion reaction ≥
grade 3, may reduce or omit corticosteroid dose for subsequent infusions.
Dosing:
Geriatric
Refer to adult
dosing.
Dosing: Renal
Impairment
CrCl ≥30
mL/minute: There are no dosage adjustments provided in the US manufacturer's
labeling; however, there were no clinically relevant pharmacokinetic effects
observed in patients with baseline CrCl ≥30 mL/minute.
CrCl <30
mL/minute: There are no dosage adjustments provided in the manufacturer's
labeling (has not been studied).
Dosing: Hepatic
Impairment
There are no
dosage adjustments provided in the manufacturer's labeling (has not been
studied).
Dosing:
Adjustment for Toxicity
Infusion
reaction: Interrupt infusion for infusion reaction (any severity). If the
reaction resolves or remains at ≤ grade 2, resume with the following
modifications (based on the grade of the initial reaction):
Grade 1 or 2
infusion reaction:
Resume at
one-half of the previous rate; may increase (see Administration) based on
patient tolerance.
Grade 3 or 4
infusion reaction: Resume infusion at 12 mL/hour; may increase (see
Administration) based on patient tolerance.
If reaction
severity does not resolve to ≤ grade 2 despite management: Consider permanent
discontinuation
Anaphylactic
reaction: Discontinue permanently
Reconstitution
Prepare all
doses in 1,000 mL NS. Begin infusion within 12 hours of preparation.
300 mg dose:
Withdraw 15 mL from a 1,000 mL NS bag. Add contents of 3 ofatumumab 100 mg
vials to NS bag. Gently invert to mix; do not shake.
1,000 mg dose:
Withdraw 50 mL from a 1,000 mL NS bag. Add contents of 1 ofatumumab 1,000 mg
vial. Gently invert to mix; do not shake.
2,000 mg dose:
Withdraw 100 mL from a 1,000 mL NS bag. Add contents of 2 ofatumumab 1,000 mg
vials to NS bag. Gently invert to mix; do not shake.
Administration
Do not
administer IV push, IV bolus, or as a subcutaneous injection. Premedicate
with acetaminophen, an antihistamine, and a corticosteroid 30 to 120 minutes
prior to administration (see Dosing). Infuse in an environment equipped to
monitor for and manage infusion reactions. Administer with infusion pump and
administration set. Do not exceed infusion rates below. Do not mix with or
infuse with other medications. Flush line before and after infusion with NS.
Begin infusion within 12 hours of preparation. Interrupt infusion for any
severity of infusion reaction; if the reaction resolves or remains at ≤ grade
2, may resume infusion (see Dosage Adjustment for Toxicity).
Previously
untreated chronic lymphocytic leukemia (CLL), relapsed CLL, and extended
treatment of CLL:
Initial 300 mg
dose: Initiate
infusion at 12 mL/hour for 30 minutes, if tolerated (no infusion reaction)
increase to 25 mL/hour for 30 minutes, if tolerated, increase to 50 mL/hour for
30 minutes, if tolerated, increase to 100 mL/hour for 30 minutes, if tolerated,
increase to 200 mL/hour for 30 minutes, if tolerated increase to 300 mL/hour
for 30 minutes, if tolerated, increase to 400 mL/hour for remainder of
infusion. Median duration of infusion: 4.8 to 5.2 hours.
Subsequent 1,000
mg infusions (if no reaction to previous infusion): Initiate infusion at 25 mL/hour
for 30 minutes, if tolerated (no infusion reaction) increase to 50 mL/hour for
30 minutes, if tolerated, increase to 100 mL/hour for 30 minutes, if tolerated,
increase to 200 mL/hour for 30 minutes, if tolerated, increase to 400 mL/hour
for remainder of infusion. Median duration of infusion: 4.2 to 4.4 hours.
Refractory CLL:
Doses 1 and 2: Initiate
infusion at 12 mL/hour for 30 minutes, if tolerated (no infusion reaction)
increase to 25 mL/hour for 30 minutes, if tolerated, increase to 50 mL/hour for
30 minutes, if tolerated, increase to 100 mL/hour for 30 minutes, if tolerated,
increase to 200 mL/hour for remainder of infusion. Median duration of infusion:
6.8 hours.
Doses 3 to 12: Initiate
infusion at 25 mL/hour for 30 minutes, if tolerated (no infusion reaction)
increase to 50 mL/hour for 30 minutes, if tolerated, increase to 100 mL/hour
for 30 minutes, if tolerated, increase to 200 mL/hour for 30 minutes, if
tolerated, increase to 400 mL/hour for remainder of infusion. Median duration
of infusion: 4.2 to 4.4 hours.
Storage
Store intact
vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light.
Solutions diluted in NS for infusion must be started within 12 hours of
preparation (may store at 2°C to 8°C [36°F to 46°F] if not used immediately);
discard any remaining solution 24 hours after preparation.
Drug
Interactions
BCG
(Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG
(Intravesical). Avoid combination
Belimumab:
Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid
combination
Coccidioides
immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of
Coccidioides immitis Skin Test. Monitor therapy
Denosumab: May
enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk
for serious infections may be increased. Monitor therapy
Echinacea: May
diminish the therapeutic effect of Immunosuppressants. Consider therapy
modification
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). Consider therapy
modification
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. Consider therapy modification
Natalizumab:
Immunosuppressants may enhance the adverse/toxic effect of Natalizumab.
Specifically, the risk of concurrent infection may be increased. Avoid
combination
Nivolumab:
Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider
therapy modification
Ocrelizumab: May
enhance the immunosuppressive effect of Immunosuppressants. Monitor
therapy
Pidotimod:
Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor
therapy
Pimecrolimus:
May enhance the adverse/toxic effect of Immunosuppressants. Avoid
combination
Roflumilast: May
enhance the immunosuppressive effect of Immunosuppressants. Consider
therapy modification
Sipuleucel-T:
Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor
therapy
Tacrolimus
(Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid
combination
Tertomotide:
Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor
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. Consider
therapy modification
Trastuzumab: May
enhance the neutropenic effect of Immunosuppressants. Monitor therapy
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.Consider therapy
modification
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. Avoid combination
Adverse
Reactions
>10%:
Central nervous
system: Fatigue (15%)
Dermatologic:
Skin rash (14%)
Gastrointestinal:
Diarrhea (18%), nausea (11%)
Hematologic
& oncologic: Neutropenia (24%; ≥grade 3: ≥22%; may be prolonged >2
weeks), anemia (16%; grades 3/4: 5%)
Infection:
Infection (65% to 70%; includes bacterial, fungal, or viral), serious infection
(20%)
Respiratory:
Pneumonia (8% to 23%), cough (19%), upper respiratory tract infection (11% to 19%),
dyspnea (14%), bronchitis (9% to 11%)
Miscellaneous:
Infusion related reaction (46%; day 1 reactions: 25% to 44%; subsequent
infusions: 2% to 29%), fever (20%)
1% to 10%:
Cardiovascular:
Peripheral edema (9%), hypertension (5%), hypotension (5%), tachycardia (5%)
Central nervous
system: Chills (8%), insomnia (5% to 7%), headache (6%)
Dermatologic:
Urticaria (8%), hyperhidrosis (5%)
Hematologic
& oncologic: Hypogammaglobulinemia (5%; grades 3/4: <1%)
Infection:
Sepsis (8%), influenza (6%), herpes zoster (5% to 6%)
Neuromuscular
& skeletal: Back pain (5% to 8%), muscle spasm (5%)
Respiratory:
Nasopharyngitis (8%), sinusitis (5%)
<1%,
postmarketing, and/or case reports: Antibody development, hepatitis B
(new-onset or reactivation), porphyria cutanea tarda, progressive multifocal
leukoencephalopathy, Stevens Johnson syndrome, tumor lysis syndrome
ALERT: U.S.
Boxed Warning
Hepatitis B
virus infection:
Hepatitis B
virus (HBV) reactivation can occur in patients receiving CD20-directed
cytolytic antibodies, including ofatumumab, in some cases resulting in
fulminant hepatitis, hepatic failure, and death.
Progressive
multifocal leukoencephalopathy:
Progressive
multifocal leukoencephalopathy (PML) resulting in death can occur in patients
receiving CD20-directed cytolytic antibodies, including ofatumumab.
Warnings/Precautions
Concerns related
to adverse effects:
• Hematologic
toxicity: Severe and prolonged (≥1 week) cytopenias (neutropenia,
thrombocytopenia, and anemia) may occur. Grade 3 or 4 late-onset neutropenia
(onset ≥42 days after last treatment dose) and/or prolonged neutropenia (not
resolved 24 to 42 days after last dose) has been reported. Pancytopenia,
agranulocytosis, and fatal neutropenic sepsis have occurred when used in
combination with chlorambucil. Monitor blood counts regularly during and after
treatment; more frequently if grade 3 or 4 cytopenias develop.
• Hepatitis B
virus infection: [US Boxed Warning]: Hepatitis B virus (HBV)
reactivation may occur in patients receiving CD20-directed antibody treatment,
including ofatumumab; may result in fulminant hepatitis, hepatic failure, and
death. Fatal cases of HBV have also occurred in patients not
previously infected with HBV. Prior to initiating therapy, obtain hepatitis B
surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) measurements
in all patients; monitor for clinical and laboratory signs of hepatitis or HBV
during and for several months after treatment. HBV reactivation has been
reported up to 12 months after therapy discontinuation. Discontinue ofatumumab
(and concomitant medications) if viral hepatitis develops and initiate
appropriate antiviral therapy. Reactivation has occurred in patients who are
HBsAg positive as well as in those who are HBsAg negative but are anti-HBc
positive; HBV reactivation has also been observed in patients who had
previously resolved HBV infection. Use cautiously in patients who show evidence
of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or
HBsAg negative but anti-HBc positive); consult with appropriate clinicians
regarding monitoring and consideration of antiviral therapy before and/or
during ofatumumab treatment. The safety of resuming ofatumumab treatment
following HBV reactivation is not known; discuss reinitiation of therapy in
patients with resolved HBV reactivation with physicians experienced in HBV
management.
- American
Society of Clinical Oncology (ASCO) provisional clinical opinion update on
hepatitis B virus screening [Hwang 2015]) recommendations: Patients receiving
anti-CD20 antibodies are at high risk for hepatitis B virus (HBV) reactivation.
Screen for HBV infection infection with hepatitis B surface antigen (HBsAg) and
hepatitis B core antibody (anti-HBc) tests prior to treatment initiation;
either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be
used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM
as it may only confirm acute HBV infection). In addition, patients who have
risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV
prevalence, household or sexual contact with HBV infected patients, high-risk
behaviors [eg, intravenous drug use], and HIV infection) should also be
screened prior to beginning therapy. Initiate prophylactic antiviral therapy
(utilizing antivirals with low rates of viral resistance) for HBsAg
-positive/anti-HBc -positive patients (without delaying cancer therapy) and
continue the antivirals during and for ~6 to 12 months after completing
treatment. HBsAg negative/anti-HBc positive patients should be monitored for
HBV reactivation with HBV DNA and ALT testing approximately every 3 months
during treatment; antiviral therapy may be initiated prophylactically or begun
promptly at the first sign of HBV reactivation.
• Infection: Bacterial,
fungal, and new or reactivated viral infections may occur during and/or
following therapy; monitor closely for signs/symptoms of infection.
• Infusion
reaction: May cause serious infusion reactions (some fatal); reactions may
include bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing,
hypertension, hypotension, syncope, cardiac ischemia/infarction, acute coronary
syndrome, arrhythmia, bradycardia, back pain, abdominal pain, fever, rash,
urticaria, angioedema, cytokine release syndrome, and/or
anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently
with the first 2 infusions and may occur despite premedication. Premedicate
prior to infusion with acetaminophen, an antihistamine, and a corticosteroid.
Interrupt infusion for reaction of any severity and institute appropriate
treatment; may require subsequent rate modification. Discontinue immediately
and permanently if anaphylactic reaction occurs.
• Progressive
multifocal leukoencephalopathy: [US Boxed Warning]: Progressive
multifocal leukoencephalopathy (PML) resulting in death may occur with
CD20-directed antibody treatment, including ofatumumab. Consider PML in any
patient with new onset or worsening neurological symptoms and if PML is
suspected, discontinue ofatumumab and evaluate promptly.
• Tumor lysis
syndrome: Tumor lysis syndrome (TLS) has occurred in patients receiving
ofatumumab; patients with a high tumor burden and/or high circulating
lymphocyte counts (>25,000/mm3) are at increased risk for TLS.
Administer prophylactic antihyperuricemic therapy and aggressive hydration
beginning 12 to 24 hours prior to ofatumumab treatment. Correct electrolyte
abnormalities; monitor renal function and hydration status.
Concurrent drug
therapy issues:
• Drug-drug interactions:
Potentially significant interactions may exist, requiring dose or frequency
adjustment, additional monitoring, and/or selection of alternative therapy.
Consult drug interactions database for more detailed information.
• Immunizations:
Live vaccines should not be given to patients who have recently received
ofatumumab; there is no data concerning secondary transmission. The ability to
generate an immune response to any vaccine following treatment is unknown.
Special
populations:
• Elderly: Patients
≥65 years experienced a higher incidence of adverse reactions (compared with
younger patients).
Monitoring
Parameters
CBC with
differential (at regular intervals during and after therapy; more frequently if
grades 3 or 4 cytopenias develop), renal function, electrolytes
Hepatitis B
virus screening recommendations (ASCO provisional clinical opinion update
[Hwang 2015]): Screen for hepatitis B virus (HBV) infection with hepatitis B
surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) tests prior to
treatment initiation; either a total anti-HBc (with both IgG and IgM) or
anti-HBc IgG test should be used to screen for chronic or resolved HBV
infection (do not use anti-HBc IgM as it may only confirm acute HBV infection).
HBsAg negative/anti-HBc positive patients should be monitored for HBV
reactivation with HBV DNA and ALT testing approximately every 3 months during
treatment.
Signs of active
hepatitis B infection (during and for up to 12 months after therapy
completion); signs/symptoms of hepatitis; signs or symptoms of infusion
reaction; signs of infection; fluid status; signs/symptoms of intestinal
obstruction (eg, abdominal pain, repeated vomiting); signs/symptoms of
progressive multifocal leukoencephalopathy (focal neurologic deficits, which may
present as hemiparesis, visual field deficits, cognitive impairment, aphasia,
ataxia, and/or cranial nerve deficits).
Pregnancy
Considerations
Adverse events
were observed in some animal reproduction studies. Based on animal data,
prolonged depletion of circulating B cells may occur; avoid administering live
vaccines to newborns exposed to ofatumumab in utero until B cell recovery
occurs.
Patient
Education
• Discuss
specific use of drug and side effects with patient as it relates to treatment.
(HCAHPS: During this hospital stay, were you given any medicine that you had
not taken before? Before giving you any new medicine, how often did hospital
staff tell you what the medicine was for? How often did hospital staff describe
possible side effects in a way you could understand?)
• Patient may
experience muscle spasms or insomnia. Have patient report immediately to
prescriber signs of infection, signs of hepatic impairment, severe asthenia,
considerable nausea, dyspepsia, intolerable diarrhea, ecchymosis, hemorrhaging,
back pain, tachycardia, bradycardia, arrhythmia, severe headache, edema of
extremities, injection site irritation, signs of tumor lysis syndrome, chills,
flushing, dyspnea, significant dizziness, syncope, or angina (HCAHPS).
• Educate
patient about signs of a significant reaction (eg, wheezing; chest tightness;
fever; itching; bad cough; blue skin color; seizures; or swelling of face,
lips, tongue, or throat). Note: This is not a comprehensive
list of all side effects. Patient should consult prescriber for additional
questions.
Intended Use and
Disclaimer: Should not be printed and given to patients. This information is
intended to serve as a concise initial reference for healthcare professionals
to use when discussing medications with a patient. You must ultimately rely on
your own discretion, experience and judgment in diagnosing, treating and
advising patients.
