drug-monograph

oFAtumumab

Other Names

Arzerra®

Appearance

Clear, colourless solution

A - Drug Name

oFAtumumab

COMMON TRADE NAME(S): Arzerra®

B - Mechanism of Action and Pharmacokinetics

Ofatumumab is a human monoclonal antibody (IgG 1 Kappa) that targets CD20 on B lymphocytes, resulting in complement-dependent and antibody-dependent cell-mediated cytotoxicity and cell death. In non-clinical studies, ofatumumab has activity in rituximab resistant models.

Distribution

Cmax increases with subsequent infusions

Metabolism

IgG molecules are catabolised by ubiquitous proteolytic enzymes and target-mediated clearance via binding to B-cells.

Elimination

Clearance is dose dependent in the usual dosing range and decreases with repeat dosing. There is large intersubject variability.

Half-life

14 days

C - Indications and Status

Health Canada Approvals:

In combination with chlorambucil for the treatment of chronic lymphocytic leukemia (CLL) in patients who have not received prior therapy and for whom fludarabine-based therapy is considered inappropriate
Treatment of CLL that is refractory to fludarabine and alemtuzumab (Note: Marketing approval for the refractory indication was based on objective response, without demonstration of symptom or overall survival benefit.)

D - Adverse Effects

Emetogenic Potential:

Minimal

Extravasation Potential: None

Adverse events noted were based on an open-label, non-randomized trial of single agent ofatumumab in patients with relapsed or refractory CLL.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Arrhythmia (6%) (including bradycardia)	I E
	Arterial/venous thromboembolism (rare)	E D
	Hypertension (4%)	E
	Hypotension (6%)	E
Dermatological	Rash (13%) (may be severe)	E
Gastrointestinal	Abdominal pain (6%)	E
	Anorexia, weight loss (4%)	E D
	Diarrhea (17%)	E
	GI obstruction (rare)	E D
	Mucositis (rare)	E
	Nausea, vomiting (13%)	E
General	Fatigue (16%)	E
	Fluid retention (11%)	E D
Hematological	Hemolysis (rare)	E
	Immunosuppression (16%) ± opportunistic infections (viral/TB infection/reactivation)	E D
	Myelosuppression ± infection, bleeding (18%) (may be severe)	E
Hepatobiliary	↑ LFTs (rare; may be severe)	E
Hypersensitivity	Hypersensitivity (4%)	I
Immune	Cytokine release syndrome (1%)	I
Metabolic / Endocrine	Hyperthyroidism (rare)	D
	Tumor lysis syndrome (rare)	E
Musculoskeletal	Musculoskeletal pain (10%)	E D
Neoplastic	Lymphoma (Hodgkin's; rare)	L
Nervous System	Cognitive disturbance (rare)	E
	Headache (6%)	E
	Insomnia (7%)	E D
	Leukoencephalopathy (PML; rare)	D
	Neuropathy (5%)	E D
Respiratory	Cough, dyspnea (24%)	E
	Pulmonary edema (during infusion, rare)	I

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

The most common side effects for ofatumumab include cough, dyspnea, myelosuppression ± bleeding, immunosuppression, infection, rash, diarrhea, fatigue, nausea, vomiting, fluid retention and musculoskeletal pain.

Infusion reactions may occur despite premedication and may be severe or fatal (e.g. anaphylactic reaction and cytokine release syndrome). Infusion reactions tend to occur more frequently in the first two treatments. Patients with decreased pulmonary function are at higher risk and should be carefully monitored during infusions.

Serious and/or severe cardiovascular events have been described. Patients with cardiac disease should be carefully monitored during infusions.

Prolonged and severe myelosuppression can occur with ofatumumab, lasting months beyond the last treatment. Complete blood counts should be monitored regularly.

Hepatitis B infection and reactivation have been described up to 12 months after treatment completion and may be fulminant. Hepatitis B testing should be performed in all patients before starting ofatumumab. Any patient who shows evidence of hepatitis B infection (surface antigen positive, or surface antigen negative but core antibody positive) should be referred to a hepatologist regarding HBV therapy and monitoring.

Infections (bacterial, viral or fungal, including opportunistic infections i.e. PJP, PML) occurred more frequently in patients treated with ofatumumab. Fatal events due to infections also occurred during and post-treatment in up to 20% of patients.

Patients at risk of tumour lysis syndrome (i.e. high tumour burden, lymphocyte count ≥ 25 x 10⁹) should be considered for prophylaxis 12-24 hours prior to ofatumumab infusion and be monitored closely.

E - Dosing

Refer to protocol by which patient is being treated.

Premedications (prophylaxis for infusion reactions):

Administer pre-medications 30 minutes to 2 hours prior to each infusion:

Acetaminophen 1000 mg PO (or equivalent)
Diphenhydramine 50 mg IV/PO or cetirizine 10 mg PO (or equivalent)
Prednisolone IV 50 mg^*

In previously untreated CLL:

If the patient does not experience a grade 3 or 4 IR in the 1st and 2nd infusion, the corticosteroid may be reduced or omitted.

In refractory CLL:

^*Dose of prednisolone is 100 mg or equivalent for these patients
Do not reduce corticosteroid dose for doses 1, 2 and 9.
For doses 3-8, based on clinical judgment, corticosteroid dose may be gradually reduced with successive infusions if a grade 3 or 4 IR did not occur with a preceding dose.
For doses 10-12, based on clinical judgment, prednisolone 50-100 mg or equivalent may be given if a grade 3 or 4 IR did not occur with dose 9

Adults:

Table 1: Single agent (Refractory CLL)

Refer to Section F for infusion rates.

Week	Infusion Number	Ofatumumab IV Dose
1	1	300 mg
2	2	2000 mg
3-8	3-8	2000 mg weekly
12	9	2000 mg
16, 20 and 24	10-12	2000 mg q 4weeks

_{*prednisolone 100mg or equivalent}

Combination with Chlorambucil (Previously untreated CLL)

Ofatumumab IV (see table 2) in combination with chlorambucil 10 mg/m²PO days 1 to 7 every 4 weeks

Table 2: Dosing in Combination with Chlorambucil

Refer to Section F for infusion rates.

Cycle Number	Ofatumumab Dose
1 (day 1)	300 mg
1 (day 8)	1000 mg
2-12^** (q 28 days)	1000 mg q 28 days

_{*prednisolone 50 mg or equivalent
**In the clinical trial, patients received treatment for a minimum of 3 cycles until best response, up to a maximum of 12 cycles}

Dosage with Toxicity:

Toxicity	Dosing*
GI obstruction	Hold; investigate and manage appropriately
Viral hepatitis or other serious infections	Discontinue
PML	Discontinue and refer to neurologist for diagnosis and treatment
Serious or life-threatening arrhythmias or other cardiac events	Discontinue
* missed or delayed doses may be administered later at MD discretion

Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Grade	Management	Re-challenge
1 or 2	Stop the infusion. Manage the symptoms. Restart: Restart the infusion at 50% of the rate at which the IR occurred (but not slower than 12 mL/hr). Infusion rate may be increased according to standard procedure.	No specific recommendations can be made at this time. Discontinue permanently if vital symptoms affected (e.g. anaphylaxis).
3	Stop the infusion. Aggressively manage symptoms. Restart: Restart the infusion at 12 mL/hour and increase according to standard procedure.
4	Stop the infusion. Aggressively manage symptoms.	Discontinue permanently (do not re-challenge).

Dosage with Hepatic Impairment:

Information not available. Elimination of ofatumumab is not restricted to hepatic tissue therefore hepatic impairment is unlikely to require dosage modification^.

Dosage with Renal Impairment:

No data available in severe renal impairment (CrCl < 30 mL/min). Baseline CrCl did not have a clinically relevant effect on pharmacokinetics.

CrCl (ml/min)	Dose
> 30	No adjustment needed
≤ 30	No data. Use with extreme caution or avoid.

Dosage in the elderly:

No dosage adjustment necessary. Patients aged 65 and older receiving ofatumumab in combination with chlorambucil experienced more serious adverse events, including myelosuppression and infections.

Dosage based on gender:

Females had higher Cmax and AUC values in pharmacokinetic studies. No dose adjustment recommended.

Children:

Safety and efficacy not established. It should not be used in children unless the benefit outweighs the risks.

F - Administration Guidelines

Ofatumumab should be administered only as an IV infusion with supplied in-line filter set. Do not administer as an IV push or bolus.
Compatible with sodium chloride 0.9%. It should not be mixed with other IV solutions or medications. Flush the line before and after ofatumumab administration with sodium chloride 0.9%.
Store diluted solution at 2° to 8°C

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Refractory CLL:

Infusions 1 and 2: Start at 12 mL/hr; if no infusion reactions with previous rate, may double rate every 30 minutes to a maximum of 200 mL/hr (approximately 6.5 hours)
Infusions 3 to 12: If no severe infusion reactions with first 2 infusions, start at 25 mL/hr. If no reaction with previous rate, may double rate every 30 minutes to a maximum of 400 mL/hr (approximately 4 hours)
Infusion rate:

Infusion Time (min)	Infusions 1 and 2 (mL/hour)	Infusions 3 to 12 (mL/hour)
0 - 30	12	25
31 - 60	25	50
61 - 90	50	100
91 - 120	100	200
>120	200	400

Previously untreated CLL:

Infusion 1: Start at 12 ml/hr, if no infusion reactions, may double rate every 30 minutes to a maximum of 400 ml/hr (approx. 4.5 hours)
Subsequent infusions: If no severe infusion reactions with first infusion, start at 25 ml/hr, may double rate every 30 minutes to a maximum of 400 ml/hr (approx. 4 hours)

Previously untreated CLL:

Infusion Time (min)	Infusion 1 (mL/hour)	Infusions 2 to 13 (mL/hour)
0 - 30	12	25
31 - 60	25	50
61 - 90	50	100
91 - 120	100	200
121 - 150	200	400
151 - 180	300	400
180 +	400	400

G - Special Precautions

Contraindications:

Patients who have a hypersensitivity to this drug or any of its components
Patients with known PML or a history of PML
Patients with active hepatitis
Avoid the use of live vaccines

Other Warnings/Precautions:

Consider risk vs. benefit of inactivated vaccines
Use with extreme caution in patients who are hepatitis B or C positive
Patients with history of cardiovascular disease should be monitored closely during and after infusions
Monitor patients with a history of decreased lung function closely during ofatumumab infusion

Pregnancy and Lactation:

Fetotoxicity: Documented in animals

Ofatumumab is not recommended for use in pregnancy. Adequate contraception (methods that result in < 1% pregnancy rate) should be used by both sexes during treatment, and for at least 6 months after the last dose.
Breastfeeding: No information available
Not recommended; human IgG is known to be secreted in milk.
Fertility effects: Unlikely

H - Interactions

Ofatumumab did not have a clinically relevant effect on the pharmacokinetics of bendamustine, chlorambucil or its active metabolite. No formal studies have been conducted with ofatumumab to determine other drug-drug or drug-laboratory interactions.

AGENT	EFFECT	MECHANISM	MANAGEMENT
Drugs that cause immunosuppression (e.g. leflunomide, etanercept, clozapine, other antineoplastics)	↑ risk of cytopenias and infections	Additive/synergistic	Caution; monitor therapy closely or avoid if possible

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
CBC	Baseline and before each dose and as clinically indicated during treatment, and after treatment completion
LFTs	Baseline and regular
Cardiac tests for all patients with cardiac risk factors	Baseline and periodic
Hepatitis B screening prior to treatment for all patients. Monitor for signs and symptoms of hepatitis B during treatment. Seropositive patients should see hepatologist and be closely monitored for several months after the last infusion.
Clinical toxicity assessment for infusion reactions (including cytokine release syndrome), cardiac (especially in patients with cardiac risk factors), infection, bleeding, neurotoxicity, respiratory, GI and skin toxicities	At each visit

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

K - References

Product Monograph: Arzerra® (ofatumumab). GlaxoSmithKline Inc. June 15, 2017

U.S. prescribing Information: Arzerra® (ofatumumab). GlaxoSmithKline Inc. September 2011.

September 2019 Updated infusion reaction information in Dosing section.

L - Disclaimer

Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.

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The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

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Last Updated: July 27, 2026

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