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Cancer Type

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Drug Monographs
Treatment Regimens
Scientific Name:
OFATUMUMAB
Brand Name(s):
Arzerra

Drug Monograph

Pharmacology

Mechanism of Action

Ofatumumab is a human monoclonal antibody (IgG1κ) that targets the CD20 molecule expressed on B lymphocytes. The binding of ofatumumab induces recruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of tumour cells. In addition, the binding of ofatumumab induces cell death through antibody-dependent cell-mediated cytotoxicity.

Pharmacokinetics

Distribution
Cmax: First Infusion-136 mcg/mL; Fourth Weekly Infusion- 1061 mcg/mL
AUC: First Infusion- 7848 mcg.h/mL; Fourth Weekly Infusion- 420,840 mcg.h/mL
Excretion
CL: First Infusion- 63.7mL/hr; Fourth Weekly Infusion-8.5mL/hr
Vss: First Infusion- 3.24L; Fourth Weekly Infusion- 1.73L
T1/2: First Infusion- 1.3 days; Fourth Weekly Infusion- 11.5 days

Side Effects

IMMEDIATE ONSET (hours to days)
   arrhythmia (6%)
   hypersensitivity (4%)
EARLY ONSET (days to weeks)
* Tumor Lysis Syndrome (rare)
* Hepatitis B Virus reactivation
* infections
* Cardiovascular Events: arrhythmia (6%), arterial/venous thromboembolism (rare), hypertension (4%), hypotension (6%)
   rash (13%)
   diarrhea (17%), abdominal pain (6%), anorexia, weight loss (4%), GI obstruction (rare), mucositis (rare), nausea and  vomiting (13%)
   fatigue (16%), fluid retention (11%), hemolysis (rare)
   immunosuppression ± opportunistic infections (viral/TB infection/reactivation)
   myelosuppression ± infection, bleeding (18%- may be severe)
   ↑ LFTs (rare; may be severe)
   musculoskeletal pain (10%)
   cognitive disturbance (rare), headache (6%)
   insomnia (7%), neuropathy (5%),
   cough, dyspnea (24%)
DELAYED ONSET (weeks to months)
* Progressive multifocal leukoencephalopathy (PML)

Therapeutics

Approved Indications

Indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.

Routes

IV

Administration

Administration
• Administer using an IV infusion pump, an administration set and the provided in-line filter extension set
Intravenous infusion that must be diluted prior to administration.
• Do not administer as an intravenous push or bolus.
• Administer with in-line filter supplied with product

IV Compatibility

Ofatumumab must not be mixed with, or administered as an infusion with, other medicinal products or intravenous solutions. Flush line before and after Ofatumumab administration with 0.9% sodium chloride to avoid this.

Dosing

Premedication:
• Acetaminophen 1,000 mg PO, IV or PO antihistamine (cetirizine 10 mg or diphenhydramine 50 mg), dexamethasone 8 mg IV or PO 30 minutes to 2 hours prior to each dose.
• Do not reduce corticosteroid dose for Doses 1, 2, and 9.
• Corticosteroid dose may be reduced as follows for Doses 3 through 8 and 10 through 12:
   • Doses 3 through 8: Gradually reduce corticosteroid dose with successive infusions if a Grade 3 or greater infusion reaction did not occur with the preceding dose.
   • Doses 10 through 12: Administer prednisolone 50 mg to 100 mg or equivalent if a Grade 3 or greater infusion reaction did not occur with Dose 9.
Recommended dose:
• First infusion: 300 mg Ofatumumab
• Subsequent infusions: 2,000 mg Ofatumumab
The infusion schedule is 8 consecutive weekly infusions, followed 4 weeks later by 4 consecutive monthly (i.e. every 4 weeks) infusions.
• First and second infusions: Administer over 6.5 hours through a peripheral linear indwelling catheter. The initial rate of the first and second infusion of Ofatumumab should be 12 mL/h. During infusion, the rate should be doubled every 30 minutes to a maximum of 200 mL/h.
• Subsequent infusions: If the second infusion has been completed without severe infusion related adverse drug reactions, the remaining infusions (3-12) should be administered over 4 hours through a peripheral line or indwelling catheter. Initiate infusion at a rate of 25 mL/h. In the absence of infusional toxicity, the rate of infusion may be increased every 30 minutes up to a maximum of 400 mL/h.
Infusion Rates:
• 0-30 minutes: Infusion 1 and 2- 12mL/hr; Infusion 3 – 12- 25 mL/hr
• 31-60 minutes: Infusion 1 and 2- 25mL/hr; Infusion 3 – 12- 50 mL/hr
• 61-90 minutes: Infusion 1 and 2- 50mL/hr; Infusion 3 – 12- 100 mL/hr
• 91-120 minutes: Infusion 1 and 2- 100mL/hr; Infusion 3 – 12- 200 mL/hr
• Over 120 minutes: Infusion 1 and 2- 200mL/hr; Infusion 3 – 12- 400mL/hr

Dose Adjustment Criteria

Infusion Related Reaction
Infusion related ADRs might lead to slower infusion rates.
Mild or Moderate ADR: the infusion should be interrupted and restarted at half of the infusion rate at the time of interruption, when the patient’s condition is stable. If the infusion rate had not been increased from the starting rate of 12 mL/hour prior to interrupting due to an ADR, the infusion should be restarted at 12 mL/hour, the standard starting infusion rate. The infusion rate can continue to be increased according to standard procedures, according to physician discretion and patient tolerance (not to exceed doubling the rate every 30 mins).

Severe ADR: the infusion should be interrupted and restarted at
12 mL/hour, when the patient’s condition is stable. The infusion rate can continue to be increased according to standard procedures, according to physician discretion and patient tolerance (not to exceed doubling the rate every 30 mins).

Contraindications

Patients who are hypersensitive to this drug or to any ingredient in the formulation or components of the container

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
• Baseline & periodic liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels]
•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.
• Observation for infusion reactions with each injection (infection, bleeding, neurotoxicity, respiratory, GI and skin toxicities)
SUGGESTED CRITERIA
• Baseline & periodic cardiac function tests (Echo RNA and/or MUGA scans) for all patients with cardiac risk factors

Significant Interactions

No formal drug-drug interaction studies have been conducted with Ofatumumab

Product Information

Commercial Product Description

Brand Name: Arzerra 100 mg/5 mL single-use vial and 1,000 mg/50 mL single-use vial.

Pharmaceutical Considerations

Refrigerate. Do not freeze. Vials should be protected from light.

Preparation
Check the concentrate for particulate matter and discoloration prior to dilution. Ofatumumab should be a clear to opalescent, colourless to pale yellow solution. Do not use the concentrate if there is discolouration. The concentrate may contain a small amount of visible particles. The filters provided as part of the extension set will remove these particles.  Do not shake the Ofatumumab vial for this inspection.

The Ofatumumab concentrate must be diluted in saline prior to administration, using aseptic technique.
• 300 mg dose: Use 3 vials (15 mL total, 5 mL per vial): Withdraw and discard 15 mL from a 1,000 mL bag of 0.9% sodium chloride for infusion. Withdraw 5 mL of ARZERRA from each of 3 vials and inject into the 1,000 mL bag. Do not shake. Mix diluted solution by gentle inversion.
• 2,000 mg dose: Use 2 vials (100 mL total, 50 mL per vial): Withdraw and discard 100 mL from a 1,000 mL bag of 0.9% sodium chloride for infusion. Withdraw 50 mL of Ofatumumab from each of 2 vials (100 mL total) and inject into the 1,000 mL bag. Do not shake. Mix diluted solution by gentle inversion.

 

Note

HANDLING RISK LEVEL:

HAZARD RISK LEVEL 3
FDA Pregnancy Risk Factor C
• Consider handling this drug using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

GUIDELINES:

NCDF Coverage Criteria: Chronic Lymphocytic Leukemia
pCODR Recommendations: Ofatumumab in combination with chlorambucin for previously untreated chronic lymphocytic leukemia and for whom fludarabine therapy is inappropriate. pCODR does NOT recommend funding of this agent and indication.     January 29, 2015

Visit the Pan-Canadian Oncology Drug Review website (www.pcodr.ca) for the guidelines on ofatumumab for chronic lymphocytic leukemia.
• Go to "Additional Information" tab (above) for links to pCODR Reviews

Availability & Funding