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  • CLASSES

    Antineoplastic Monoclonal Antibodies Targeting CD20
    MS Agents

    BOXED WARNING

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. PML has occurred with ofatumumab intravenous therapy in patients with CLL; some cases were fatal. Although no cases of PML were reported for the drug during subcutaneous trials for multiple sclerosis (MS), PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold ofatumumab and perform an appropriate diagnostic evaluation, including neurology consultation. If PML is confirmed, discontinue ofatumumab.

    Hepatitis, hepatitis B exacerbation

    Screen all patients for hepatitis B viral infection by measuring HBsAg and anti-HBc before ofatumumab initiation. When used to treat multiple sclerosis (MS), ofatumumab is contraindicated in patients with active hepatitis B virus (HBV) infection, confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. Consult liver disease experts before starting and during treatment with ofatumumab for patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+]. Do not administer ofatumumab to patients with active hepatitis. During treatment, monitor patients for clinical and laboratory signs of hepatitis (e.g., elevated hepatic enzymes and/or bilirubin levels, jaundice) or HBV reactivation during and for several months after ofatumumab therapy. HBV reactivation has been reported at 12 months or longer following completion of therapy. Immediately discontinue therapy and institute appropriate treatment in patients who develop reactivation of HBV. Discuss restarting therapy with a physician with expertise in managing HBV; there are insufficient data regarding the safety of resuming ofatumumab in CLL patients who develop HBV reactivation. Hepatitis B virus (HBV) infection or hepatitis B exacerbation with fulminant hepatitis, hyperbilirubinemia, hepatic failure, and death has been reported with ofatumumab therapy. While not reported during MS clinical trials, reactivation of HBV and fatal infections caused by HBV in patients who have not been previously infected have occurred in patients being treated with ofatumumab for CLL (at higher intravenous doses than the recommended dose in multiple sclerosis but for a shorter duration of treatment) or in patients receiving other anti-CD20 antibodies.

    DEA CLASS

    Rx

    DESCRIPTION

    A parenteral CD20-directed monoclonal antibody causing B-cell depletion; risk for progressive multifocal leukoencephalopathy and hepatitis B virus reactivation
    Approved for use IV for chronic lymphocytic leukemia (CLL) as a single-agent (as extended therapy following a response to at least 2 lines of therapy for recurrent or progressive CLL; and in fludarabine- and alemtuzumab-refractory CLL) and in combination with chlorambucil (previously untreated CLL in patients who are not eligible for fludarabine-based therapy) or fludarabine and cyclophosphamide (in relapsed CLL)
    Subcutaneous dosage form approved for use in relapsing forms of multiple sclerosis in adults

    COMMON BRAND NAMES

    Arzerra, Kesimpta

    HOW SUPPLIED

    Arzerra/Kesimpta Intravenous Inj Sol: 0.4mL, 1mL, 20mg

    DOSAGE & INDICATIONS

    For the treatment of chronic lymphocytic leukemia (CLL).
    NOTE: The FDA has designated ofatumumab as an orphan drug for the treatment of CLL.
    For the treatment of CLL refractory to fludarabine and alemtuzumab.
    Intravenous dosage
    Adults

    300 mg IV on day 1 followed 1 week later by ofatumumab 2,000 mg IV weekly for 7 doses (infusions 2 to 8); after a 4-week rest, give ofatumumab 2,000 mg IV every 4 weeks for 4 doses (infusions 9 to 12). Premedicate 30 minutes to 2 hours before the ofatumumab infusion with acetaminophen 1,000 mg PO and an IV or oral antihistamine (e.g., diphenhydramine 50 mg or cetirizine 10 mg or equivalent). Premedicate with an IV corticosteroid (e.g., prednisolone 100 mg or equivalent) prior to infusions 1, 2, and 9. For infusions 3 to 8, the corticosteroid may be dose reduced or omitted if no grade 3 or greater infusion-related reactions occur with the preceding infusion(s); for infusions 10 to 12, the corticosteroid may be dose reduced (e.g., prednisolone 50 mg to 100 mg or equivalent) if no grade 3 or greater infusion-related reactions occur with infusion 9. Stop the ofatumumab infusion if a patient experiences an infusion-related reaction of any severity. At a planned interim analysis of a multinational, phase II study in 138 patients with refractory chronic lymphocytic leukemia (CLL) who received ofatumumab, the objective response rate (ORR) at 24 weeks (primary endpoint) assessed by an independent review committee (IRC) were 58% and 47% in patients who were refractory to at least 1 fludarabine-containing regimen and either refractory to at least 1 alemtuzumab-containing regimen (FA-ref; n = 59) or considered less suitable for alemtuzumab treatment due to bulky (> 5 cm) lymphadenopathy (BF-ref; n = 79), respectively. Additionally, the response duration times were 7.1 months and 5.6 months in the FA-ref and BF-ref arms, respectively. In patients in the FA-ref arm, the median progression survival (PFS) and overall survival (OS) times were 5.7 months and 13.7 months, respectively. In patients in the BF-ref arm, the median PFS and OS times were 5.9 months and 15.4 months, respectively. In the final analysis of this study (median follow-up of 24 months), the ORRs were 49% and 43%, the median PFS times were 4.6 months and 5.5 months, and the median OS times were 13.9 months and 17.4 months, in the FA-ref (n = 95) and BF-ref (n = 112) arms, respectively.

    For the treatment of fludarabine-refractory CLL with bulky (larger than 5 cm) lymphadenopathy†.
    Intravenous dosage
    Adults

    300 mg IV once followed 1 week later by 2,000 mg IV weekly for 7 additional weeks; then give 2,000 mg IV once monthly for 4 infusions (total of 12 doses over 24 weeks). Ofatumumab was administered in fludarabine-refractory patients with chronic lymphocytic leukemia who were either also refractory to alemtuzumab (FA-ref) or had bulky (greater than 5 cm) lymphadenopathy (BF-ref) in a multinational clinical study. Patients received premedication with acetaminophen 1,000 mg and cetirizine 10 mg prior to each ofatumumab infusion. Additionally, prednisolone 100 mg (or equivalent) was administered prior to ofatumumab doses 1, 2, and 9, although this dose could be lowered if the initial ofatumumab infusion was well tolerated. In 111 BF-ref patients included in the final study analysis, the overall response rate was 44%; additionally, 2 patients achieved complete remission. The median progression-free survival time was 5.5 months and the overall survival time was 17.4 months. Infusion-related reactions (most grades 1 or 2) occurred in 63% of all patients and fatal infections were reported in 5% of BF-ref patients.

    For the first-line treatment of CLL in combination with chlorambucil in patients for whom fludarabine is considered inappropriate.
    Intravenous dosage
    Adults

    300 mg IV on day 1 followed 1 week later by ofatumumab 1,000 mg IV on day 8 in combination with chlorambucil on cycle 1; begin the next cycle of therapy on day 29. For subsequent cycles of therapy, administer ofatumumab 1,000 mg IV on day 1 repeated every 28 days in combination with chlorambucil for a minimum of 3 cycles until best response or a maximum of 12 cycles. Premedicate 30 minutes to 2 hours before the ofatumumab infusion with acetaminophen 1,000 mg PO and an IV or oral antihistamine (e.g., diphenhydramine 50 mg or cetirizine 10 mg or equivalent). Premedicate with an IV corticosteroid (e.g., prednisolone 50 mg or equivalent) prior to infusions 1 and 2; for infusions 3 and beyond, the corticosteroid may be dose reduced or omitted if no grade 3 or greater infusion-related reactions occur during the first 2 infusions. Stop the ofatumumab infusion if a patient experiences an infusion-related reaction of any severity. Combination therapy with ofatumumab plus chlorambucil (10 mg/m2 PO on days 1 to 7 repeated every 28 days) was compared with chlorambucil alone in previously untreated patients with chronic lymphocytic leukemia who were considered ineligible for fludarabine-based therapy (median age, 69 years; range, 35 to 92 years) in a multinational, randomized, phase III trial (n = 447; the COMPLEMENT-1 trial). Most patients (87%) were age 65 years or older and had 2 or more comorbidities or reduced renal function (creatinine clearance < 70 mL/min). A median of 6 treatment cycles (range, 1 to 12 cycles) were administered in both study arms. The progression-free survival time evaluated by independent central review (primary endpoint) was significantly improved with combination therapy compared with chlorambucil alone (22.4 months vs. 13.1 months; hazard ratio = 0.57; 95% CI, 0.45 to 0.72; p < 0.0001) at a median follow-up time of 28.9 months. The median overall survival (OS) time had not been reached in either arm; the estimated 3-year OS rates were 85% and 83% in the combination therapy and chlorambucil alone arms, respectively.

    For extended treatment in patients who have a complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL.
    Intravenous dosage
    Adults

    300 mg IV on day 1 followed 1 week later by ofatumumab 1,000 mg IV on day 8 on cycle 1; begin the next cycle of therapy 7 weeks later. For subsequent cycles of therapy, administer ofatumumab 1,000 mg IV on day 1 repeated every 8 weeks for a maximum of 2 years. Premedicate 30 minutes to 2 hours before the ofatumumab infusion with acetaminophen 1,000 mg PO and an IV or oral antihistamine (e.g., diphenhydramine 50 mg or cetirizine 10 mg or equivalent). Premedicate with an IV corticosteroid (e.g., prednisolone 50 mg or equivalent) prior to infusions 1 and 2; for infusions 3 and beyond, the corticosteroid may be dose reduced or omitted if no grade 3 or greater infusion-related reactions occur during the first 2 infusions. Stop the ofatumumab infusion if a patient experiences an infusion-related reaction of any severity. Up to 2 years of ofatumumab maintenance therapy was compared with observation in patients with chronic lymphocytic leukemia in complete or partial remission after second- or third-line treatment in a prespecified interim analysis of a multinational, randomized, phase III trial (n = 474; the PROLONG trial). Patients with refractory disease or who had previously received maintenance therapy or an autologous or allogeneic stem-cell transplant were excluded. The investigator-assessed median progression-free survival (PFS) (primary endpoint), evaluated by physical exam, was significantly improved with ofatumumab compared with observation (29.4 months vs. 15.2 months; hazard ratio (HR) = 0.5; 95% CI, 0.38 to 0.66; p < 0.0001) at a median follow-up time of 19.1 months. The significant PFS advantage (by physical exam) for ofatumumab was confirmed by an independent review committee. The investigator-assessed median PFS, evaluated by CT scan, was 23.7 months in the ofatumumab arm and 13.5 months in the observation arm (HR = 0.66, 95% CI 0.50 to 0.87; p = 0.002). Overall survival was not significantly different between the treatment arms at the time of analysis.

    For the treatment of relapsed CLL in combination with fludarabine and cyclophosphamide.
    Intravenous dosage
    Adults

    300 mg IV on day 1 followed 1 week later by ofatumumab 1,000 mg IV on day 8 in combination with fludarabine (25 mg/m2 IV daily on days 1, 2, and 3) and cyclophosphamide (250 mg/m2 IV daily on days 1, 2, and 3) on cycle 1; begin the next cycle of therapy on day 29. For subsequent cycles of therapy, administer ofatumumab 1,000 mg IV on day 1 in combination with fludarabine and cyclophosphamide repeated every 28 days for a maximum of 6 cycles. Premedicate 30 minutes to 2 hours before the ofatumumab infusion with acetaminophen 1,000 mg PO and an IV or oral antihistamine (e.g., diphenhydramine 50 mg or cetirizine 10 mg or equivalent). Premedicate with an IV corticosteroid (e.g., prednisolone 50 mg or equivalent) prior to infusions 1 and 2; for infusions 3 and beyond, the corticosteroid may be dose reduced or omitted if no grade 3 or greater infusion-related reactions occur during the first 2 infusions. Stop the ofatumumab infusion if a patient experiences an infusion-related reaction of any severity. Treatment with ofatumumab plus fludarabine and cyclophosphamide (OFC regimen) was compared with fludarabine and cyclophosphamide (FC regimen) alone in patients with relapsed chronic lymphocytic leukemia (median age, 61 years; range, 32 to 90 years) in a multinational, randomized, phase III trial (n = 365; the COMPLEMENT-2 trial). The progression-free survival time evaluated by independent central review (primary endpoint) was significantly improved with OFC compared with FC alone (28.9 months vs. 18.8 months; hazard ratio (HR) = 0.67; 95% CI, 0.51 to 0.88; p = 0.0032) at a median follow-up time of 34 months. The median overall survival time was nonsignificantly improved with OFS at the time of this analysis (56.4 months vs. 45.8 months; HR = 0.78; 95% CI, 0.56 to 1.09).

    For the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
    Subcutaneous dosage (i.e., Kesimpta)
    Adults

    20 mg subcutaneously once weekly for 3 doses (week 0, 1, and 2), then a maintenance dose of 20 mg subcutaneously once monthly beginning at week 4. MISSED DOSE: Administer any missed dose as soon possible, and follow with subsequent doses at the recommended intervals. PRIOR TO TREATMENT: Perform hepatitis B virus (HBV) infection screening and quantitative serum immunoglobulins before starting ofatumumab treatment.

    For the treatment of non-Hodgkin's lymphoma (NHL)†.
    For the treatment of relapsed or refractory diffuse large B-cell lymphoma in transplant eligible patients, in combination with dexamethasone, cytarabine, and cisplatin (DHAP regimen).
    Intravenous dosage
    Adults

    1,000 mg IV on days 1 and 8 of cycle 1 then ofatumumab 1,000 mg IV on day 1 of cycles 2 and 3 in combination with dexamethasone 40 mg PO/IV on days 1, 2, 3, and 4; cisplatin 100 mg/m2 as a continuous IV infusion over 24 hours on day 1; and cytarabine 2 grams/m2 IV over 3 hours every 12 hours for 2 doses on day 2 (DHAP regimen) was evaluated in a randomized, phase III trial (n = 445; the ORCHARRD trial). Cycles were repeated every 21 days for a total of 3 cycles of therapy. Premedication (acetaminophen 1,000 mg PO, diphenhydramine 50 mg IV or PO, and an IV glucocorticoid equivalent to prednisolone 50 mg) was administered between 30 minutes to 2 hours prior to the infusion. If dexamethasone from the DHAP chemotherapy was dosed on the same day as ofatumumab, then the glucocorticoid premedication was omitted and substituted with the 40-mg dose of dexamethasone. Granulocyte colony-stimulating factor use was recommended as follows: filgrastim 5 micrograms (mcg)/kg on days 6 to 13 or pegfilgrastim 6 mg on day 6 on cycles of therapy with no stem-cell mobilization and filgrastim 5 to 10 mcg/kg on days 6 to 13 on cycles of therapy that were followed by stem-cell mobilization. Central nervous system prophylaxis using intrathecal therapy was permitted. Supportive care during treatment consisted of irradiated blood products, oral antibiotics, and antifungal prophylaxis as clinically indicated.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    20 mg/month subcutaneously for multiple sclerosis maintenance treatment; 2,000 mg/dose IV for chronic lymphocytic leukemia.

    Geriatric

    20 mg/month subcutaneously for multiple sclerosis maintenance treatment; 2,000 mg/dose IV for chronic lymphocytic leukemia.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Ofatumumab use has not been evaluated in patients with hepatic impairment.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Intravenous ofatumumab has not been evaluated in patients with a creatinine clearance less than 30 mL/minute; subcutaneous use has not been evaluated in patients with renal impairment.

    ADMINISTRATION

    Emetic Risk
    Minimal

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    The colorless intravenous solution should be clear to opalescent and may contain a small amount of visible translucent-to-white, amorphous, ofatumumab particles. Do not use the intravenous injection it is discolored, cloudy, or if foreign particulate matter is present.
    Do not use the subcutaneous injection if the liquid contains visible particles or is cloudy.

    Intravenous Administration

    Do not administer as an intravenous push or bolus, or as a subcutaneous injection.
    Premedicate with acetaminophen 1,000 mg PO, an antihistamine (e.g., diphenhydramine 50 mg IV or PO), and a glucocorticoid (equivalent to prednisolone 50 mg) at 30 minutes to 2 hours prior to the infusion as recommended.
    Administer ofatumumab in an environment where facilities to adequately monitor and treat infusion reactions are available.
     
    Dilution:
    Prepare all doses in 1,000 mL of 0.9% Sodium Chloride Injection. Do not mix ofatumumab with other medicinal products.
    300-mg dose: Withdraw and discard 15 mL from a 1,000 mL bag of 0.9% Sodium Chloride Injection. Withdraw 5 mL from each of 3 single-use 100-mg vials of ofatumumab and add to the bag. Mix diluted solution by gentle inversion. Do not shake.
    1,000-mg dose: Withdraw and discard 50 mL from a 1,000 mL bag of 0.9% Sodium Chloride Injection. Withdraw 50 mL from a single-use 1,000-mg vial of ofatumumab and add to the bag. Mix diluted solution by gentle inversion. Do not shake.
    2,000-mg dose: Withdraw and discard 100 mL from a 1,000 mL bag of 0.9% Sodium Chloride Injection. Withdraw 50 mL from each of 2 single-use 1,000-mg vials of ofatumumab and add to the bag. Mix diluted solution by gentle inversion. Do not shake.
    Storage following dilution: the diluted solution may be stored between 2 to 8 degrees C (36 to 46 degrees F); start the infusion within 12 hours of preparation and discard after 24 hours.
    Intermittent infusion:
    Flush the intravenous line with 0.9% Sodium Chloride Injection before and after each dose.
    Do not infuse ofatumumab with other medicinal products.
    Administer using an infusion pump with an administration set. No incompatibilities between ofatumumab and polyvinylchloride (PVC) or polyolefin bags and administration sets have been observed.
    Previously Untreated CLL (Chronic Lymphocytic Leukemia), Relapsed CLL, or Extended Treatment in CLL:
    First Infusion (300-mg dose; 0.3 mg/mL): Administer intravenously at an initial rate of 12 mL/hour for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate as follows: 25 mL/hour during minutes 31 to 60; 50 mL/hour during minutes 61 to 90; 100 mL/hour during minutes 91 to 120; 200 mL/hour during minutes 121 to 150; 300 mL/hour during minutes 151 to 180, and up to a maximum rate of 400 mL/hour after 180 minutes. The median infusion time for the 300-mg dose was 4.8 to 5.2 hours.
    Subsequent Infusions (1,000-mg dose; 1 mg/mL): Administer intravenously at an initial rate of 25 mL/hour for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate as follows: 50 mL/hour during minutes 31 to 60; 100 mL/hour during minutes 61 to 90; 200 mL/hour during minutes 91 to 120; and up to a maximum rate of 400 mL/hour after 120 minutes. The median infusion time for 1000-mg doses was 4.2 to 4.4 hours.
    Refractory CLL:
    First infusion (300-mg dose; 0.3 mg/mL): Administer intravenously at an initial rate of 12 mL/hour for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate as follows: 25 mL/hour during minutes 31 to 60; 50 mL/hour during minutes 61 to 90; 100 mL/hour during minutes 91 to 120; and up to a maximum rate of 200 mL/hour after 120 minutes. The median infusion time for infusion 1 of cycle 1 was 6.8 hours.
    Second infusion (2,000-mg dose; 2 mg/mL): Administer intravenously at an initial rate of 12 mL/hour for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate as follows: 25 mL/hour during minutes 31 to 60; 50 mL/hour during minutes 61 to 90; 100 mL/hour during minutes 91 to 120; and up to a maximum rate of 200 mL/hour after 120 minutes. The median infusion time for infusion 2 of cycle 1 was 6.8 hours.
    Subsequent infusions (2,000-mg dose; 2 mg/mL): Administer intravenously at an initial rate of 25 mL/hour for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate as follows: 50 mL/hour during minutes 31 to 60; 100 mL/hour during minutes 61 to 90; 200 mL/hour during minutes 91 to 120; and up to a maximum rate of 400 mL/hour after 120 minutes. The median infusion time for subsequent infusions was 4.2 to 4.4 hours.
    Relapsed/Refractory Diffuse Large B-cell Lymphoma:
    NOTE: Ofatumumab is not approved by the FDA for this indication.
    First Infusion (1,000-mg dose; 1 mg/mL): Administer intravenously at an initial rate of 12 mL/hour for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate as follows: 25 mL/hour during minutes 31 to 60; 50 mL/hour during minutes 61 to 90; 100 mL/hour during minutes 91 to 120; 200 mL/hour during minutes 121 to 150; 300 mL/hour during minutes 151 to 180, and up to a maximum rate of 400 mL/hour after 180 minutes.
    Subsequent Infusions (1,000-mg dose; 1 mg/mL): Administer intravenously at an initial rate of 25 mL/hour for 30 minutes (0 to 30 minutes). If no hypersensitivity or infusion-related events occur, increase the infusion rate as follows: 50 mL/hour during minutes 31 to 60; 100 mL/hour during minutes 61 to 90; 200 mL/hour during minutes 91 to 120; and up to a maximum rate of 400 mL/hour after 120 minutes.

    Subcutaneous Administration

    Before every dose of ofatumumab, determine whether there is an active infection. In case of an active infection, delay ofatumumab administration until the infection resolves.
    Administer the first subcutaneous dose of ofatumumab under the guidance of a health care provider. Patient self-administration may occur following proper training of the patient and/or caregiver.
    Before administration, allow the pen or pre-filled syringe to sit at room temperature for 15 to 30 minutes. Do not warm using any other method. Do not shake.
    Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting directly into raised, thick, red, or scaly skin patch or lesion, or areas with scars or stretch marks.
     
    Subcutaneous administration (Kesimpta Sensoready Pen)
    Clean the injection site on the front of the thigh or the lower abdomen (avoiding 2 inches around the navel) with an alcohol wipe, and allow skin to dry. The outer upper arm may be used if a health care provider or caregiver is giving the injection.
    Remove and discard the pen cap. Use the pen within 5 minutes of cap removal.
    Hold the pen at a 90-degree angle to the skin and press firmly.
    Listen for a loud click indicating the injection has started. A second click indicates the injection is almost complete. Keep holding the pen against the skin until the green indicator fills the window and stops moving.
    For single-use only. Discard the used pen in an FDA-cleared sharps disposal container. Do not discard in household trash.
    Storage: If needed, the pen may be stored for up to 7 days at room temperature, up to 30 degrees C (86 degrees F). If stored below 30 degrees C (86 degrees F), unused medication may be returned to refrigeration and used within 7 days. Discard any medication that is not used within 7 days.
     
    Subcutaneous administration (Kesimpta Prefilled syringe)
    Clean the injection site on the front of the thigh or the lower abdomen (avoiding 2 inches around the navel) with an alcohol wipe, and allow skin to dry. The outer upper arm may be used if a healthcare provider or caregiver is giving the injection.
    Remove and discard the needle cap.
    Gently pinch the skin at the injection site. Insert the needle at a 45-degree angle. Press the plunger to administer the dose. Hold the syringe in place while continuing to press on the plunger for an additional 5 seconds to ensure dose delivery.
    Slowly release the plunger head until the needle is covered.
    For single-use only. Discard the used syringe in an FDA-cleared sharps disposal container. Do not discard in household trash.
    Storage: If needed, store the prefilled syringe for up to 7 days at room temperature, up to 30 degrees C (86 degrees F). If stored below 30 degrees C (86 degrees F), unused medication may be returned to refrigeration and used within 7 days. Discard medication not used within 7 days.

    STORAGE

    Arzerra:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store diluted product in accordance with package insert instructions
    Kesimpta:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Infusion-related reactions, serious hypersensitivity reactions or anaphylaxis

    There is a risk of serious hypersensitivity reactions or anaphylaxis with ofatumumab use for any indication. Serious and sometimes fatal infusion-related reactions have occurred when ofatumumab was given intravenously to CLL patients; reactions may occur despite use of appropriate premedication and most frequently occur with the first 2 infusions. Premedicate with oral acetaminophen and an IV or oral antihistamine prior to each ofatumumab infusion. Premedicate with an IV corticosteroid prior to infusions 1 and 2; for infusions 3 and beyond, the corticosteroid may be dose reduced or omitted if no grade 3 or greater infusion-related reactions occur during the first 2 infusions. Interrupt the ofatumumab infusion if a patient experiences an infusion-related reaction of any severity; therapy may be restarted at the discretion of the health care prescriber. Decrease the infusion rate when the reaction resolves to grade 2 or less. Consider permanent discontinuation if the severity of the infusion reaction does not resolve to less than or equal to Grade 2 despite adequate clinical intervention; permanently discontinue therapy for patients who develop anaphylaxis and initiate appropriate medical treatment. Symptoms of an infusion reaction may include bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia, back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylaxis. Only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen was observed in multiple sclerosis (MS) clinical trials with ofatumumab. The first subcutaneous injection of ofatumumab should be performed under the guidance of an appropriately trained health care provider. Injection-related reactions with systemic symptoms and local injection-site reaction symptoms have been observed with subcutaneous administration. If injection-related reactions occur, symptomatic treatment is recommended.

    Progressive multifocal leukoencephalopathy

    Progressive multifocal leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. PML has occurred with ofatumumab intravenous therapy in patients with CLL; some cases were fatal. Although no cases of PML were reported for the drug during subcutaneous trials for multiple sclerosis (MS), PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold ofatumumab and perform an appropriate diagnostic evaluation, including neurology consultation. If PML is confirmed, discontinue ofatumumab.

    Corticosteroid therapy, hypogammaglobulinemia, immunosuppression, infection

    Due to the mode of action, ofatumumab has immunosuppression effects that may increase the risk for infection. An increased risk of infections has been observed with other anti-CD20 B-cell depleting therapies. There is a potential for serious bacterial, fungal, and new or reactivated viral infections; some of these types of infections have been fatal in patients treated with other anti-CD20 antibodies. As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed during the clinical trials for multiple sclerosis (MS). Perform testing for quantitative serum immunoglobulins before starting ofatumumab treatment in patients with MS. For MS patients with hypogammaglobulinemia, consult immunology experts before starting treatment with ofatumumab. Monitor the concentrations of quantitative serum immunoglobulins during treatment with ofatumumab, especially in patients with opportunistic or recurrent infection, and until B-cell repletion after discontinuation of therapy. Consider discontinuing ofatumumab therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins. Concomitant usage of ofatumumab with immunosuppressant drugs, including systemic corticosteroid therapy, may increase the risk of infection in patients with MS. Consider the risk of additive immune system effects when coadministering therapies that cause immunosuppression with ofatumumab.

    Hepatitis, hepatitis B exacerbation

    Screen all patients for hepatitis B viral infection by measuring HBsAg and anti-HBc before ofatumumab initiation. When used to treat multiple sclerosis (MS), ofatumumab is contraindicated in patients with active hepatitis B virus (HBV) infection, confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. Consult liver disease experts before starting and during treatment with ofatumumab for patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+]. Do not administer ofatumumab to patients with active hepatitis. During treatment, monitor patients for clinical and laboratory signs of hepatitis (e.g., elevated hepatic enzymes and/or bilirubin levels, jaundice) or HBV reactivation during and for several months after ofatumumab therapy. HBV reactivation has been reported at 12 months or longer following completion of therapy. Immediately discontinue therapy and institute appropriate treatment in patients who develop reactivation of HBV. Discuss restarting therapy with a physician with expertise in managing HBV; there are insufficient data regarding the safety of resuming ofatumumab in CLL patients who develop HBV reactivation. Hepatitis B virus (HBV) infection or hepatitis B exacerbation with fulminant hepatitis, hyperbilirubinemia, hepatic failure, and death has been reported with ofatumumab therapy. While not reported during MS clinical trials, reactivation of HBV and fatal infections caused by HBV in patients who have not been previously infected have occurred in patients being treated with ofatumumab for CLL (at higher intravenous doses than the recommended dose in multiple sclerosis but for a shorter duration of treatment) or in patients receiving other anti-CD20 antibodies.

    Agranulocytosis, anemia, neutropenia, sepsis, thrombocytopenia

    Severe neutropenia, thrombocytopenia, and anemia may occur with ofatumumab therapy for oncology indications; pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ofatumumab in combination with chlorambucil. Neutropenia may be delayed (i.e., onset at 42 days or longer after the last dose) and/or prolonged (i.e., duration longer than 24 to 42 days after the last dose). Regularly monitor complete blood counts (CBC) during and after therapy; increase the frequency of CBC monitoring in patients who develop grade 3 or 4 cytopenias.

    Tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has occurred with ofatumumab therapy for oncology indications; some patients required hospitalization. Patients with high tumor burden or high circulating lymphocyte counts (greater than 25 x 109 cells/L) are at a greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemic agents and hydration beginning 12 to 24 hours prior the ofatumumab infusion. If treatment is required, administer aggressive IV hydration and antihyperuricemic agents and correct electrolyte abnormalities. Monitor patients for signs of TLS (e.g., serum creatinine, serum electrolytes, uric acid).

    Vaccination

    Administer all live-attenuated or live vaccines according to immunization guidelines at least 4 weeks before initiation of ofatumumab. Vaccination with live-attenuated or live vaccines is not recommended during ofatumumab treatment and until B-cell repletion. Administer all inactivated vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines in treated patients.

    Infants, neonates, pregnancy

    There are no adequate data on the developmental risk associated with the use of ofatumumab during human pregnancy. Ofatumumab is a humanized IgG1 monoclonal antibody, and immunoglobulins are known to cross the placental barrier. Based on animal data, ofatumumab can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to ofatumumab. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. B-cell concentrations in infants after maternal exposure to ofatumumab have not been studied in clinical trials, and the potential duration of B-cell depletion in such infants, and the impact of B-cell depletion on vaccine safety and effectiveness, is unknown.  Teratogenicity was not observed in the offspring of pregnant monkeys who received ofatumumab at doses that were 0.3- and 2.4-times the maximum recommended human dose of 2,000 mg. Ofatumumab administration did cause a depletion of maternal circulating B-cells, a depletion of peripheral and splenic fetal B-cells, and decreased fetal spleen weights in this animal study. After delivery, neonates or infants with in utero exposure to ofatumumab require special consideration; do not administer live or live-attenuated vaccines before confirming recovery of B-cell counts in an exposed infant. Depletion of B-cells in the exposed infant may increase the risks from live or live-attenuated vaccines. Non-live vaccines, as indicated, may be administered before recovery from B-cell and immunoglobulin concentration depletion; however, consider consultation with a qualified specialist to assess whether a protective immune response was mounted.

    Contraception requirements, reproductive risk

    Ofatumumab is associated with reproductive risk. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies. Specific contraception requirements are recommended for female patients with multiple sclerosis (MS). Advise females of reproductive potential to use effective contraception while receiving ofatumumab for MS treatment and for 6 months after the last dose. Instruct patients that if they are pregnant or plan to become pregnant while taking ofatumumab to inform their health care provider.

    Breast-feeding

    There are no data regarding the presence of ofatumumab in human milk, the effects on a breast-fed infant, or the effects on milk production. Ofatumumab is a humanized IgG1 monoclonal antibody, and human IgG is excreted in human milk. The potential for absorption of ofatumumab to lead to B-cell depletion in the breast-fed infant is unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ofatumumab and any potential adverse effects on the breastfed infant from ofatumumab or from the underlying maternal condition.

    Geriatric

    In patients with previously untreated chronic lymphocytic leukemia (CLL), geriatric patients aged 65 years and older who received ofatumumab plus chlorambucil for CLL experienced a higher incidence of grade 3 or greater neutropenia (30% vs. 17%) and pneumonia (5% vs. 1%) compared with younger patients.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 22.0-60.0
    infection / Delayed / 0-29.0
    lymphopenia / Delayed / 12.0-29.0
    leukopenia / Delayed / 23.0-23.0
    infusion-related reactions / Rapid / 0-10.0
    anemia / Delayed / 8.0-8.0
    dyspnea / Early / 5.0-5.0
    sinusitis / Delayed / 0-2.0
    peripheral edema / Delayed / 2.0-2.0
    headache / Early / 0-1.0
    insomnia / Early / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    progressive multifocal leukoencephalopathy / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    porphyria / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    bradycardia / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known
    pulmonary edema / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    cytokine release syndrome / Rapid / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known

    Moderate

    cystitis / Delayed / 10.0-10.0
    hypertension / Early / 8.0-8.0
    hypotension / Rapid / 3.0-3.0
    antibody formation / Delayed / 0.2-1.0
    immunosuppression / Delayed / Incidence not known
    tracheitis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    fever / Early / 2.0-25.0
    injection site reaction / Rapid / 11.0-21.0
    diarrhea / Early / 19.0-19.0
    cough / Delayed / 19.0-19.0
    rash / Early / 17.0-17.0
    fatigue / Early / 2.0-15.0
    nausea / Early / 12.0-12.0
    chills / Rapid / 2.0-10.0
    pharyngitis / Delayed / 0-8.0
    influenza / Delayed / 0-6.0
    urticaria / Rapid / 5.0-5.0
    hyperhidrosis / Delayed / 5.0-5.0
    muscle cramps / Delayed / 3.0-3.0
    myalgia / Early / 2.0
    pruritus / Rapid / 2.0
    rhinitis / Early / Incidence not known
    laryngitis / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    syncope / Early / Incidence not known
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    Alemtuzumab: (Moderate) Concomitant use of ofatumumab with alemtuzumab may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as alemtuzumab. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Anifrolumab: (Major) Coadministration is not recommended. Anifrolumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as ofatumumab. Potential concerns with use of these drugs together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Anthrax Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Azelastine; Fluticasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Beclomethasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Belimumab: (Major) Avoid use together. Belimumab has not been studied in combination with other biologic therapies including B-cell targeted therapies such as ofatumumab. Therefore, belimumab use is not recommended in combination with biologic therapies. Potential concerns with use together include an increased susceptibility to immunosuppression and serious infections, some of which might be fatal.
    Betamethasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Budesonide: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Budesonide; Formoterol: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciclesonide: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Cladribine: (Moderate) Concomitant use of ofatumumab with cladribine may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as cladribine. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Cortisone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Deflazacort: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Dexamethasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Dimethyl Fumarate: (Moderate) Concomitant use of ofatumumab with dimethyl fumarate may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as dimethyl fumarate. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Haemophilus influenzae type b Conjugate Vaccine; Hepatitis B Vaccine, Recombinant; Inactivated Poliovirus Vaccine, IPV: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Haemophilus influenzae type b Conjugate Vaccine; Inactivated Poliovirus Vaccine, IPV: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Hepatitis B Vaccine, Recombinant; Inactivated Poliovirus Vaccine, IPV : (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Diphtheria Toxoid, Tetanus Toxoid, Acellular Pertussis Vaccine, DTaP; Inactivated Poliovirus Vaccine, IPV: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Diphtheria Toxoid; Tetanus Toxoid Adsorbed, DT, Td: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Diphtheria/Tetanus Toxoids; Pertussis Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Diphtheria/Tetanus Toxoids; Pertussis Vaccine; Haemophilus influenzae type b Conjugate Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Diroximel Fumarate: (Moderate) Concomitant use of ofatumumab with diroximel fumarate may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as diroximel fumarate. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Fingolimod: (Moderate) Concomitant use of ofatumumab with fingolimod may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as fingolimod. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Fludrocortisone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Flunisolide: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Fluticasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Formoterol; Mometasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Glatiramer: (Moderate) Concomitant use of ofatumumab with glatiramer may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as glatiramer. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Haemophilus influenzae type b Conjugate Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Haemophilus influenzae type b Conjugate Vaccine; Hepatitis B Vaccine, Recombinant: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Hepatitis A Vaccine, Inactivated: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Hepatitis A Vaccine, Inactivated; Hepatitis B Vaccine, Recombinant: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Hepatitis B Vaccine, Recombinant: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Human Papillomavirus 9-Valent Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Human Papillomavirus Bivalent Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Human Papillomavirus Quadrivalent Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Hydrocortisone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Influenza Virus Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Interferon Beta-1a: (Moderate) Concomitant use of ofatumumab with interferon beta may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as interferon beta. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Interferon Beta-1b: (Moderate) Concomitant use of ofatumumab with interferon beta may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as interferon beta. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Intranasal Influenza Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Japanese Encephalitis Virus Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Live Vaccines: (Major) Administer all live and live-attenuated vaccines according to immunization guidelines at least 4 weeks before initiation of ofatumumab. Vaccination with live-attenuated or live vaccines is not recommended during treatment with ofatumumab; wait until B-cell recovery occurs after discontinuation of ofatumumab before administering these vaccines to a patient.
    Meningococcal Conjugate Vaccine (MCV4): (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Meningococcal Group B Vaccine (3 strain): (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Meningococcal Group B Vaccine (4 strain): (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Meningococcal Haemophilus influenzae type b Conjugate Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Meningococcal Polysaccharide Vaccine (MPSV4): (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Methylprednisolone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Mitoxantrone: (Moderate) Concomitant use of ofatumumab with mitoxantrone may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as mitoxantrone. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients. The median elimination half-life of mitoxantrone is 75 hours (range 23 to 215 hours).
    Mometasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Monomethyl Fumarate: (Moderate) Concomitant use of ofatumumab with monomethyl fumarate may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as monomethyl fumarate. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Natalizumab: (Major) Natalizumab should generally not be used in combination with ofatumumab because of the potential for increased risk of progressive multifocal leukoencephalopathy (PML) and other serious infections. Ordinarily, patients receiving other chronic immunomodulatory therapy should not be treated with natalizumab.
    Non-Live Vaccines: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Ocrelizumab: (Moderate) Concomitant use of ofatumumab with ocrelizumab may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as ocrelizumab. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Olopatadine; Mometasone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Ozanimod: (Moderate) Concomitant use of ofatumumab with ozanimod may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as ozanimod. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Peginterferon beta-1a: (Moderate) Concomitant use of ofatumumab with peginterferon beta-1a may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as peginterferon beta-1a. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pneumococcal Vaccine, Polyvalent: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Poliovirus Vaccine, Inactivated, IPV: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Prednisolone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Prednisone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Rabies Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Sarilumab: (Major) Avoid using sarilumab with other biological agents, including anti-CD20 monoclonal antibodies such as ofatumumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Siponimod: (Moderate) Concomitant use of ofatumumab with siponimod may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as siponimod. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients.
    Teriflunomide: (Moderate) Concomitant use of ofatumumab with teriflunomide may increase the risk of immunosuppression. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, such as teriflunomide. Consider the duration and mechanism of action of drugs with immunosuppressive effects when switching therapies for multiple sclerosis patients. The median half-life of teriflunomide is 18 to 19 days, and teriflunomide may remain in plasma for up to 2 years following discontinuation.
    Tetanus Toxoid: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Tick-Borne Encephalitis Vaccine: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Tocilizumab: (Major) Avoid the concomitant use of ofatumumab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.
    Triamcinolone: (Moderate) Concomitant use of ofatumumab with corticosteroids may increase the risk of immunosuppression. Monitor patients carefully for signs and symptoms of infection. Ofatumumab has not been studied in combination with other immunosuppressive or immune modulating therapies used for the treatment of multiple sclerosis, including immunosuppressant doses of corticosteroids.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data regarding the presence of ofatumumab in human milk, the effects on a breast-fed infant, or the effects on milk production. Ofatumumab is a humanized IgG1 monoclonal antibody, and human IgG is excreted in human milk. The potential for absorption of ofatumumab to lead to B-cell depletion in the breast-fed infant is unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ofatumumab and any potential adverse effects on the breastfed infant from ofatumumab or from the underlying maternal condition.

    MECHANISM OF ACTION

    Ofatumumab is a fully human immunoglobulin G1-kappa (IgG1-kappa) monoclonal antibody that binds specifically to the CD20 antigen on B cells. Ofatumumab binds epitopes that encompass amino acid residues in the small extracellular loop of the CD20 antigen as well as amino acid residues 163 and 166 in the large extracellular loop. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Compared to rituximab, ofatumumab binds a different CD20 epitope and it binds CD20 with a reduced off rate, through which the ability to kill cells is maintained over relatively long periods of time. Ofatumumab induces complement-mediated cytotoxicity (CDC) mediated cell lysis and antibody-dependent cell-mediated cytotoxicity (ADCC). The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions to result in B-cell lysis. This effect is especially seen in cells with a low CD20-antigen density and in cells expressing high levels of complement regulatory proteins (CD55 and CD59); effectiveness against cells with these characteristics may be due to ofatumumab's slow off-rate and more stable binding of CD20. In vitro, ofatumumab lyses rituximab-resistant Raji cells and CD20 low-expressing chronic lymphocytic leukemia cells in the presence of human plasma or unfractionated blood. These findings suggest that ofatumumab may be capable of inducing lysis of chronic lymphocytic leukemia cells that are known to express relatively low levels of CD20 on their surface.
     
    The precise mechanism by which ofatumumab exerts its therapeutic effects in multiple sclerosis is not known, but is presumed to be the result of antibody-dependent cellular cytolysis and complement-mediated lysis following cell surface binding to B lymphocytes.

    PHARMACOKINETICS

    Ofatumumab is administered intravenously or subcutaneously. After subcutaneous administration, ofatumumab is believed to be predominantly absorbed via the lymphatic system similarly to other therapeutic monoclonal antibodies. The volume of distribution at steady-state was estimated to be 5.42 L following subcutaneous administration of repeated 20 mg doses. The expected metabolic pathway of ofatumumab is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes. The active metabolite is phenylacetic acid mustard. Ofatumumab is eliminated through a target-independent route and a B cell-mediated route. Higher baseline B-cell count results in greater component of target-mediated elimination clearance and shorter ofatumumab half-life at the start of therapy. Clearance of ofatumumab is dose-dependent within the dose range of 100 to 2,000 mg IV. After repeated administration (4, 5, 6, 8, or 12 infusions) of 1,000 mg or 2,000 mg (n = 744), the geometric mean value for clearance was 9.3 mL/hour (coefficient of variation (CV), 91%), volume of distribution at steady state was 6.1 L (CV, 52%), and half-life was 17.6 days (CV, 83%); these values were similar across doses in patients with chronic lymphocytic leukemia (CLL). Following B cell depletion, clearance was estimated to be 0.34 L/day following repeated subcutaneous administration of 20 mg doses. The half-life at steady state was estimated to be approximately 16 days following repeated 20 mg subcutaneous doses. Ofatumumab is not likely to undergo renal excretion.
     
    In patients with refractory CLL, the median decrease in circulating CD19-positive B cells (an earlier cell marker expressed on B cells) was 91% with the eighth infusion (n = 50) and 85% with the 12th infusion (n = 32). At 6 months after the last dose, the median reductions in CD19-positive B cells were greater than 99% in patients with previously untreated CLL who received ofatumumab in combination with chlorambucil (n = 155). In relapsed CLL patients who received ofatumumab in combination with fludarabine and cyclophosphamide, complete and near-complete B cell depletion occurred in 39% and 82% of patients, respectively. In patients treated with extended treatment for CLL after response to therapy for their recurrent or progressive disease, the median decreases in B-cell counts were 61% after the first infusion (n = 168) and 80% prior to the sixth infusion (n = 114). The time to recovery of lymphocytes to normal levels has not been determined. B-cell depletion has not been shown to be directly correlated to clinical response.
     
    In patients with multiple sclerosis, subcutaneous administration of ofatumumab during 2 clinical trials resulted in a reduction of CD19+ B cells to below the lower limit of normal (LLN) in 77.0% and 78.8% of patients, respectively, 1 week after treatment initiation, and in 95.0% and 95.8% of patients, respectively, 2 weeks after treatment initiation. At 12 weeks, 99.3% to 99.5% of patients had CD19+ B cell counts below the LLN. Counts remained below the LLN for 97% and 92% of patients through 120 weeks of subcutaneous treatment. Data indicate median B cell recovery to the LLN or baseline value at 24.6 weeks post-treatment discontinuation. The median predicted time to B cell recovery to the LLN is 23 weeks post-treatment discontinuation.
     
    Affected cytochrome P450 isoenzymes and drug transporters: None

    Intravenous Route

    Compared to after the fourth infusion, the Cmax and AUC values after the eighth intravenous infusion were approximately 40% and 60% higher, respectively.

    Subcutaneous Route

    The mean AUC of ofatumumab is 483 mcg x hour/mL and the mean Cmax is 1.43 mcg/mL following a subcutaneous dose of 20 mg at steady state.