OFATUMUMAB: 29,913 Adverse Event Reports & Safety Profile

ARZERRA (ofatumumab) is an IgG1κ human monoclonal antibody with a molecular weight of approximately 149 kDa. The antibody was generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line (NS0) using standard mammalian cell cultivation and purification technologies. ARZERRA is a sterile, clear to opalescent, colorless, preservative-free liquid concentrate for intravenous administration. ARZERRA is supplied at a concentration of 20 mg/mL in single-use vials. Each single-use vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. Inactive ingredients include: 10 mg/mL arginine, diluted hydrochloric acid, 0.019 mg/mL edetate disodium, 0.2 mg/mL polysorbate 80, 6.8 mg/mL sodium acetate, 2.98 mg/mL sodium chloride, and Water for Injection, USP. The pH is 5.5.

AND USAGE Chronic Lymphocytic Leukemia (CLL) ARZERRA (ofatumumab) is indicated: in combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate [see Clinical Studies (14.1)] in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed CLL [see Clinical Studies (14.2)] for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL [see Clinical Studies (14.3)] for the treatment of patients with CLL refractory to fludarabine and alemtuzumab [see Clinical Studies (14.4)] ARZERRA (ofatumumab) is a CD20-directed cytolytic monoclonal antibody indicated for the treatment of chronic lymphocytic leukemia (CLL) ( 1 ): in combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed CLL. for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL. for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.

AND ADMINISTRATION Dilute and administer as an intravenous infusion. Do not administer subcutaneously or as an intravenous push or bolus. ( 2.1 ) Previously untreated CLL in combination with chlorambucil recommended dosage and schedule is: 300 mg on Day 1 followed by 1,000 mg on Day 8 (Cycle 1) 1,000 mg on Day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles. ( 2.1 ) Relapsed CLL in combination with fludarabine and cyclophosphamide recommended dosage and schedule is: 300 mg on Day 1 followed by 1,000 mg on Day 8 (Cycle 1) 1,000 mg on Day 1 of subsequent 28-day cycles for a maximum of 6 cycles ( 2.1 ) Extended treatment in CLL recommended dosage and schedule is: 300 mg on Day 1 followed by 1,000 mg 1 week later on Day 8, followed by 1,000 mg 7 weeks later and every 8 weeks thereafter for up to a maximum of 2 years. ( 2.1 ) Refractory CLL recommended dosage and schedule is: 300 mg initial dose, followed 1 week later by 2,000 mg weekly for 7 doses, followed 4 weeks later by 2,000 mg every 4 weeks for 4 doses. ( 2.1 ) Administer where facilities to adequately monitor and treat infusion reactions are available. ( 2.2 ) Pre-medicate with acetaminophen, antihistamine, and corticosteroid. ( 2.4 )

2.1 Recommended Dosage Regimen Dilute and administer as an intravenous infusion according to the following schedules. Do not administer as an intravenous push or bolus or as a subcutaneous injection. Pre-medicate before each infusion <span class="opacity-50 text-xs">[see Dosage and Administration (2.4)]</span> .

Previously

Untreated CLL: The recommended dosage and schedule in combination with chlorambucil is: 300 mg on Day 1, followed 1 week later by 1,000 mg on Day 8 (Cycle 1), followed by 1,000 mg on Day 1 of subsequent 28-day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles. Relapsed CLL: The recommended dosage and schedule in combination with fludarabine and cyclophosphamide is: 300 mg on Day 1, followed 1 week later by 1,000 mg on Day 8 (Cycle 1), followed by 1,000 mg on Day 1 of subsequent 28-day cycles for a maximum of 6 cycles.

Extended

Treatment in CLL: The recommended dosage and schedule as single-agent extended treatment in CLL is: 300 mg on Day 1, followed by 1,000 mg 1 week later on Day 8, followed by 1,000 mg 7 weeks later and every 8 weeks thereafter for up to a maximum of 2 years. Refractory CLL: The recommended dosage and schedule is 12 doses administered as follows: 300 mg initial dose on Day 1, followed 1 week later by 2,000 mg weekly for 7 doses (Infusions 2 through 8), followed 4 weeks later by 2,000 mg every 4 weeks for 4 doses (Infusions 9 through 12).

2.2 Administration Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> . Prepare all doses in 1,000 mL of 0.9% Sodium Chloride Injection, USP <span class="opacity-50 text-xs">[see Dosage and Administration (2.5)]</span> .

Previously

Untreated CLL, Relapsed CLL, and Extended Treatment in CLL: For initial 300-mg dose: Initiate infusion at a rate of 3.6 mg/hour (12 mL/hour). For subsequent infusions of 1,000 mg: Initiate infusion at a rate of 25 mg/hour (25 mL/hour). Initiate infusion at a rate of 12 mg/hour if a Grade 3 or greater infusion-related adverse event was experienced during the previous infusion. In the absence of an infusion-related adverse event, the rate of infusion may be increased every 30 minutes (Table 1). Do not exceed the infusion rates in Table 1.

Table

1.

Infusion

Rates for ARZERRA in Previously Untreated CLL, Relapsed CLL, and Extended Treatment in CLL a Initial 300 mg: median durations of infusions = 4.8 to 5.2 hours. b Subsequent infusions of 1,000 mg: median durations of infusions = 4.2 to 4.4 hours.

Interval After

Start of Infusion (min)

Initial

300 mg Dose a (mL/hour)

Subsequent

Infusions b (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 Refractory CLL: Infusion 1 (300-mg dose): Initiate infusion at a rate of 3.6 mg/hour (12 mL/hour).

Infusion

2 (2,000-mg dose): Initiate infusion at a rate of 24 mg/hour (12 mL/hour).

Infusions

3 through 12 (2,000-mg doses): Initiate infusion at a rate of 50 mg/hour (25 mL/hour). In the absence of an infusion-related adverse event, the rate of infusion may be increased every 30 minutes (Table 2). Do not exceed the infusion rates in Table 2.

Table

2.

Infusion

Rates for ARZERRA in Refractory CLL a Infusions 1 and 2 (300 mg and 2,000 mg): median duration of infusions = 6.8 hours. b Subsequent infusions of 2,000 mg: median durations of infusions = 4.2 to 4.4 hours. Interval after Start of Infusion (min)

Infusions

1 and 2 a (mL/hour)

Subsequent

Infusions b (mL/hour) 0-30 12 25 31-60 25 50 61-90 50 100 91-120 100 200 >120 200 400

2.3 Infusion Rate Dose Modification for Infusion Reactions Interrupt infusion for infusion reactions of any severity <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> . Treatment can be resumed at the discretion of the treating physician. The following infusion rate modifications can be used as a guide. If the infusion reaction resolves or remains less than or equal to Grade 2, resume infusion with the following modifications according to the initial Grade of the infusion reaction.

Grade

1 or 2: Infuse at one‑half of the previous infusion rate.

Grade

3 or 4: Infuse at a rate of 12 mL/hour. After resuming the infusion, the infusion rate may be increased according to Tables 1 and 2 above, based on patient tolerance. Consider permanent discontinuation of ARZERRA 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 an anaphylactic reaction to ARZERRA.

2.4 Premedication Patients should receive all of the following premedication agents 30 minutes to 2 hours prior to each infusion of ARZERRA.

See Table

3 for pre-medication schedule prior to each infusion.

Table

3.

Premedication

Schedule for ARZERRA a Up to 13 infusions in previously untreated CLL; up to 7 infusions in relapsed CLL, up to 14 infusions in extended treatment in CLL. b Corticosteroid may be reduced or omitted for subsequent infusions if a Grade 3 or greater infusion-related adverse event did not occur with the preceding infusion(s). c Prednisolone may be given at reduced dose of 50 mg to 100 mg (or equivalent) if a Grade 3 or greater infusion-related adverse event did not occur with Infusion 9.

Previously

Untreated CLL, Relapsed CLL or Extended Treatment in CLL Refractory CLL Infusion Number 1 and 2 3 and beyond a 1, 2, and 9 3 to 8 10 to 12 Intravenous corticosteroid (prednisolone or equivalent) 50 mg 0-50 mg b 100 mg 0-100 mg b 50-100 mg c Oral acetaminophen 1,000 mg Oral or intravenous antihistamine Diphenhydramine 50 mg or cetirizine 10 mg (or equivalent)

2.5 Preparation and Administration Do not shake product. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. ARZERRA should be a clear to opalescent, colorless solution. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present. Preparation of Solution: 300-mg dose: Withdraw and discard 15 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP.

Withdraw

5 mL from each of 3 single-use 100-mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion. 1,000-mg dose: Withdraw and discard 50 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP.

Withdraw

50 mL from 1 single-use 1,000-mg vial of ARZERRA and add to the bag. Mix diluted solution by gentle inversion. 2,000-mg dose: Withdraw and discard 100 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP.

Withdraw

50 mL from each of 2 single-use 1,000-mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion. Store diluted solution between 2° to 8°C (36° to 46°F). No incompatibilities between ARZERRA and polyvinylchloride or polyolefin bags and administration sets have been observed.

Administration

Instructions: Do not mix ARZERRA with, or administer as an infusion with other medicinal products. Administer using an infusion pump and an administration set. Flush the intravenous line with 0.9% Sodium Chloride Injection, USP before and after each dose. Start infusion within 12 hours of preparation. Discard prepared solution after 24 hours.

KESIMPTA is contraindicated in patients with: Active HBV infection [see Warnings and Precautions (5.1)] . History of hypersensitivity to ofatumumab or life-threatening injection-related reaction to KESIMPTA. Hypersensitivity reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.2)] . Active HBV infection. ( 4 ) History of hypersensitivity to ofatumumab or life-threatening injection-related reaction to KESIMPTA. ( 4 )

REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Infusion Reactions [see Warnings and Precautions (5.1)] Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)] Hepatitis B Virus Infection [see Warnings and Precautions (5.3)]

Progressive Multifocal

Leukoencephalopathy [see Warnings and Precautions (5.4)]

Tumor Lysis

Syndrome [see Warnings and Precautions (5.5)] Cytopenias [see Warnings and Precautions (5.6)]

Previously

Untreated CLL: Common adverse reactions (≥10%) were infusion reactions and neutropenia. ( 6 ) Relapsed CLL: Common adverse reactions (>10%) were infusion reactions, neutropenia, leukopenia and febrile neutropenia. ( 6 )

Extended

Treatment in CLL: Common adverse reactions (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection. ( 6 ) Refractory CLL: Common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Previously

Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m 2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6. The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 4). The data described in Table 4 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 5 includes relevant hematologic laboratory abnormalities.

Table

4.

Adverse

Reactions with ≥5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also ≥2% More than Patients Receiving Chlorambucil a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex.

Adverse

Reactions ARZERRA plus Chlorambucil (N = 217) Chlorambucil (N = 227)

All

Grades % Grade ≥3 % All Grades % Grade ≥3 % Infusion reactions a 67 10 0 0 Neutropenia 27 26 18 14 Asthenia 8 <1 5 0 Headache 7 <1 3 0 Leukopenia 6 3 2 <1 Herpes simplex b 6 0 4 <1 Lower respiratory tract infection 5 1 3 <1 Arthralgia 5 <1 3 0 Upper abdominal pain 5 0 3 0 Table 5. Post-baseline Hematologic Laboratory Abnormalities Occurring with ≥5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also ≥2% More than Patients Receiving Chlorambucil Investigations ARZERRA plus Chlorambucil (N = 217) Chlorambucil (N = 227)

All

Grades % Grade ≥3 % All Grades % Grade ≥3 % Leukopenia 67 23 28 4 Neutropenia 66 29 56 24 Lymphopenia 52 29 20 7 Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients. Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone. Relapsed CLL: The safety of ARZERRA in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide was evaluated in a randomized, open-label, parallel-arm, multicenter trial (Study 2) in 359 patients with relapsed CLL. Patients were randomized to receive ARZERRA as an intravenous infusion (Cycle 1: 300 mg on Day 1 and 1,000 mg on Day 8; followed by 1,000 mg on Day 1 of subsequent 28-day cycles for a maximum of 6 cycles). Standard fludarabine and cyclophosphamide therapy was administered as a 3-day course starting on the first day of each cycle, with initial dosages of 25 mg/m 2 for fludarabine and 250 mg/m 2 for cyclophosphamide.

Table

6 includes adverse reactions occurring up to 60 days after the last dose of study medication. The most common adverse reactions (≥10%) were infusion reactions, neutropenia, leukopenia and febrile neutropenia (Table 6).

Table

6.

Adverse

Reactions with ≥5% Incidence in Patients Receiving ARZERRA plus FC and Also ≥2% More than in Patients in Fludarabine and Cyclophosphamide Arm a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.

Adverse

Reactions ARZERRA plus Fludarabine and Cyclophosphamide (N = 181) Fludarabine and Cyclophosphamide Arm (N = 178)

All

Grades % Grade >3 % All Grades % Grade >3 % Infusion reactions a 60 9 28 3 Neutropenia 55 49 39 36 Leukopenia 15 12 6 3 Febrile neutropenia 10 10 8 8 Bronchitis 6 1 4 <1 Adverse reactions associated with decreased platelet counts (including but not limited to thrombocytopenia, platelet count decreased and pancytopenia) and decreased hemoglobin (including but not limited to anemia, hemoglobin decreased and pancytopenia) occurred less frequently in the ARZERRA plus fludarabine and cyclophosphamide arm than in the fludarabine and cyclophosphamide arm up to 60 days after the last dose of study treatment: 30% (all grades) and 15% (Grade ≥3) vs 38% (all grades) and 28% (Grade ≥3), respectively for decreased platelet counts; and 23% (all grades) and 10% (Grade ≥3) vs 33% (all grades) and 16% (Grade ≥3), respectively for decreased hemoglobin.

Infusion

Reactions : On Day 1 of infusion, infusion reactions occurred in 49% (7% were >Grade 3) of patients treated with ARZERRA plus fludarabine and cyclophosphamide, compared to 16% (1% were >Grade 3) of patients treated with fludarabine and cyclophosphamide and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients in the ARZERRA plus fludarabine and cyclophosphamide. Serious adverse events of infusion reactions occurred in 2% of patients in the ARZERRA plus fludarabine and cyclophosphamide compared to <1% of patients treated with fludarabine and cyclophosphamide. Neutropenia : The proportion of patients that had Grade 3 or greater neutropenia reported up to 60 days after the last dose of study medication was higher in patients treated with ARZERRA plus fludarabine and cyclophosphamide (51%) compared to the fludarabine and cyclophosphamide arm (37%).

Grade

3 or greater neutropenic sepsis occurred in 2 patients (1%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 3 patients (2%) in the fludarabine and cyclophosphamide arm. Prolonged neutropenia occurred in 18 patients (10%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 20 patients (11%) in the fludarabine and cyclophosphamide arm. Late-onset neutropenia occurred in 13 patients (7%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 5 patients (3%) in the fludarabine and cyclophosphamide arm. During the period between the first dose and 60 days after last dose there were five (3%) patients who died in the ARZERRA plus fludarabine and cyclophosphamide arm and ten (6%) patients who died in the fludarabine and cyclophosphamide arm.

Extended

Treatment in CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 3) in 474 patients who had responded to therapy for their recurrent or progressive disease. Patients were randomized to receive ARZERRA as an intravenous infusion every 8 weeks or observation. The infusion schedule for ARZERRA was 300 mg on Day 1 followed 1 week later by 1,000 mg on Day 8 followed 7 weeks later by 1,000 mg and every 8 weeks thereafter for up to a maximum of 2 years. The data described in Table 7 include relevant adverse reactions occurring up to 60 days after the last dose of study medication (last visit for observation arm). The most common adverse reactions (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection (Table 7).

Table

7.

Adverse

Reactions with ≥5% Incidence in Patients Receiving ARZERRA and Also ≥2% More than in Patients in Observation Arm a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. ARZERRA (N = 237)

Observation

Arm (N = 237)

Adverse Reactions All

Grades % Grade ≥3 % All Grades % Grade ≥3 % Infusion reactions a 46 4 - - Neutropenia 24 22 9 8 Upper respiratory tract infection 19 1 9 0 Bronchitis 9 <1 7 <1 Pneumonia 8 5 5 3 Influenza 6 0 3 0 Herpes zoster 5 <1 3 <1 Insomnia 5 <1 2 0 Back pain 5 0 3 0 Hypogammaglobulinemia 5 <1 <1 <1 Infusion Reactions: Infusion reactions occurred in 25% of patients on the day of Infusion 1 (300 mg) and decreased with subsequent infusions (between 2% to 10%). Infections: A total of 154 patients (65%) treated with ARZERRA compared with 120 patients (51%) in the observation arm experienced bacterial, viral, or fungal infections. The incidence of serious infections, however, was similar for patients treated with ARZERRA (20%) and the observation arm (18%). The proportions of fatal infections in patients treated with ARZERRA and in the observation arm were 2% and 3% respectively. Neutropenia: The proportion of patients that had Grade 3 or greater neutropenia reported up to 60 days after the last dose of study medication was higher in patients treated with ARZERRA (22%) compared with the observation arm (8%). There were no cases of neutropenic sepsis reported with ARZERRA. Prolonged neutropenia occurred in 13 patients (5%) treated with ARZERRA and in 5 patients (2%) in the observation arm. Late-onset neutropenia occurred in 2 patients (<1%) treated with ARZERRA and 1 patient (<1%) in the observation arm. During the period between the first dose and 60 days after last dose there were two (1%) patients in the ofatumumab group who died due to adverse events and five (2%) patients in the observation group. Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 4 [n = 154]) or 3 doses (Study 5 [n = 27]). The data described in Table 8 and other sections below are derived from 154 patients in Study 4. All patients received 2,000 mg weekly from the second dose onward. Ninety percent (90%) of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white. In refractory CLL, the most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 8). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation.

Table

8. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset a Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Includes rash, rash macular, and rash vesicular. c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock.

Adverse Reaction Total

Population (N = 154) Fludarabine‑ and Alemtuzumab‑refractory (N = 59)

All

Grades % Grade ≥3 % All Grades % Grade ≥3 % Pneumonia a 23 14 25 15 Pyrexia 20 3 25 5 Cough 19 0 19 0 Diarrhea 18 0 19 0 Anemia 16 5 17 8 Fatigue 15 0 15 0 Dyspnea 14 2 19 5 Rash b 14 <1 17 2 Bronchitis 11 <1 19 2 Nausea 11 0 12 0 Upper respiratory tract infection 11 0 3 0 Edema peripheral 9 <1 8 2 Back pain 8 1 12 2 Chills 8 0 10 0 Nasopharyngitis 8 0 8 0 Sepsis c 8 8 10 10 Urticaria 8 0 5 0 Insomnia 7 0 10 0 Headache 6 0 7 0 Herpes zoster 6 1 7 2 Hyperhidrosis 5 0 5 0 Hypertension 5 0 8 0 Hypotension 5 0 3 0 Muscle spasms 5 0 3 0 Sinusitis 5 2 3 2 Tachycardia 5 <1 7 2 Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections : A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine‑ and alemtuzumab‑refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.

6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 926 patients with CLL were tested during and after treatment for antibodies to ARZERRA. Formation of anti-ofatumumab antibodies was observed in less than 1% of patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARZERRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion-related Cardiac Events Cardiac arrest Mucocutaneous Reactions Stevens-Johnson syndrome, porphyria cutanea tarda

AND PRECAUTIONS Infections: Serious, including life-threatening and fatal infections, have occurred in patients treated with anti-CD20 therapies. Delay KESIMPTA administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with KESIMPTA and after discontinuation, until B-cell repletion. ( 5.1 ) Injection-Related Reactions and Hypersensitivity Reactions: Management for injection-related reactions and hypersensitivity reactions depends on the type and severity of the reaction. ( 4 , 5.2 ) Reduction in Immunoglobulins: Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with KESIMPTA until B-cell repletion. Consider discontinuing KESIMPTA if a patient develops a serious opportunistic infection or recurrent infections if immunoglobulin levels indicate immune compromise. ( 5.3 )

Liver

Injury: Clinically significant liver injury has occurred. Obtain serum aminotransferases, alkaline phosphatase, and bilirubin levels before initiating KESIMPTA, and during treatment as clinically indicated. Discontinue KESIMPTA in patients with evidence of liver injury in the absence of an alternative etiology. ( 5.4 )

Fetal

Risk: May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for 6 months after stopping KESIMPTA. ( 5.5 , 8.1 )

5.1 Infections Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies. In KESIMPTA Study 1 and Study 2 <span class="opacity-50 text-xs">[see Clinical Studies (14)]</span> , the overall rate of infections and serious infections in patients treated with KESIMPTA was similar to patients who were treated with teriflunomide (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by KESIMPTA-treated patients in the randomized clinical relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay KESIMPTA administration in patients with an active infection until the infection is resolved.

Possible Increased

Risk of Immunosuppressant Effects with Other Immunosuppressants When initiating KESIMPTA after an immunosuppressive therapy or initiating an immunosuppressive therapy after KESIMPTA, consider the potential for increased immunosuppressive effects [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)] . KESIMPTA has not been studied in combination with other MS therapies. Hepatitis B Virus Reactivation There were no reports of HBV reactivation in patients with MS treated with KESIMPTA. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (CLL) (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment) and in patients treated with other anti-CD20 antibodies. Infection KESIMPTA is contraindicated in patients with active hepatitis B disease. 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 MS but for a shorter duration of treatment). HBV screening should be performed in all patients before initiation of treatment with KESIMPTA. At a minimum, screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with KESIMPTA. These patients should be monitored and managed following local medical standards to prevent HBV infection or reactivation.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML have been reported for KESIMPTA in the RMS clinical studies, PML resulting in death has occurred in patients being treated with ofatumumab for CLL (at substantially higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). In addition, JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold KESIMPTA and perform an appropriate diagnostic evaluation. Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. If PML is confirmed, treatment with KESIMPTA should be discontinued.

Vaccinations

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines. KESIMPTA may interfere with the effectiveness of inactivated vaccines. The safety of immunization with live or live-attenuated vaccines following KESIMPTA therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion [see Clinical Pharmacology (12.2)] . Vaccination of Infants Born to Mothers Treated with KESIMPTA During Pregnancy In infants of mothers treated with KESIMPTA during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines. Inactivated vaccines may be administered, as indicated, prior to recovery from B-cell depletion, but an assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.

5.2 Injection-Related Reactions and Hypersensitivity Reactions KESIMPTA can result in systemic injection-related reactions and hypersensitivity reactions, which may be serious or life-threatening.

In Study

1 and Study 2, systemic and local injection reactions were reported in 21% and 11% of patients treated with KESIMPTA, compared to 15% and 6% of patients treated with teriflunomide who received matching placebo injections, respectively [see Adverse Reactions (6.1) and Clinical Studies (14)] . Injection-related reactions with systemic symptoms observed in clinical studies occurred most commonly within 24 hours of the first injection, but were also observed with later injections. Symptoms observed included fever, headache, myalgia, chills, and fatigue, and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening injection reactions in the RMS clinical studies. In the post-marketing setting, additional systemic injection-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, angioedema, pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, dizziness, nausea, and tachycardia. Most cases were non-serious and occurred with the first injection. Most serious cases resulted in permanent discontinuation of KESIMPTA. Symptoms of systemic injection-related reactions may be clinically indistinguishable from acute hypersensitivity reactions. A hypersensitivity reaction may occur with any injection. New or more severe symptoms compared to those experienced with previous injections should prompt consideration of a potential hypersensitivity reaction. Only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen was observed in RMS clinical studies. The first injection of KESIMPTA should be performed under the guidance of an appropriately trained healthcare professional. If systemic injection-related reactions occur, initiate appropriate therapy. Patients who experience symptoms of systemic injection-related reactions or hypersensitivity reactions with KESIMPTA should be instructed to seek immediate medical attention. If a hypersensitivity reaction or life-threatening systemic injection-related reaction occurs, immediately and permanently discontinue KESIMPTA [see Contraindications (4)] . If restarting KESIMPTA after a severe (but not life-threatening) systemic injection-related reaction or other event after which rechallenge is considered appropriate, administer the next KESIMPTA injection under clinical observation. If a mild to moderate injection-related reaction occurs, consider rechallenge under clinical observation. Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching, and pain. If local injection-related reactions occur, symptomatic treatment is recommended.

5.3 Reduction in Immunoglobulins As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Decrease in immunoglobulin M (IgM) was reported in 7.7% of patients treated with KESIMPTA compared to 3.1% of patients treated with teriflunomide in RMS clinical trials <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . Treatment was discontinued because of decreased immunoglobulins in 3.4% of patients treated with KESIMPTA and in 0.8% of patients treated with teriflunomide. No decline in immunoglobulin G (IgG) was observed at the end of the study. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing KESIMPTA therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

5.4 Liver Injury Clinically significant liver injury, without findings of viral hepatitis, has been reported in the postmarketing setting in patients treated with anti-CD20 B-cell depleting therapies approved for the treatment of MS, including KESIMPTA. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred weeks to months after administration. Patients treated with KESIMPTA found to have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3x the upper limit of normal (ULN) with serum total bilirubin greater than 2x ULN, are potentially at risk for severe drug-induced liver injury. Obtain liver function tests prior to initiating treatment with KESIMPTA <span class="opacity-50 text-xs">[see Dosage and Administration (2.1)]</span> , and monitor for signs and symptoms of any hepatic injury during treatment. Measure serum aminotransferases, alkaline phosphatase, and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If liver injury is present and an alternative etiology is not identified, discontinue KESIMPTA.

5.5 Fetal Risk Based on animal data, KESIMPTA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to KESIMPTA in utero . Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving KESIMPTA and for at least 6 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span> .

INTERACTIONS

7.1 Immunosuppressive or Immune-Modulating Therapies Concomitant usage of KESIMPTA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with KESIMPTA. When switching from therapies with immune effects, the duration and mechanism of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating KESIMPTA.