Arzerra

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. • Premedicate before each infusion [see Dosage and Administration (2.4)].

Previously Untreated CLL: The recommended dosage and schedule 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.

Refractory CLL: The recommended dosage and schedule is 12 doses administered as follows:

• 300 mg initial dose (Dose 1), followed 1 week later by • 2,000 mg weekly for 7 doses (Doses 2 through 8), followed 4 weeks later by • 2,000 mg every 4 weeks for 4 doses (Doses 9 through 12). 2.2 Administration

Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available [see Warnings and Precautions (5.1)].

Prepare all doses in 1,000 mL of 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)].

Previously Untreated CLL:

• Cycle 1, Day 1 (300-mg dose): Initiate infusion at a rate of 3.6 mg/hour (12 mL/hour). • Cycle 1, Day 8 and Cycles 2 through 12 (1,000-mg doses): 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

Interval After

Start of Infusion (min)

Cycle 1, Day 1a

(mL/hour)

Cycle 1, Day 8b and

Cycles 2‑12c

(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

aCycle 1, Day 1 = 300 mg; median duration of infusion = 5.2 hours.

b Cycle 1, Day 8 = 1,000 mg; median duration of infusion = 4.4 hours.

c Cycles 2 through 12 = 1,000 mg; median durations of infusion = 4.2 to 4.4 hours.

Refractory CLL:

• Dose 1 (300-mg dose): Initiate infusion at a rate of 3.6 mg/hour (12 mL/hour). • Dose 2 (2,000-mg dose): Initiate infusion at a rate of 24 mg/hour (12 mL/hour). • Doses 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

Interval After Start of Infusion (min)

Dose 1a

(mL/hour)

Dose 2b

(mL/hour)

Doses 3-12b

(mL/hour)

0-30

12

12

25

31-60

25

25

50

61-90

50

50

100

91-120

100

100

200

>120

200

200

400

aDose 1 = 300 mg; median duration of infusion = 6.8 hours.

b Doses 2 and 3 through 12 = 2,000 mg; median duration of infusion for Dose 2 = 6.8 hours; median durations of infusion for Doses 3 through 12 = 4.2 to 4.4 hours.

2.3 Infusion Rate Dose Modification for Infusion Reactions • Interrupt infusion for infusion reactions of any severity [see Warnings and Precautions (5.1)]. 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. o Grade 1 or 2: Infuse at one‑half of the previous infusion rate. o 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 the following premedication 30 minutes to 2 hours prior to each infusion of ARZERRA:

Previously Untreated CLL:

• Oral acetaminophen 1,000 mg (or equivalent) plus • Oral or intravenous antihistamine (diphenhydramine 50 mg or cetirizine 10 mg or equivalent) plus • Intravenous corticosteroid (prednisolone 50 mg or equivalent).

If the patient did not experience a Grade 3 or greater infusion-related adverse event during the first 2 infusions of ARZERRA, the dose of corticosteroid may be reduced or omitted for subsequent infusions.

Refractory CLL:

• Oral acetaminophen 1,000 mg (or equivalent) plus • Oral or intravenous antihistamine (diphenhydramine 50 mg or cetirizine 10 mg or equivalent) plus • Intravenous corticosteroid (prednisolone 100 mg or equivalent).

Do not reduce corticosteroid dose for Doses 1, 2, and 9. Corticosteroid dose may be reduced as follows:

• Doses 3 through 8: Corticosteroid may be reduced or omitted with subsequent infusions if a Grade 3 or greater infusion reaction did not occur with the preceding dose. • Doses 10 through 12: Administer prednisolone 50 mg to 100 mg or equivalent if a Grade 3 or greater infusion reaction did not occur with Dose 9. 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.