ARZERRA (Page 2 of 6)

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.
    • 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 beyonda 1, 2, and 9 3 to 8 10 to 12
Intravenous corticosteroid (prednisolone or equivalent) 50 mg 0-50 mgb 100 mg 0-100 mgb 50-100 mgc
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.

3 DOSAGE FORMS AND STRENGTHS

  • 100 mg/5 mL single‑use vial for intravenous infusion.
  • 1,000 mg/50 mL single‑use vial for intravenous infusion.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Infusion Reactions

ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)].

Pre-medicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4)]. Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3)]. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment.

5.2 Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy.

In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation.

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