Zevalin (Page 4 of 6)

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of the Zevalin therapeutic regimen in hematologic malignancies. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to the Zevalin therapeutic regimen.

Cutaneous and mucocutaneous reactions: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous dermatitis, and exfoliative dermatitis [see Boxed Warning and Warnings and Precautions (5.3) ].
Infusion site erythema and ulceration following extravasation [see Warnings and Precautions ( 5.5)].
Radiation injury in tissues near areas of lymphomatous involvement within a month of Zevalin administration.

6.3 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the incidence of antibodies to the Zevalin therapeutic regimen in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

HAMA and HACA response data on 446 patients from 8 clinical studies conducted over a 10-year time period are available. Overall, 11/446 (2.5%) had evidence of either HAMA formation (N=8) or HACA formation (N=4). Six of these patients developed HAMA/HACA after treatment with Zevalin and 5 were HAMA/HACA positive at baseline. Of the 6 who were HAMA/HACA positive, only one was positive for both. Furthermore, in 6 of the 11 patients, the HAMA/HACA reverted to negative within 2 weeks to 3 months. No patients had increasing levels of HAMA/HACA at the end of the studies.

Only 6/446 patients (1.3%) had developed evidence of antibody formation after treatment with Zevalin, and of these, many either reverted to negative or decreased over time. This data demonstrates that HAMA/HACA develop infrequently, are typically transient, and do not increase with time.

7 DRUG INTERACTIONS

Patients receiving medications that interfere with platelet function or coagulation should have more frequent laboratory monitoring for thrombocytopenia. No formal drug interaction studies have been performed with Zevalin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its radioactivity, Y-90 Zevalin may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. Immunoglobulins are known to cross the placenta. There are no available data on Zevalin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Advise women of childbearing potential to use adequate contraception for a minimum of twelve months. Inform women who become pregnant while receiving Zevalin of the potential fetal risks.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

8.2 Lactation

Risk Summary

There are no data on the presence of Zevalin or its metabolites in human milk, the effects of Zevalin on the breastfed child, or its effects on milk production. Because human IgG is excreted in human milk, it is expected that Zevalin would be present in human milk. Due to the potential for serious adverse reactions in a breastfeeding child from Zevalin, advise lactating women to avoid breastfeeding during treatment with the Zevalin therapeutic regimen and for 6 months after the last dose.

8.3 Females and Males of Reproductive Potential

Zevalin may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Conduct pregnancy testing in females of reproductive potential prior to treatment with Zevalin.

Contraception

Females

Based on its radioactivity, Y-90 Zevalin may cause fetal harm. Advise females of reproductive potential to use effective contraceptive methods during treatment and for 12 months after the last dose of the Zevalin therapeutic regimen [see Clinical Pharmacology (12.1)].

Males

Based on its radioactivity, Y-90 Zevalin may cause fetal harm. Advise males with female partners of reproductive potential to use effective contraceptive methods during treatment and for 12 months after the final dose of the Zevalin therapeutic regimen [see Clinical Pharmacology (12.1)].

Infertility

Based on its radioactivity, there is a potential risk that the Zevalin therapeutic regimen could cause toxic effects on the male and female gonads [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Zevalin have not been established in pediatric patients.

8.5 Geriatric Use

Of 349 patients with relapsed/refractory NHL treated with the Zevalin therapeutic regimen in clinical studies, 38% (132 patients) were age 65 years and over, while 12% (41 patients) were age 75 years and over.

Of 414 patients enrolled in the FIT study (Zevalin following first-line chemotherapy) 206 patients received Zevalin. Of these patients 14% (29 patients) were 65 years and over, while 2% (4 patients) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

10 OVERDOSAGE

Severe cytopenias which may require stem cell support have occurred at doses higher than the recommended maximum total dose of 32 mCi (1184 MBq).

11 DESCRIPTION

Zevalin (ibritumomab tiuxetan) is the immunoconjugate resulting from a stable thiourea covalent bond between the monoclonal antibody ibritumomab and the linker-chelator tiuxetan [N-[2-bis(carboxymethyl)amino]-3-(p-isothiocyanatophenyl)-propyl]-[N-[2-bis(carboxymethyl)amino]-2-(methyl)-ethyl]glycine. This linker-chelator provides a high affinity, conformationally restricted chelation site for Yttrium-90. The approximate molecular weight of ibritumomab tiuxetan is 148 kD. The antibody moiety of Zevalin is ibritumomab, a murine IgG1 kappa monoclonal antibody directed against the CD20 antigen.

Ibritumomab tiuxetan is a clear, colorless, sterile, pyrogen-free, preservative-free solution that may contain translucent particles. Each single-use vial includes 3.2 mg of ibritumomab tiuxetan in 2 mL of 0.9% Sodium Chloride.

Physical/Radiochemical Characteristics of Y-90

Yttrium-90 decays by emission of beta particles, with a physical half-life of 64.1 hours (2.67 days). The product of radioactive decay is non-radioactive Zirconium-90. The range of beta particles in soft tissue (χ90 ) is 5 mm. Radiation emission data for Y-90 are summarized in Table 5.

Table 5. Principal Y-90 Radiation Emission Data
Radiation Mean % per Disintegration Mean Energy (keV)
Beta minus 100 750-935

External Radiation

The exposure rate for 1 mCi (37 MBq) of Y-90 is 8.3 x 10-3 C/kg/hr (32 R/hr) at the mouth of an open Y-90 vial.

To allow correction for physical decay of Y-90, the fractions that remain at selected intervals before and after the time of calibration are shown in Table 6.

Table 6. Physical Decay Chart: Y-90 Half-life 2.67 Days (64.1 Hours)
Calibration Time (Hrs.) Fraction Remaining Calibration Time (Hrs.) Fraction Remaining
-36 1.48 0 1.00
-24 1.30 1 0.99
-12 1.14 2 0.98
-8 1.09 3 0.97
-7 1.08 4 0.96
-6 1.07 5 0.95
-5 1.06 6 0.94
-4 1.04 7 0.93
-3 1.03 8 0.92
-2 1.02 12 0.88
-1 1.01 24 0.77
0 1.00 36 0.68

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