men resulted in sustained depletion of circulating B cells. At four weeks, the median number of circulating B cells was zero (range, 0-1084/mm3). B-cell recovery began at approximately 12 weeks following treatment, and the median level of B cells was within the normal range (32 to 341/mm3) by 9 months after treatment. Median serum levels of IgG and IgA remained within the normal range throughout the period of B-cell depletion. Median IgM serum levels dropped below normal (median 49 mg/dL, range 13-3990 mg/dL) after treatment and recovered to normal values by 6-months post therapy.
12.3 Pharmacokinetics
Pharmacokinetic and biodistribution studies were performed using In-111 Zeva lin (5 mCi [185 MBq] In-111, 1.6 mg ibritumomab tiuxetan). In an early study designed to assess the need for pre-administration of unlabeled antibody, only 18% of known sites of disease were imaged when In-111 Zeva lin was administered without unlabeled ibritumomab. When preceded by unlabeled ibritumomab (1.0 mg/kg or 2.5 mg/kg), In-111 Zeva lin detected 56% and 92% of known disease sites, respectively. These studies were conducted with a Zeva lin therapeutic regimen that included unlabeled ibritumomab.
In pharmacokinetic studies of patients receiving the Zeva lin therapeutic regimen, the mean effective half-life for Y-90 activity in blood was 30 hours, and the mean area under the fraction of injected activity (FIA) vs. time curve in blood was 39 hours. Over 7 days, a median of 7.2% of the injected activity was excreted in urine.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and mutogenicity studies have not been conducted. However, radiation is a potential carcinogen and mutagen. No animal studies have been performed to determine the effects of Zeva lin on fertility in males or females. In clinical studies, the Zeva lin therapeutic regimen results in a significant radiation dose to the testes: the radiation dose to the ovaries has not been established [see Dosage and Administration (2.6)]. There is a potential risk that the Zeva lin therapeutic regimen could cause toxic effects on the male and female gonads. Effective contraceptive methods should be used during treatment and for up to 12 months following the Zeva lin therapeutic regimen [see Patient Counseling Information (17)].
13.2 Animal Toxicology and/or Pharmacology
Animal reproductive toxicology studies of the Zeva lin therapeutic regimen have not been conducted. Because the Zeva lin therapeutic regimen includes the use of rituximab, also see prescribing information for rituximab.
14 CLINICAL STUDIES
14.1 Relapsed or Refractory, Low-grade or Follicular Lymphoma
Study 1 was a single arm study of 54 patients with relapsed follicular lymphoma, who were refractory to rituximab treatment. Patients had a World Health Organization (WHO) Performance Status (PS) 0-2, <25% bone marrow involvement by NHL, no prior bone marrow transplantation, and acceptable hematologic, renal, and hepatic function. Refractoriness to rituximab was defined as failure to achieve a complete or partial response or time-to-disease-progression (TTP) of < 6 months. The main efficacy outcome measure of the study was the overall response rate (ORR) using the International Workshop Response Criteria (IWRC). Other efficacy outcome measures included time-to-disease-progression (TTP) and duration of response (DR). Table 9 summarizes efficacy data from Study 1.
Study 2 was a ra |
