Please refer to the PRECAUTIONS: Potential for Stimulation of Tumor Growth and CLINICAL PHARMACOLOGY: Mechanism of Action sections regarding the potential for tumor stimulatory effects in KGF receptor-expressing tumors.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are based upon 409 patients with hematologic malignancies (NHL, Hodgkin's disease, AML, ALL, CML, CLL, or multiple myeloma) who received Kepivance® and 241 patients who received placebo in 3 randomized, placebo-controlled clinical studies and a pharmacokinetic study. Patients received Kepivance® either before, or before and after regimens of myelotoxic chemotherapy, with or without TBI, followed by PBPC support. The patients were predominantly between the ages of 41 and 60 years (median 48 yrs), male (62%), white (83%). NHL was the most common malignancy followed by Hodgkins disease, multiple myeloma, and leukemia.

The most common serious adverse reaction attributed to Kepivance® was skin rash, which was reported in less than 1% (3/409) of patients treated with Kepivance® . Grade 3 skin rashes occurred in 14 patients, 9 of 409 (3%) receiving Kepivance® and 5 of 241 (2%) receiving placebo. In seven patients (5 Kepivance® , 2 placebo), study drug was discontinued due to skin rash. Other serious adverse reactions occurred at a similar rate in patients who received Kepivance® (20%) or placebo (21%). The most frequently reported serious adverse events in Kepivance® and placebo-treated patients were fever, gastrointestinal events, and respiratory events.

The most common adverse reactions attributed to Kepivance® were skin toxicities (rash, erythema, edema, pruritus), oral toxicities (dysesthesia, tongue discoloration, tongue thickening, alteration of taste), pain arthralgias, and dysesthesia. The median time to onset of cutaneous toxicity was 6 days following the first of 3 consecutive daily doses of Kepivance® , with a median duration of 5 days. In patients receiving Kepivance® , dysesthesia (including hyperesthesia, hypoesthesia, and paresthesia) was usually localized to the perioral region, whereas in patients receiving placebo dysesthesias were more likely to occur in extremities. Adverse events occurring more frequently in Kepivance® -treated patients as compared to placebo-treated patients (a higher incidence of ≥ 5%) are listed in Table 2.

In a phase 1 placebo-controlled study in patients undergoing hematopoietic transplantation and receiving Kepivance^™ (3 doses pre-myelotoxic therapy and 3 doses post-transplant), the proportion of Kepivance^™-treated patients reporting an adverse event of hypertension in the 60- and 80-mcg/kg/day Kepivance^™ cohorts was greater than in the placebo group (2/15 patients [13%], 2/14 [14%], and 2/23 [9%], respectively). These events were transient and did not require treatment discontinuation in any patient. In an integrated analysis of adverse events across Kepivance^™ studies in the hematology transplant setting, hypertensive events were reported in 30/409 Kepivance^™ (7%) patients and 13/241 placebo (5%) patients.

In a placebo-controlled study conducted in 145 patients with metastatic colorectal cancer receiving multi-cycle chemotherapy (5-FU/lecovorin), serial urine specimens were collected for 27 placebo-treated and 54 Kepivance^™-treated patients. Among the 54 Kepivance^™-treated patients, nine patients with a baseline urinalysis negative for protein subsequently developed 2+ or greater proteinuria after treatment with Kepivance^™. Among the 27 placebo-treated patients evaluated, none developed 2+ or greater proteinuria. Because of the study design, the number of cycles with urine analysis data collected was higher in the Kepivance^™- treated patients. In addition, for the 9 patients with proteinuria, underlying medical conditions known to be associated with proteinuria were present at baseline. A causal relationship between Kepivance® and proteinuria has not been established.

Reversible elevations in serum lipase and amylase, which did not require treatment intervention, are shown in Table 2. In general, peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of PBPC infusion. Fractionation of amylase revealed it to be predominantly salivary in origin.

As with all therapeutic proteins, there is a potential for immunogenicity. The clinical significance of antibodies to Kepivance® is unknown but may include lessened activity and/or cross reactivity with other members of the FGF family of growth factors.

A sensitive electrochemiluminescence-based binding assay was performed on post-treatment sera from 645 patients treated with Kepivance® in clinical studies. Twelve (2%) of these 645 patients tested positive for antibodies to Kepivance® following treatment. None of the samples had evidence of neutralizing activity in a cell-based assay.

The incidence of antibody positivity is highly dependent on the specific assay and its sensitivity. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to Kepivance® with the incidence of antibodies to other products may be misleading.

No formal drug-drug interaction studies have been conducted for Kepivance® with drugs that may be used in the intended patient population. Kepivance® has been shown to bind to heparin in vitro. Therefore, if heparin is used to maintain an IV line, saline should be used to rinse the line prior to and after Kepivance® administration.

Kepivance® should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy (see CLINICAL STUDIES and DOSAGE AND ADMINISTRATION). In a clinical trial, administration of Kepivance® within 24 hours of chemotherapy resulted in increased severity and duration of oral mucositis.

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