KEPIVANCE SIDE EFFECTS

SIDE EFFECTS

Clinical Trials Experience

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 clinical practice.

The data described in Table 1 and the discussion below reflect exposure to Kepivance in 409 patients with hematologic malignancies who were enrolled in 3 randomized, placebo-controlled clinical trials and a pharmacokinetic study. Patients received Kepivance either before, or before and after, regimens of myelotoxic chemotherapy, with or without total body irradiation (TBI), followed by hematopoietic stem cell support. Kepivance was administered in daily doses ranging from 5 to 80 mcg/kg/day. The total dose of Kepivance ranged from 15 to 480 mcg/kg with a median of 360 mcg/kg. The population had a median age of 48 years (range: 41 to 60 years), 62% were male and 83% were White with 7.4 % Black and 6.2 % Hispanic. Non Hodgkin’s lymphoma (NHL) was the most common malignancy followed by Hodgkin’s disease, multiple myeloma, and leukemia.

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.

The most common serious adverse reaction attributed to Kepivance was skin rash, reported in less than 1% (3/409) of patients treated. Grade 3 skin rashes occurred in 3% of patients (9/409) receiving Kepivance and 2% (5/241) receiving placebo.

Table 1: Incidence of Adverse Reactions Occurring with a Between-Group Difference of ≥ 5%

Cataracts

In a postmarketing safety study, the incidence of cataracts was numerically higher among patients receiving Kepivance than in the control population.

Infections

In a randomized, double-blind, placebo-controlled post-approval study designed to determine the efficacy of Kepivance with a high-dose melphalan preparative regimen, the incidence of treatment-emergent infections was significantly greater in patients treated with Kepivance compared to placebo. A total of 281 patients were randomized to 3 arms: Kepivance before melphalan on days -6, -5, -4 and after melphalan on days 0, 1, and 2 (pre-post) (n=115); Kepivance before melphalan on days -6, -5, -4 (pre) (n=109); or placebo (n=57). The incidence of reported infections were pre-post -50%; pre -47%; and placebo -25% .

Laboratory Test Findings

Reversible elevations in serum lipase and amylase, which did not require treatment, were reported in 28% and 62% of patients receiving Kepivance and 23% and 54%of patients receiving placebo. In general, peak increases were observed during the period of cytotoxic therapy and returned to baseline by the day of hematopoietic stem cell infusion. Amylase was mainly salivary in origin.

Immunogenicity

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

In clinical trials, serum samples from patients treated with Kepivance were tested for antibodies to Kepivance using an electrochemiluminescence-based binding assay. Twelve of 645 patients (2%) tested positive; none 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.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Kepivance in the stem cell transplant setting. 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.

• Vaginal edema and erythema;
• Palmar-plantar Erythrodysaesthesia Syndrome (also known as “hand-foot syndrome”)