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Sylatron

"This week the U.S. Food and Drug Administration approved Mekinist (trametinib) in combination with Tafinlar (dabrafenib) to treat patients with advanced melanoma that is unresectable (cannot be removed by surgery) or metastatic (late-stage).

"...

Sylatron

Sylatron

CLINICAL PHARMACOLOGY

Mechanism of Action

Peginterferon alfa-2b is a pleiotropic cytokine; the mechanism by which it exerts its effects in patients with melanoma is unknown.

Pharmacokinetics

The pharmacokinetics were studied in 32 patients receiving adjuvant therapy for melanoma with SYLATRON according to the recommended dose and schedule (6 mcg/kg/week for 8 doses, followed by 3 mcg/kg/week thereafter). At a dose of 6 mcg/kg/week once weekly, the geometric mean Cmax was 4.4 ng/mL (CV 51%) and the geometric mean AUC(tau) was 430 ng•hr/mL (CV 35%) at week 8. The mean terminal half-life was approximately 51 hours (CV 18%). The mean accumulation from week 1 to week 8 was 1.7. After administration of 3 mcg/kg/week once weekly, the mean geometric Cmax was 2.5 ng/mL (CV 33%) and the geometric mean AUC(tau) was 228 ng•hr/mL (CV 24%) at week 4. The mean terminal half-life was approximately 43 hours (CV 19%).

Renal Dysfunction

The disposition of peginterferon alfa-2b was studied in 26 subjects with varying degrees of renal function after administration of a single subcutaneous dose of peginterferon alfa-2b at 1 mcg/kg. Renal clearance accounts for approximately 30% of total peginterferon alfa-2b clearance. The AUClast increased by 1.3-, 1.7- and 1.9-fold in mild, moderate and severe renal impairment, respectively. The mean elimination half-life and maximal plasma concentration (Cmax) increased in subjects with renal impairment. The mean AUClast was similar in subjects with severe renal impairment on and not on hemodialysis, suggesting that no clinical meaningful amounts of peginterferon alfa-2b were removed during hemodialysis.

After subcutaneous administration of 1 mcg/kg of peginterferon alfa-2b once weekly for four weeks in 21 subjects with varying degrees of renal function, AUCtau at week 4 increased 1.3-fold in moderate and 2.1-fold in severe renal impairment. The Cmax at week 4 increased 1.8-fold in severe renal impairment, but no difference was observed in moderate renal impairment [see Use In Specific Populations].

The effect of varying degrees of renal impairment on pharmacokinetics of peginterferon alfa-2b at 3 mcg/kg and 6 mcg/kg recommended for patients with melanoma has not been studied.

Drug Interactions

In a two-way crossover trial, 12 healthy subjects were administered probe drugs of metabolic enzymes: caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), midazolam (CYP3A4), and dapsone (N-acetyltransferase, NAT), with or without a single subcutaneous (SC) dose of peginterferon alfa-2b at 1 mcg/kg. The results suggest that single doses of peginterferon alfa-2b do not affect activities of CYP1A2, CYP2C9, CYP2D6, CYP3A4 and NAT enzymes.

In 24 healthy subjects, the effect of subcutaneous doses of peginterferon alfa-2b at 1 mcg/kg/week for 4 weeks on the pharmacokinetics of caffeine, tolbutamide, dextromethorphan and midazolam were studied. A measure of CYP2C9 activity increased to 125% (90% CI: 116% to 135%) of baseline, whereas a measure of CYP2D6 activity decreased to 51% (90% CI: 38% to 67%) of baseline when coadministered with peginterferon alfa-2b at week 4, indicating that peginterferon alfa-2b may affect the metabolism of CYP2C9 and CYP2D6 drugs. A measure of CYP1A2 and CYP3A4 activity did not show clinically meaningful changes.

When patients are administered SYLATRON with medications metabolized by CYP2C9 or CYP2D6, the therapeutic effect of these drugs may be altered.

The effects of peginterferon alfa-2b at the clinical doses for melanoma (3 mcg/kg/week and 6 mcg/kg/week) on the systemic exposure of drugs metabolized by cytochrome P-450 enzymes have not been studied [see DRUG INTERACTIONS].

Clinical Studies

The safety and effectiveness of SYLATRON were evaluated in an open-label, multicenter, randomized (1:1) study conducted in 1256 patients with surgically resected, AJCC Stage III melanoma within 84 days of regional lymph node dissection. Patients were randomized to observation (no therapy) (n=629) or to SYLATRON (n=627) at a dose of 6 mcg/kg by subcutaneous injection once weekly for 8 doses followed by a 3 mcg/kg subcutaneous injection once weekly for a period of up to 5 years total treatment. The dose of SYLATRON was adjusted to maintain an ECOG Performance Status of 0 to 1.

The median age of the population was 50 years with 11% of patients 65 years or older, and 42% were female. Forty percent of the study population had microscopic, nonpalpable nodal involvement and 59% had clinically palpable nodes prior to lymphadenectomy. A total of 54% of subjects had one pathologically positive lymph node, 34% had 2 to 4 positive nodes, and 12% had 5 or more. Most subjects had no second primary lesion (98%). Ulceration of the primary lesion was present in 30% of subjects (52% had no ulceration of the primary lesion, and the status was missing/unknown for 18% of subjects). The most common sites were the trunk (43%) or the leg (32%). Eighty-four percent had an International Prognostic Index (IPI) score of 0 and 16% had an IPI score of 1. The main outcome measure was relapse-free survival (RFS), defined as the time from randomization to the earliest date of any relapse (local, regional, in-transit, or distant), or death from any cause. Secondary outcome measures included overall survival.

Patients in the SYLATRON arm received 6 mcg/kg/week for a median of 8.0 weeks. Less than 1% of patients took longer than 9 weeks to complete the 6 mcg/kg/week dosing regimen. Approximately one-third (36%) of patients required dose reductions and 29% of patients required a dose delay, with an average delay of 1.2 weeks, during the initial 8 weeks of SYLATRON. Ninety-four patients (16%) did not continue on to the 3 mcg/kg/week dosing regimen.

Patients who continued on SYLATRON after the initial 8 doses, received 3 mcg/kg/week for a median duration of treatment of 14.3 months. Approximately half (52%) of the patients underwent dose reductions and 70% required dose delays (average delay 2.2 weeks).

Based on 696 RFS events, determined by the Independent Review Committee, median RFS was 34.8 months (95% CI: 26.1, 47.4) and 25.5 months (95% CI: 19.6, 30.8) in the SYLATRON and observation arms, respectively. The estimated hazard ratio for RFS was 0.82 (95% CI: 0.71, 0.96; unstratified log-rank p =0.011) in favor of SYLATRON. Figure 1 shows the Kaplan-Meier curves of RFS.

FIGURE 1: Kaplan-Meier Curves for Relapse-Free Survival

Kaplan-Meier Curves for Relapse-Free Survival - Illustration

There was no statistically significant difference in survival between the SYLATRON and the observation arms. Based on 525 deaths, the estimated hazard ratio of SYLATRON versus observation was 0.98 (95% CI: 0.82, 1.16).

Last reviewed on RxList: 1/23/2013
This monograph has been modified to include the generic and brand name in many instances.

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