jueves, 10 de diciembre de 2015

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves PORTRAZZA (necitumumab)

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FDA Approves PORTRAZZA (necitumumab) in Combination with Gemcitabine and Cisplatin, for First-Line Treatment of Patients with Metastatic Squamous Non-Small Cell Lung Cancer
On November 24, 2015, the United States Food and Drug Administration (FDA) approved PORTRAZZA (necitumumab) in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC). PORTRAZZA is not indicated for treatment of non squamous NSCLC. The approved recommended dosage of PORTRAZZA is 800 mg as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle (Q3W) prior to gemcitabine and cisplatin infusion. Patients receiving PORTRAZZA should be pre-medicated as follows:
  • For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent PORTRAZZA infusions.
  • For patients who have experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each PORTRAZZA infusion.
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Necitumumab
  • MOA: Necitumumab is a recombinant human IgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands.
  • Dose proportionality: Necitumumab PK is characterized by a target-mediated drug disposition, exhibiting dose-dependent kinetics on total clearance and steady state volume of distribution.
  • Accumulation: Steady state exposure is achieved after 3 cycles of treatment.
  • Terminal half-life (mean): Approximately 14 days.
  • Exposure-safety: No apparent relationship between average serum necitumumab concentrations (Css,ave) and all grades hypomagnesemia, rash, arterial (ATE) or venous (VTE) thromboembolic events.
Drug Interaction Potential
  • Coadministration of necitumumab (800 mg) with gemcitabine (1250 mg/m2) and cisplatin increased the geometric mean dose-normalized gemcitabine AUC by 22% and Cmax by 63% compared to administration of gemcitabine and cisplatin alone. This increased exposure to gemcitabine may have contributed to the higher toxicity observed with the necitumumab containing arm. The coadministration of necitumumab did not have an effect on the exposure to cisplatin (as measured by dose-normalized AUC0-5h and dose-normalized Cmax for total platinum) in the presence of gemcitabine.
  • Gemcitabine and cisplatin have no effect on the exposure to necitumumab. 
Use in Specific Populations
The following population characteristics were not associated with a clinically significant effect on the PK of necitumumab: age (range: 19-84 years), sex (75% male), race (85% Whites), renal function [as measured by Cockcroft-Gault creatinine clearance (CLcr), range:11-250 mL/min] or hepatic function [as measured by alanine aminotransferase (range: 2-615 U/L), aspartate aminotransferase (range:1.2-619 U/L) and total bilirubin (range: 0.1-106 μmol/L). Body weight is identified as a covariate in the population PK analysis; however, weight-based dosing is not expected to significantly decrease the variability in exposure. No dose adjustment based on body weight is recommended.
Efficacy and Safety
The efficacy and safety of necitumumab at the recommended dose were demonstrated in an open-label, global, multi-center, 2-arm, randomized trial in 1093 patients with squamous NSCLC (Trial JFCC [SQUIRE]). A 1.6-month improvement in median overall survival (OS) among patients in the gemcitabine/ cisplatin + necitumumab Arm compared with those in the gemcitabine/cisplatin Arm (HR = 0.842 [0.736, 0.962]; p=0.012) was demonstrated.  The most common adverse reactions (all grades) observed in PORTRAZZA-treated patients at a rate of  greater than or equal to 30% and greater than or equal to 2% higher than gemcitabine and cisplatin alone arm were rash and hypomagnesemia. Cardiopulmonary arrest and/or sudden death occurred in 3% of patients treated with PORTRAZZA in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after PORTRAZZA administration.

Full prescribing information is available at: http://go.usa.gov/cBtyW
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/cBtVA). 
We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.
This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov

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