VECTIBIX- panitumumab solution
Amgen Inc
WARNING: DERMATOLOGIC TOXICITY
Dermatologic Toxicity : Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.1 )] .
1 I NDICATIONS AND USAGE
1.1 Metastatic Colorectal Cancer
Vectibix is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:
� As first-line therapy in combination with FOLFOX [ see Clinical Studies ( 14.2)].
� As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy [see Clinical Studies ( 14.1)].
Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS -mutant mCRC or for whom RAS mutation status is unknown [see Dosage and Administration ( 2.1), Warnings and Precautions ( 5.2), and Clinical Pharmacology ( 12.1)].
DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Prior to initiation of treatment with Vectibix, assess RAS mutational status in colorectal tumors and confirm the absence of a RAS mutation. Information on FDA-approved tests for the detection of KRAS mutations in patients with metastatic colorectal cancer is available at: https://www.fda.gov/CompanionDiagnostics.
2. 2 Recommended Dose
The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. If the first infusion is tolerated, administer subsequent infusions over 30 to 60 minutes. Administer doses higher than 1000 mg over 90 minutes [see Dosage and Administration ( 2.4)].
Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions [see Warnings and Precautions ( 5.4)].
2.3 Dose Modifications
Dose Modifications for Infusion Reactions [ see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 , 6.3 ) ]
Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.
Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.
Dose Modi fi cations for Dermatologic Toxicity [ see Boxed Warning , Warnings and Precautions ( 5.1 ), and Adverse Reactions ( 6.1 , 6.3 ) ]
� Upon first occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < grade 3, reinitiate Vectibix at the original dose.
� Upon the second occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < grade 3, reinitiate Vectibix at 80% of the original dose.
� Upon the third occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, withhold 1 to 2 doses of Vectibix. If the reaction improves to < grade 3, reinitiate Vectibix at 60% of the original dose.
� Upon the fourth occurrence of a grade 3 (NCI-CTC/CTCAE) dermatologic reaction, permanently discontinue Vectibix.
Permanently discontinue Vectibix following the occurrence of a grade 4 dermatologic reaction or for a grade 3 (NCI-CTC/CTCAE) dermatologic reaction that does not recover after withholding 1 or 2 doses.
3 DOSAGE FORMS AND STRENGTHS
100 mg panitumumab in 5 mL (20 mg/mL) single-use vial.
200 mg panitumumab in 10 mL (20 mg/mL) single-use vial.
400 mg panitumumab in 20 mL (20 mg/mL) single-use vial.
DESCRIPTION
Vectibix (panitumumab) is a recombinant, human IgG2 kappa monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR). Panitumumab has an approximate molecular weight of 147 kDa. Panitumumab is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Vectibix is a sterile, colorless, pH 5.6 to 6.0 liquid for intravenous (IV) infusion, which may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates. Each single-use 5 mL vial contains 100 mg of panitumumab, 29 mg sodium chloride, 34 mg sodium acetate, and Water for Injection, USP. Each single-use 10 mL vial contains 200 mg of panitumumab, 58 mg sodium chloride, 68 mg sodium acetate, and Water for Injection, USP. Each single-use 20 mL vial contains 400 mg of panitumumab, 117 mg sodium chloride, 136 mg sodium acetate, and Water for Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. EGFR is constitutively expressed in normal epithelial tissues, including the skin and hair follicle. EGFR is overexpressed in certain human cancers, including colon and rectum cancers. Interaction of EGFR with its normal ligands (eg, EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular proteins, which in turn regulate transcription of genes involved with cellular growth and survival, motility, and proliferation. KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) and NRAS (Neuroblastoma RAS viral oncogene homologue) are highly related members of the RAS oncogene family. Signal transduction through the EGFR can result in activation of the wild-type KRAS and NRAS proteins; however, in cells with activating RAS somatic mutations, the RAS-mutant proteins are continuously active and appear independent of EGFR regulation.
Panitumumab binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding of ligands for EGFR. Nonclinical studies show that binding of panitumumab to the EGFR prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, decreased proinflammatory cytokine and vascular growth factor production, and internalization of the EGFR. In vitro assays and in vivo animal studies demonstrate that panitumumab inhibits the growth and survival of selected human tumor cell lines expressing EGFR.
