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  • CLASSES

    Monoclonal Antibodies that Target EGFR

    BOXED WARNING

    Infection, sepsis, serious rash, skin disease, sunlight (UV) exposure

    Severe dermatologic and soft tissue toxicities have been commonly reported with panitumumab use. Monitor patients who develop a serious rash for complications from inflammation or infection (e.g., necrotizing fasciitis, abscesses, and sepsis); an interruption or discontinuation of therapy may be necessary for severe or life-threatening skin toxicity. Subsequent dosage adjustment is required in patients who have therapy withheld due to dermatologic toxicity. Advise patients receiving panitumumab to wear sunscreen, hats, and limit sunlight (UV) exposure during therapy and for 2 months after the last dose, as UV exposure can exacerbate any skin reactions that may occur. Fatal or life-threatening bullous mucocutaneous skin disease with blisters, erosions, and skin sloughing have been observed; it could not be determined whether these reactions were due to EGFR inhibition or idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). The median time to development of dermatologic toxicity was 12 days after the first dose of panitumumab, with a median time to resolution of 98 days; dose interruption was required in 11% of patients.

    DEA CLASS

    Rx

    DESCRIPTION

    Anti-EGFR monoclonal antibody
    Used for wild-type RAS metastatic colorectal cancer as monotherapy or in combination with chemotherapy
    Dermatologic adverse reactions and severe infusion reactions may occur

    COMMON BRAND NAMES

    Vectibix

    HOW SUPPLIED

    Vectibix Intravenous Sol: 1mL, 20mg

    DOSAGE & INDICATIONS

    For the treatment of wild-type RAS (both KRAS and NRAS) metastatic colorectal cancer.
    For the first-line treatment of wild-type RAS (both KRAS and NRAS) metastatic colorectal cancer in combination with FOLFOX4.
    Intravenous dosage
    Adults

    6 mg/kg IV over 60 minutes (infuse doses higher than 1,000 mg over 90 minutes) on day 1, every 2 weeks prior to FOLFOX4 chemotherapy; if the first infusion is tolerated, subsequent doses of 1,000 mg or lower may be infused over 30 to 60 minutes. After completion of the panitumumab infusion, administer FOLFOX4 chemotherapy: leucovorin 200 mg/m2 IV and oxaliplatin 85 mg/m2 IV (both over 120 minutes via Y-site) on day 1 followed by 5-fluorouracil (5-FU) 400 mg/m2 IV bolus. The 5-FU bolus should be followed by a continuous IV infusion of 5-FU 600 mg/m2 over 22 hours on day 1. On day 2, administer leucovorin 200 mg/m2 IV over 2 hours followed by 5-FU 400 mg/m2 IV bolus and 5-FU 600 mg/m2 IV continuous infusion over 22 hours. The order of administration is panitumumab, followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label trial of patients with previously untreated metastatic colorectal cancer, panitumumab plus FOLFOX4 significantly improved progression-free survival (PFS) in the subgroups of patients with wild-type RAS (10.1 vs. 7.9 months) and wild-type KRAS (9.6 vs. 8 months) compared with FOLFOX4 alone; the overall response rate was also improved in the panitumumab arm. Overall survival was estimated to be 23.3 months for combination therapy and 19.4 months with FOLFOX4 alone in patients with wild-type KRAS; results were similar in patients with wild-type RAS (25.8 vs. 20.2 months).

    For the monotherapy treatment of wild-type RAS (both KRAS and NRAS) metastatic colorectal cancer that has progressed during or after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens.
    Intravenous dosage
    Adults

    6 mg/kg IV over 60 minutes (infuse doses higher than 1,000 mg over 90 minutes) on day 1, every 2 weeks. If the first infusion is tolerated, subsequent doses of 1,000 mg or lower may be infused over 30 to 60 minutes. Panitumumab was found to be noninferior to cetuximab in terms of overall survival in an open-label, randomized clinical trial of patients with wild-type KRAS mCRC (10.4 vs. 10 months). In an open-label, randomized study in patients with wild-type KRAS metastatic colorectal cancer (mCRC), patients who had received prior therapy with irinotecan, oxaliplatin, and a thymidylate synthase inhibitor had significantly improved overall survival (OS) when treated with panitumumab compared with best supportive care (BSC) (10 vs. 7.4 months); median progression-free survival (PFS) was 3.6 months versus 1.7 months, respectively. The RAS mutation status was available in 86% of patients; the OS (10 vs. 6.9 months) and PFS (5.2 vs. 1.7 months) results for patients with wild-type RAS were similar to those with wild-type KRAS compared with BSC. In a separate open-label, randomized clinical trial, panitumumab also significantly improved PFS compared with BSC in patients with EGFR-expressing mCRC who had progressed on or following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (96 days vs. 60 days); retrospectively, 57% of patients had no detectable KRAS mutations.

    For the first-line treatment of wild-type RAS (both KRAS and NRAS) metastatic colorectal cancer in combination with mFOLFOX6.
    Intravenous dosage
    Adults

    6 mg/kg IV over 60 minutes (infuse doses higher than 1,000 mg over 90 minutes) given on day 1, every 2 weeks prior to mFOLFOX6 chemotherapy; if the first infusion is tolerated, subsequent doses of 1,000 mg or lower may be infused over 30 to 60 minutes. After completion of the panitumumab infusion, administer mFOLFOX6 chemotherapy: leucovorin 400 mg/m2 IV and oxaliplatin 85 mg/m2 IV (both over 120 minutes via Y-site) on day 1 followed by 5-fluorouracil (5-FU) 400 mg/m2 IV bolus. The 5-FU bolus should be followed by a continuous IV infusion of 5-FU 1,200 mg/m2/day by continuous IV infusion on days 1 and 2 (total infusional dose, 2,400 mg/m2 CIV over 46 to 48 hours). The order of administration is panitumumab, followed by oxaliplatin and leucovorin, followed by 5-FU. This 2-day regimen is repeated every 2 weeks until disease progression or unacceptable toxicity. In a randomized, multicenter, open-label clinical trial of patients with previously untreated metastatic colorectal cancer and wild-type KRAS (exon2), panitumumab plus mFOLFOX6 did not significantly improve the primary endpoint of median progression-free survival (PFS) compared with bevacizumab plus mFOLFOX6 (10.9 vs. 10.1 months); however, the secondary endpoint of median overall survival (OS) (34.2 vs. 24.3 months) was significantly improved. In a preplanned analysis of patients with wild-type RAS, panitumumab plus mFOLFOX6 significantly improved median PFS (13 vs. 9.5 months) and OS (41.3 vs. 28.9 months) compared with bevacizumab plus mFOLFOX6.

    MAXIMUM DOSAGE

    Adults

    6 mg/kg IV every 2 weeks.

    Geriatric

    6 mg/kg IV every 2 weeks.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Confirm the absence of a RAS mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both KRAS and NRAS with an FDA-approved test prior to initiation of therapy.
    Panitumumab should only be given in a hospital or clinic setting with full resuscitation equipment and under the supervision of a physician experienced with chemotherapy administration. Appropriate medical resources for the treatment of severe infusion reactions should be available. For individuals who experience infusion-related reactions, a prolonged infusion and observation period may be required.

    Injectable Administration
    Intravenous Administration

    Reconstitution:
    Panitumumab solution should be colorless, but may contain a small amount of visible translucent-to-white, amorphous, proteinaceous particulates. Do not administer if there is any discoloration.
    Using aseptic technique and a 21-gauge or larger needle, withdraw the necessary amount for a dose of 6 mg/kg. Do not use needle-free devices (e.g., vial adapters) to withdraw vial contents.
    Vials of panitumumab do not contain preservatives; discard any unused portion remaining in the vial.
     
    Preparation:
    Dilute doses of 1,000 mg or less to a total volume of 100 mL with 0.9% sodium chloride injection.
    Dilute doses higher than 1,000 mg to a total volume of 150 mL with 0.9% sodium chloride injection.
    The final concentration should not exceed 10 mg/mL.
    Mix diluted solution by gentle inversion; do not shake.
    Storage following dilution: The diluted infusion should be used within 6 hours of preparation if stored at room temperature, or within 24 hours if stored under refrigeration (2 to 8 degrees C or 36 to 46 degrees F); do not freeze.
     
    Intravenous Infusion:
    Administer only as an IV infusion via a controlled rate IV infusion pump or syringe pump using a low-protein binding 0.2 micron or 0.22 micron in-line filter; do not administer IV push or as a bolus injection.
    Flush line with 0.9% sodium chloride injection before and after administration. Do not mix panitumumab with, or administer as an infusion with, other medicines or infusions.
    Infuse doses of 1,000 mg or lower over 60 minutes through a peripheral line or indwelling catheter. If the first infusion is tolerated, subsequent doses of 1,000 mg or lower may be infused over 30 to 60 minutes. Infuse doses higher than 1,000 mg over 90 minutes.
    Monitor for infusion-related reactions (e.g., fever, chills, dyspnea, bronchospasm, and hypotension).

    STORAGE

    Vectibix:
    - Diluted product should be used within 6 hours if stored at room temperature or within 24 hours if stored at 36 to 46 degrees F
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from direct sunlight
    - Store in original carton in refrigerator (35 to 46 degrees F) until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    KRAS mutations

    Panitumumab is not indicated for the treatment of patients with colorectal cancer with somatic RAS mutations (either NRAS or KRAS mutations) in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146), or if the RAS mutation status is unknown. Assess the RAS mutational status of colorectal tumors and confirm the absence of a RAS mutation in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of both KRAS and NRAS prior to starting treatment with panitumumab. In retrospective subset analyses across several randomized clinical trials, the administration anti-EGFR monoclonal antibodies (e.g., panitumumab) increased adverse reactions without clinical benefit. Additionally, in an exploratory subgroup analysis of one clinical trial, patients with RAS-mutant metastatic colorectal cancer had a shorter overall survival when treated with panitumumab plus FOLFOX compared with FOLFOX alone (HR 1.21; 95% CI, 1.02 to 1.45).

    Hamster protein hypersensitivity

    Panitumumab should be used with caution in patients with known hamster protein hypersensitivity or hypersensitivity to any component of the product. Panitumumab is a human IgG2 kappa monoclonal antibody that is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

    Acute bronchospasm, fever, hypotension, infusion-related reactions

    Severe infusion-related reactions (acute bronchospasm, fever, chills, and hypotension) have occurred in patients receiving panitumumab; fatalities have been reported. Adjustments to the infusion rate are recommended if a mild or moderate reaction occurs. Stop the panitumumab infusion for severe reactions; permanent discontinuation of therapy may be necessary. Appropriate medical therapy including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen should be available for use in the treatment of such a reaction.

    Infection, sepsis, serious rash, skin disease, sunlight (UV) exposure

    Severe dermatologic and soft tissue toxicities have been commonly reported with panitumumab use. Monitor patients who develop a serious rash for complications from inflammation or infection (e.g., necrotizing fasciitis, abscesses, and sepsis); an interruption or discontinuation of therapy may be necessary for severe or life-threatening skin toxicity. Subsequent dosage adjustment is required in patients who have therapy withheld due to dermatologic toxicity. Advise patients receiving panitumumab to wear sunscreen, hats, and limit sunlight (UV) exposure during therapy and for 2 months after the last dose, as UV exposure can exacerbate any skin reactions that may occur. Fatal or life-threatening bullous mucocutaneous skin disease with blisters, erosions, and skin sloughing have been observed; it could not be determined whether these reactions were due to EGFR inhibition or idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). The median time to development of dermatologic toxicity was 12 days after the first dose of panitumumab, with a median time to resolution of 98 days; dose interruption was required in 11% of patients.

    Pneumonitis, pulmonary disease, pulmonary fibrosis

    Use panitumumab with caution in patients with pre-existing pulmonary disease, or a history of interstitial pneumonitis or pulmonary fibrosis. Interstitial lung disease (ILD)/pneumonitis and pulmonary fibrosis have been observed in patients treated with panitumumab in clinical studies; some cases have been fatal. Hold panitumumab therapy for acute onset or worsening of pulmonary symptoms; permanently discontinue panitumumab if ILD is confirmed.

    Electrolyte imbalance, hypocalcemia, hypokalemia, hypomagnesemia

    Use panitumumab with caution in patients with a known electrolyte imbalance; replete electrolytes as appropriate during therapy. Electrolytes (e.g., magnesium and calcium) should be monitored prior to starting panitumumab, periodically during treatment, and for 8 weeks after the completion of therapy. Severe hypomagnesemia has occurred across clinical trials; hypocalcemia and hypokalemia have also been reported.

    Keratitis, ocular disease

    Use panitumumab with caution in patients with pre-existing ocular disease. Monitor for evidence of keratitis or ulcerative keratitis, both of which are known risk factors for corneal perforation and have been reported with panitumumab use. Hold or discontinue panitumumab therapy for acute or worsening keratitis. After the first panitumumab dose, the median time to ocular toxicity development was 12 days, and the median time to the most severe ocular toxicity was 15 days. After the last panitumumab dose, the median time to resolution was 98 days.

    Geriatric

    Geriatric patients (age, older than 65 years) treated with panitumumab plus FOLFOX4 (n = 128) experienced an increased incidence of serious adverse events (52% vs. 36%) and an increased incidence of serious diarrhea (15% vs. 5%) compared to younger patients (n = 194) in a clinical trial. No overall differences in safety or efficacy were observed in geriatric patients treated with panitumumab monotherapy (n = 265) in 2 other clinical trials.

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during panitumumab treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant women, panitumumab can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving panitumumab should be apprised of the potential hazard to the fetus. Panitumumab is a human IgG monoclonal antibody and may be transferred across the placenta during pregnancy. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Reproduction studies in cynomolgus monkeys treated at exposures of 1.25 to 5 times the recommended human dose of panitumumab during organogenesis resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. Panitumumab was not detected in the serum of neonates, but anti-panitumumab antibody titers were present in 14 of 27 offspring.

    Contraception requirements, infertility, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during panitumumab treatment. Panitumumab can be embryolethal if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 2 months after treatment with panitumumab. Females of reproductive potential should undergo pregnancy testing prior to initiation of panitumumab. Women who become pregnant while receiving panitumumab should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of panitumumab on human fertility, female infertility (e.g., prolonged menstrual cycles and/or amenorrhea) has been observed in animal studies; these effects were reversible upon discontinuation of panitumumab treatment. The effects of panitumumab on male fertility have not been studied; however, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from panitumumab, advise women to discontinue breast-feeding during treatment and for 2 months after the final dose. It is not known whether panitumumab is present in human milk, although many drugs are excreted in human milk. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.

    ADVERSE REACTIONS

    Severe

    diarrhea / Early / 2.0-18.0
    rash / Early / 1.0-17.0
    acneiform rash / Delayed / 7.0-10.0
    hypokalemia / Delayed / 0-10.0
    hypomagnesemia / Delayed / 0-7.0
    erythema / Early / 2.0-6.0
    thrombosis / Delayed / 0-5.3
    stomatitis / Delayed / 0-5.0
    asthenia / Delayed / 0-5.0
    dyspnea / Early / 5.0-5.0
    anorexia / Delayed / 0-4.0
    fatigue / Early / 4.0-4.0
    pruritus / Rapid / 0-3.0
    acne vulgaris / Delayed / 1.0-3.0
    vomiting / Early / 3.0-3.0
    infection / Delayed / 2.0-3.0
    xerosis / Delayed / 0-2.0
    dehydration / Delayed / 0-2.0
    conjunctivitis / Delayed / 0-2.0
    pulmonary embolism / Delayed / 1.3-1.3
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    skin ulcer / Delayed / 0-1.0
    skin necrosis / Early / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    infusion-related reactions / Rapid / 0-1.0
    angioedema / Rapid / 0-1.0
    nausea / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    pulmonary fibrosis / Delayed / 0-1.0
    GI obstruction / Delayed / 0.9-0.9
    bronchospasm / Rapid / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    keratitis / Delayed / Incidence not known
    necrotizing fasciitis / Delayed / Incidence not known

    Moderate

    hypocalcemia / Delayed / 0-5.6
    antibody formation / Delayed / 0.2-5.3
    skin erosion / Delayed / 0-1.0
    bullous rash / Early / 0-1.0
    pneumonitis / Delayed / 1.0-1.0
    hypotension / Rapid / Incidence not known

    Mild

    fever / Early / 16.6-16.6
    alopecia / Delayed / 0-15.0
    epistaxis / Delayed / 3.9-14.0
    hypertrichosis / Delayed / 6.0-6.0
    xerostomia / Early / 4.8-4.8
    chills / Rapid / 3.1-3.1
    flushing / Rapid / 0-3.0
    paresthesias / Delayed / 1.0
    photosensitivity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Bevacizumab: (Major) Do not use panitumumab with bevacizumab in combination with chemotherapy as increased mortality and toxicity may occur. In an interim analysis of an open-label, multicenter, randomized clinical trial of patient with previously untreated metastatic colorectal cancer, the combination of panitumumab, bevacizumab, and chemotherapy resulted in decreased overall survival and an increased incidence of grade 3 to 5 adverse reactions compared with bevacizumab plus chemotherapy without panitumumab, including fatalities. Patients randomized to the panitumumab arm also received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, and 5-fluorouracil) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during panitumumab treatment and for at least 2 months after the last dose. Although there are no adequately controlled studies in pregnant women, panitumumab can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving panitumumab should be apprised of the potential hazard to the fetus. Panitumumab is a human IgG monoclonal antibody and may be transferred across the placenta during pregnancy. Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Reproduction studies in cynomolgus monkeys treated at exposures of 1.25 to 5 times the recommended human dose of panitumumab during organogenesis resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. Panitumumab was not detected in the serum of neonates, but anti-panitumumab antibody titers were present in 14 of 27 offspring.

    Due to the potential for serious adverse reactions in nursing infants from panitumumab, advise women to discontinue breast-feeding during treatment and for 2 months after the final dose. It is not known whether panitumumab is present in human milk, although many drugs are excreted in human milk. Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.

    MECHANISM OF ACTION

    Panitumumab is an epidermal growth factor receptor (EGFR) antagonist and human IgG2 kappa monoclonal antibody. It binds specifically to EGFR on both normal and tumor cells, and competitively inhibits the binding ligands for EGFR. Nonclinical studies show that the binding of panitumumab to 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.
     
    EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases, including EGFR, HER2, HER3, and HER4. It is constitutively expressed in normal epithelial tissues, including the skin and hair follicle, and is overexpressed in certain human cancers, such as colorectal cancers. Interaction of EGFR with its normal ligands (e.g., 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.

    PHARMACOKINETICS

    Panitumumab is administered as an intravenous infusion. Panitumumab clearance decreased from 30.6 to 4.6 mL/kg per day as the dose increased from 0.75 to 9 mg/kg. The mean clearance is 4.9 +/- 1.4 mL/kg per day, and the elimination half-life is approximately 7.5 days (range, 3.6 to 10.9 days).

    Intravenous Route

    When administered as a single agent, panitumumab exhibits nonlinear pharmacokinetics. Following a single-dose administration of panitumumab as a 1-hour infusion, the AUC increased in a greater than dose-proportional manner at doses below 2 mg/kg; however, at doses above 2 mg/kg, the AUC increased in an approximately dose-proportional manner. The mean AUC was 1,306 +/- 374 mcg*day/mL when administered at the recommended dose regimen. Panitumumab concentrations reached steady-state by the third infusion, with mean peak concentrations (Cmax) of 213 +/- 59 mcg/mL and mean trough concentrations (Cmin) of 39 +/- 14 mcg/mL.