Panitumumab is an epidermal growth factor receptor (EGFR) antagonist and a human IgG2 kappa monoclonal antibody, produced in genetically engineered mammalian (Chinese hamster ovary) cells. Panitumumab is FDA approved as monotherapy and in combination with chemotherapy for the treatment of patients with wild-type RAS metastatic colorectal cancer. It differs from cetuximab in that it has a higher affinity for the EGFR receptor and has a lower incidence of hypersensitivity reactions. Dermatologic adverse reactions are common, occurring in up to 90% (grade 3 or 4, 15%) of patients treated with panitumumab as monotherapy. Patients who develop dermatologic toxicities should be monitored closely for inflammatory or infectious sequelae. Severe infusion-related reactions may also occur; monitor vital signs closely during and after administration.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-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.
Emetic Risk
-Low
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
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).
Dermatologic toxicities are common in patients treated with panitumumab and occurred in more than 90% of patients treated with monotherapy (grade 3 or 4, 15%), including acneiform rash, pruritus, erythema, rash, exfoliative dermatitis, xerosis, and skin fissures. Exposure to sunlight can exacerbate dermatologic toxicity (photosensitivity). Life-threatening and fatal bullous mucocutaneous disease (bullous rash) with blisters, skin erosion, and skin sloughing has also been observed in postmarketing experience; it was unable to be determined if this was directly related to EGFR inhibition or to 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. Panitumumab should be held for dermatologic toxicity associated with severe or life-threatening inflammatory or infectious complications; dose modifications or discontinuation of therapy may be necessary. In clinical trials where panitumumab was administered as monotherapy and compared with best supportive care, the following dermatologic adverse reactions were reported: erythema (all grade, 66%; grade 3 or 4, 6%), pruritus (all grade, 58%; grade 3 or 4, 3%), acneiform rash (all grade, 57%; grade 3 or 4, 7%), rash (all grade, 22%; grade 3 or 4, 1%), skin fissures (all grade, 20%; grade 3 or 4, 1%), acne vulgaris (all grade, 14%; grade 3 or 4, 1%), xerosis (grade 1 or 2, 10%), nail disorder (grade 1 or 2, 10%), exfoliative dermatitis (all grade, 9%; grade 3 or 4, less than 1%), skin ulcer (all grade, 6%; grade 3 or 4, less than 1%), pustular rash (4.4%), and papular rash (1.7%). Dermatologic toxicity also occurred more often in patients with metastatic colorectal cancer treated with panitumumab plus FOLFOX4 compared with FOLFOX4 alone, including rash (all grade, 56% vs. 7%; grade 3 or 4, 17% vs. less than 1%), acneiform dermatitis (all grade, 32% vs. 0%; grade 3 or 4, 10% vs. 0%), pruritus (all grade, 23% vs. 4%; grade 3 or 4, less than 1% vs. 0%), xerosis (all grade, 21% vs. 4%; grade 3 or 4, 2% vs. 0%), erythema (all grade, 16% vs. 4%; grade 3 or 4, 2% vs. 0%), skin fissures (all grade, 16% vs. less than 1%; grade 3 or 4, less than 1% vs. 0%), alopecia (all grade, 15% vs. 9%), acne (all grade, 14% vs. less than 1%; grade 3 or 4, 3% vs. 0%), nail disorder (all grade, 10% vs. 1%; grade 3 or 4, 1% vs. 0%), palmar-plantar erythrodysesthesia (hand and foot syndrome) (all grade, 9% vs. 3%; grade 3 or 4, 1% vs. less than 1%), and flushing (3% vs. less than 1%). Skin necrosis was also reported in postmarketing experience.
Infusion-related reactions, manifesting as fever, chills, shortness of breath, bronchospasm, and hypotension, occurred in 3% (grade 3 or 4, less than 1%) of patients treated with panitumumab across clinical trials (n = 725); fatal infusion reactions and angioedema have been reported in postmarketing experience. When administered as monotherapy, chills were reported in 3.1% of panitumumab-treated patients and fever in 16.6%. If a mild infusion reaction occurs, slow the rate by 50% for the duration of the infusion; discontinuation of therapy may be necessary for a severe reaction. The ability of premedication to prevent the first or subsequent episodes of infusional toxicity is unknown because its use was not standardized in clinical trials.
Among 229 recipients of single-agent panitumumab in a randomized, open-label clinical trial, gastrointestinal adverse events included nausea (all grade, 23%; grade 3 or 4, less than 1%), diarrhea (all grade, 21%; grade 3 or 4, 2%), vomiting (all grade, 19%; grade 3 or 4, 3%), mild stomatitis (grade 1 or 2, 7%), mucosal inflammation (all grade, 7%; grade 3 or 4, less than 1%), and xerostomia (all grade, 4.8%). GI obstruction was also reported in 2 patients (0.9%), resulting in discontinuation of panitumumab therapy. Gastrointestinal toxicity that occurred more often in patients with metastatic colorectal cancer treated with panitumumab plus FOLFOX4 (n = 322) compared with FOLFOX4 alone (n = 327) in a separate randomized clinical trial included diarrhea (all grade, 62% vs. 52%; grade 3 or 4, 18% vs 9%), abdominal pain (all grade, 28% vs. 23%), stomatitis (all grade, 27% vs. 13%; grade 3 or 4, 5% vs. less than 1%), mucosal inflammation (all grade, 25% vs. 16%; grade 3 or 4, 4% vs. less than 1%), weight loss (all grade, 18% vs. 7%; grade 3 or 4, less than 1% vs. 0%), and anorexia (all grade, 36% vs. 26%; grade 3 or 4, 4% vs. 2%). Severe diarrhea and dehydration, leading to acute renal failure (unspecified) and other complications, have been observed in patients treated with panitumumab in combination with chemotherapy. While dehydration was reported in 2.6% of patients receiving panitumumab monotherapy (compared with 1.7% of those receiving best supportive care), the incidence increased to 8% when given in combination with FOLFOX4 (compared with 3% of patients treated with FOLFOX4 alone; the incidence of severe dehydration was 2% in each arm.
Across clinical trials, up to 7% of patients treated with panitumumab experienced progressively decreasing magnesium levels leading to grade 3 to 4 hypomagnesemia. In a randomized, clinical trial of patients with metastatic colorectal cancer, patients with wild-type KRAS treated with panitumumab in combination with FOLFOX (n = 322) experienced more electrolyte disturbances than those treated with FOLFOX alone (n = 327), including hypomagnesemia (all grade, 30% vs. 8%; grade 3 or 4, 7% vs. less than 1%), hypokalemia (all grade, 21% vs. 13%; grade 3 or 4, 10% vs. 5%), and hypocalcemia (all grade, 5.6% vs. 2.1%); one patient treated with panitumumab experienced grade 5 hypokalemia. Monitor electrolytes before starting therapy with panitumumab, periodically during treatment, and for up to 8 weeks after completion of therapy. Replete electrolytes as needed.
Among 229 recipients of panitumumab monotherapy in a randomized, open-label clinical trial, fatigue occurred in 26% (grade 3 or 4, 4%) of patients compared with 15% (grade 3 or 4, 3%) of those who received best supportive care. A general physical deterioration of health resulting in discontinuation of panitumumab occurred in 2 patients (0.9%). Asthenia was more common in metastatic colorectal cancer patients receiving panitumumab plus FOLFOX4 (n = 322) compared with FOLFOX4 alone (n = 327) in another randomized clinical trial (all grade, 25% vs. 19%; grade 3 or 4, 5% vs. 3%).
Panitumumab antibody formation has been evaluated using an enzyme-linked immunosorbent assay (ELISA), which detects high-affinity antibodies, and a Biacore biosensor immunoassay detecting both high- and low-affinity antibodies. Following the administration of panitumumab monotherapy in 1,295 patients, treatment-emergent binding anti-panitumumab antibodies were detected in 0.5% of patients using the ELISA assay and 5.3% of patients using the Biacore assay; neutralizing antibodies were detected in 0.8% of patients. Pharmacokinetic parameters or safety were not altered in patients who developed anti-panitumumab antibodies. Following the administration of panitumumab in combination with chemotherapy (n = 1,297), treatment-emergent binding anti-panitumumab antibodies were detected in 0.9% of patients using the ELISA assay and 0.7% of patients using the Biacore assay; neutralizing antibodies were detected in 0.2% of patients. The safety profile was not altered in patients who developed anti-panitumumab antibodies.
Serious cases of keratitis, ulcerative keratitis, and corneal perforation have occurred in patients treated with panitumumab in postmarketing experience. Monitor for evidence of acute or worsening keratitis, ulcerative keratitis, or corneal perforation; an interruption or discontinuation of therapy may be necessary. Ocular toxicities occurred in 16% of patients who received panitumumab monotherapy in a clinical trial (n = 229), including conjunctivitis (4.8%). 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. The incidence of conjunctivitis was higher in patients treated with panitumumab plus FOLFOX4 (n = 322) compared with FOLFOX4 alone (n = 327) in another clinical trial of patients with metastatic colorectal cancer (all grade, 18% vs. 3%; grade 3 or 4, 2% vs. 0%).
Fatal and nonfatal cases of pulmonary fibrosis (less than 1%) and interstitial lung disease (ILD)/pneumonitis (1%) have been reported across clinical trials in patients treated with panitumumab. Panitumumab therapy should be held for any new or worsening pulmonary symptoms, and discontinued if a diagnosis of ILD is confirmed. In one clinical trial, dyspnea (all grade, 18% vs. 13%; grade 3 or 4, 5% vs. 3%) and cough (all grade, 15% vs. 7%; grade 3 or 4, less than 1% vs. 0%) occurred more often with panitumumab monotherapy (n = 229) compared with best supportive care (n = 234).
Mild (grade 1 to 2) eyelash growth (eyelash hypertrichosis) was reported in 6% of patients treated with panitumumab monotherapy in an open-label, randomized clinical trial and was not reported in patients who received only best supportive care (n = 234).
In a randomized, open-label clinical trial, pulmonary embolism occurred in 1.3% of patients treated with panitumumab monotherapy (n = 229) and was not reported in those who received best supportive care (n = 234). Deep vein thrombosis occurred in 5.3% of patients who received panitumumab plus FOLFOX4 (n = 322) compared with 3.1% of those receiving FOLFOX4 alone (n = 327).
Epistaxis (all grade, 3.9% vs. 0%) occurred more often with panitumumab monotherapy (n = 229) compared with best supportive care (n = 234) in one clinical trial. Epistaxis was also reported in 14% of patients with metastatic colorectal cancer treated with panitumumab plus FOLFOX4 (n = 322), compared with 9% of patients who received FOLFOX4 alone (n = 327).
Life-threatening and fatal infection related to severe dermatologic toxicities has been reported with panitumumab monotherapy in clinical trials, including sepsis, necrotizing fasciitis, and abscesses requiring incisions and drainage. Paronychia was reported in 21% to 25% (grade 3 or 4, 2% to 3%) of patients with metastatic colorectal cancer treated with panitumumab either as monotherapy (n = 229) or in combination with FOLFOX4 (n = 322) in separate clinical trials, and was not reported in patients receiving either best supportive care (n = 234) or FOLFOX4 alone (n = 327). Patients also reported a higher incidence of localized infection (3.7% vs. less than 1%) and cellulitis (2.5% vs. 0%) when treated with panitumumab plus FOLFOX4 compared with FOLFOX4 alone.
Paresthesias were reported in patients with metastatic colorectal cancer treated with panitumumab plus FOLFOX4 (n = 322) in a randomized, open-label clinical trial, and was among the most commonly reported adverse reactions leading to discontinuation of therapy, in greater than or equal to 1% of patients.
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).
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.
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.
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.
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.
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.
Use panitumumab with caution in patients with pre-existing ocular disease. Serious cases of keratitis, ulcerative keratitis, and corneal perforation have occurred in patients treated with panitumumab. Monitor for evidence of acute or worsening keratitis, ulcerative keratitis, or corneal perforation; an interruption or discontinuation of therapy may be necessary. 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 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 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.
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).
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.
For the treatment of wild-type RAS (both KRAS and NRAS) metastatic colorectal cancer:
NOTE: Information on FDA-approved tests for the detection of RAS mutations in patients with metastatic colorectal cancer is available at www.fda.gov/CompanionDiagnostics
-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 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.
-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.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
Infusion Reactions
-Mild or moderate (Grade 1 or 2) infusion reactions: Reduce infusion rate by 50% for the duration of that infusion.
-Severe (Grade 3 or 4) infusion reactions: Terminate the infusion. Permanently discontinue panitumumab depending on the severity and/or persistence of the reaction.
Dermatologic toxicity
-Grade 3: Hold 1 to 2 doses of panitumumab. Upon improvement to grade 3 or less, panitumumab may be resumed at the original dose after the first occurrence, at 80% of the original dose after the second occurrence, and at 60% of the original dose after the third occurrence. Permanently discontinue panitumumab if grade 3 dermatologic toxicity occurs for a fourth time. If the toxicity does not improve to less than grade 3 after holding 1 to 2 doses, permanently discontinue panitumumab.
-Grade 4: Permanently discontinue panitumumab.
Maximum Dosage Limits:
-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.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
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.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
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.
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).
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
Mild-to-moderate hepatic dysfunction had no apparent impact on the pharmacokinetic parameters of panitumumab. No formal pharmacokinetic studies have been conducted in patients with hepatic impairment.
Renal Impairment
Mild-to-moderate renal dysfunction had no apparent impact on the pharmacokinetic parameters of panitumumab. No formal pharmacokinetic studies have been conducted in patients with renal impairment.
Pediatrics
Panitumumab exposures were comparable in adult and adolescent patients (age, 12 to 17 years) at doses ranging for 2.5 mg/kg IV weekly, 6 mg/kg IV every 2 weeks, or 9 mg/kg IV every 3 weeks (n = 28). Limited data suggest that pediatric patients (age, 2 to 11 years) had lower panitumumab exposure and higher clearance than in adolescent patients following administration of panitumumab 6 mg/kg IV. There was no evidence of an anti-tumor treatment effect in these patients; the safety and efficacy of panitumumab have not been established in pediatric patients.
Geriatric
Age (21 to 88 years) had no apparent impact on the pharmacokinetic parameters of panitumumab.
Gender Differences
Gender had no apparent impact on the pharmacokinetic parameters of panitumumab.
Ethnic Differences
Ethnicity had no apparent impact on the pharmacokinetic parameters of panitumumab.
Other
EGFR membrane-staining intensity (1+, 2+, 3+) in tumor cells had no apparent impact on the pharmacokinetic parameters of panitumumab.