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Panitumumab

Pronunciation

(pan i TOOM yoo mab)

Index Terms

  • ABX-EGF
  • MOAB ABX-EGF
  • Monoclonal Antibody ABX-EGF
  • rHuMAb-EGFr

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Vectibix: 100 mg/5 mL (5 mL); 400 mg/20 mL (20 mL)

Brand Names: U.S.

  • Vectibix

Pharmacologic Category

  • Antineoplastic Agent, Epidermal Growth Factor Receptor (EGFR) Inhibitor
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Recombinant human IgG2 monoclonal antibody which binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands. Binding to the EGFR blocks phosphorylation and activation of intracellular tyrosine kinases, resulting in inhibition of cell survival, growth, proliferation and transformation. EGFR signal transduction may result in KRAS and NRAS wild-type activation; cells with RAS mutations appear to be unaffected by EGFR inhibition.

Half-Life Elimination

~7.5 days (range: 4 to 11 days)

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC), either as first-line therapy in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or as a single agent following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens

Limitations of use: Panitumumab is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

Use: Unlabeled

Treatment of metastatic colorectal cancer (KRAS wild-type) in combination with other chemotherapy agents

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: History of severe or life-threatening hypersensitivity reactions to panitumumab or any component of the formulation.

Dosage

Colorectal cancer, metastatic, KRAS wild-type: Adults: IV: 6 mg/kg every 14 days as a single agent (Van Cutsem, 2007) or in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) (Douillard, 2010; Douillard, 2013); continue until disease progression or unacceptable toxicity (Douillard, 2010; Van Cutsem, 2007)

Colorectal cancer, metastatic, KRAS wild-type in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan; off-label combination): Adults: IV: 6 mg/kg every 14 days; continue until disease progression or unacceptable toxicity (Peeters, 2010)

Missed doses (Canadian labeling): Doses should be administered within 3 days before or after the scheduled dose (unless withheld for toxicity). If a dose is missed, administer as soon as possible; the next dose should then be administered on a new every 2 week schedule based on the day of the most recently administered dose.

Dosing adjustment for toxicity:

Infusion reactions, mild to moderate (grade 1 or 2): Reduce the infusion rate by 50% for the duration of infusion.

Infusion reactions, severe (grade 3 or 4): Stop infusion; consider permanent discontinuation (depending on severity or persistence of reaction).

Dermatologic toxicity:

Grade 3 toxicity (first occurrence): Withhold 1 to 2 doses; if reaction improves to <grade 3, resume therapy at the initial dose.

Grade 3 toxicity (second occurrence): Withhold 1 to 2 doses; if reaction improves to <grade 3, resume therapy at 80% of the initial dose.

Grade 3 toxicity (third occurrence): Withhold 1 to 2 doses; if reaction improves to <grade 3, resume therapy at 60% of the initial dose.

Grade 3 toxicity (fourth occurrence), grade 3 toxicity that does not recover to <grade 3 after withholding 1 or 2 doses, or grade 4 toxicity: Permanently discontinue.

Ocular toxicity (acute or worsening keratitis): Interrupt or discontinue treatment.

Pulmonary toxicity:

Acute onset or worsening pulmonary symptoms: Interrupt treatment.

Interstitial lung disease: Permanently discontinue treatment.

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Reconstitution

Inspect vial prior to use; solution is colorless but may contain a small amount of translucent-to-white amorphous panitumumab protein particles (will be removed with administration filter). Dilute in 100 mL (for doses ≤1000 mg) or 150 mL (doses >1000 mg) of normal saline to a final concentration of ≤10 mg/mL. Gently invert to mix; do not shake. Discard any unused portion remaining in the vial.

Administration

IV: Administer via infusion pump; do not administer IV push or as a bolus. Doses ≤1000 mg, infuse over 1 hour; if first infusion is tolerated, subsequent doses may be administered over 30 to 60 minutes. Doses >1000 mg, infuse over 90 minutes. Administer through a low protein-binding 0.2 or 0.22 micrometer in-line filter. Flush line with NS before and after infusion; do not mix or administer with other medications. Reduce infusion rate by 50% for mild-to-moderate infusion reactions (grades 1 and 2); stop infusion for severe infusion reactions (grades 3 and 4) and consider permanent discontinuation. Appropriate medical support for the management of infusion reactions should be readily available.

Compatibility

Stable in NS

Storage

Store intact vials in the original cartons under refrigeration at 2°C to 8°C (36°F to 46°F) until the time of use. Do not freeze; do not shake; protect from direct sunlight. Solution diluted for infusion should be used within 6 hours of preparation if stored at room temperature or within 24 hours of dilution if stored at 2°C to 8°C (36°F to 46°F); do not freeze.

Drug Interactions

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Adverse Reactions

Monotherapy:

>10%:

Central nervous system: Fatigue (26%)

Dermatologic: Skin toxicity (90%; grades 3/4: 15%), erythema (66%; grades 3/4: 6%), pruritus (58%; grades 3/4: 3%), acneiform eruption (57%; grades 3/4: 7%), paronychia (25%; grades 3/4: 2%), rash (22%; grades 3/4: 1%), skin fissure (20%; grades 3/4: 1%), exfoliative dermatitis (18%; grades 3/4: 2%), acne vulgaris (14%; grades 3/4: 1%)

Endocrine & metabolic: Hypomagnesemia (grades 3/4: 7%)

Gastrointestinal: Nausea (23%), diarrhea (21%; grades 3/4: 2%), vomiting (19%)

Ophthalmic: Ocular toxicity (16%)

Respiratory: Dyspnea (18%), cough (15%)

Miscellaneous: Fever (17%)

1% to 10%:

Cardiovascular: Pulmonary embolism (1%)

Central nervous system: Chills (3%)

Dermatologic: Nail toxicity (10%), xeroderma (10%), desquamation (9%; grades 3/4: <1%), dermal ulcer (6%; grades 3/4: <1%), pustular rash (4%), papular rash (2%)

Endocrine & metabolic: Dehydration (3%)

Gastrointestinal: Mucositis (7%), stomatitis (7%), xerostomia (5%)

Immunologic: Antibody formation (≤5%)

Ophthalmic: Abnormal eyelash growth (6%), conjunctivitis (5%)

Respiratory: Epistaxis (4%), interstitial pulmonary disease (1%)

Miscellaneous: Infusion related reaction (3%; grades 3/4: <1%)

<1%: Hypersensitivity reaction, pulmonary fibrosis

Combination therapy with FOLFOX:

>10%:

Dermatologic: Skin rash (56%; grades 3/4: 17% to 26%), acneiform eruption (32%; grades 3/4: 10%), pruritus (23%; grades 3/4: <1%), paronychia (21%; grades 3/4: 3%), xeroderma (21%; grades 3/4: 2%), erythema (16%; grades 3/4: 2%), skin fissure (16%; grades 3/4: <1%), alopecia (15%), acne vulgaris (14%; grades 3/4: 3%)

Endocrine & metabolic: Hypomagnesemia (30%), hypokalemia (21%), weight loss (18%)

Gastrointestinal: Diarrhea (62%), anorexia (36%), abdominal pain (28%), stomatitis (27%), mucosal inflammation (25%)

Neuromuscular & skeletal: Weakness (25%)

Ophthalmic: Conjunctivitis (18%)

Respiratory: Epistaxis (14%)

1% to 10%:

Cardiovascular: Deep vein thrombosis (5%)

Central nervous system: Fatigue (≥1%), paresthesia (≥1%)

Dermatologic: Nail disorder (10%; grades 3/4: 1%), palmar-plantar erythrodysesthesia (9%; grades 3/4: 1%), cellulitis (3%)

Endocrine & metabolic: Dehydration (8%), hypocalcemia (6%)

Hypersensitivity: Hypersensitivity (≥1%)

Local: Localized infection (4%)

<1%: Antibody development

Postmarketing and/or case reports (Limited to important or life-threatening) (mono- and combination therapy): Abscess, angioedema, bullous skin disease (mucocutaneous), corneal ulcer, keratitis, necrotizing fasciitis, sepsis, skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis

ALERT: U.S. Boxed Warning

Dermatologic toxicity:

Dermatologic toxicities occurred in 90% of patients and were severe (National Cancer Institute Common Toxicity Criteria [NCI-CTC] grade 3 and higher) in 15% of patients receiving panitumumab monotherapy.

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic toxicity: [US Boxed Warning]: Dermatologic toxicities have been reported in 90% of patients receiving single agent panitumumab and were severe (grade 3 or higher) in 15% of patients; may include dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Severe skin toxicities may be complicated by infection, sepsis, necrotizing fasciitis, or abscesses. The median time to development of skin (or ocular) toxicity was 2 weeks, with resolution ~12 weeks after discontinuation. The severity of dermatologic toxicity is predictive for response; grades 2 to 4 skin toxicity correlates with improved progression free survival and overall survival, compared to grade 1 skin toxicity (Peeters, 2009; Van Cutsem, 2007). Monitor all dermatologic toxicities for development of inflammation or infection. Rare cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported; bullous mucocutaneous disease (life-threatening/fatal) have been observed. Withhold treatment for severe or life-threatening dermatologic or soft tissue toxicities associated with severe/life-threatening inflammatory or infectious complications; dermatologic toxicity may require dose reduction or permanent discontinuation. Patients should minimize sunlight exposure and wear sunscreen and protective clothing/hat; sunlight may exacerbate skin reactions. Nail toxicity has also been reported.

• Diarrhea: May cause diarrhea; the incidence and severity of chemotherapy-induced diarrhea is increased with combination chemotherapy. Severe diarrhea and dehydration (which may lead to acute renal failure) has been observed with panitumumab in combination with chemotherapy. Gastric mucosal toxicity has also been reported.

• Electrolyte depletion: Magnesium and/or calcium depletion may occur during treatment (may be delayed; hypomagnesemia occurred ≥8 weeks after completion of panitumumab) and after treatment is discontinued; electrolyte repletion may be necessary. Monitor for hypomagnesemia and hypocalcemia during treatment and for at least 8 weeks after completion. Hypokalemia has also been reported.

• Infusion reactions: Severe infusion reactions (bronchospasm, dyspnea, fever, chills, and hypotension) have been reported in ~1% of patients; fatal infusion reactions have been reported with postmarketing surveillance. Discontinue infusion for severe reactions; permanently discontinue in patients with persistent severe infusion reactions. Appropriate medical support for the management of infusion reactions should be readily available. Mild-to-moderate infusion reactions are managed by slowing the infusion rate.

• Ocular toxicity: Keratitis and ulcerative keratitis (known risk factors for corneal perforation) have occurred. Monitor for evidence of ocular toxicity; interrupt or discontinue treatment for acute or worsening keratitis.

• Pulmonary toxicity: Pulmonary fibrosis and interstitial lung disease have been observed (rarely) in clinical trials; fatalities have been reported. Interrupt treatment for acute onset or worsening of pulmonary symptoms; permanently discontinue treatment if interstitial lung disease is confirmed. Patients with a history of or evidence of interstitial pneumonitis or pulmonary fibrosis were excluded from most clinical trials; consider the benefits of therapy versus the risk of pulmonary complications in such patients.

Disease-related concerns:

• Colorectal cancer and RAS (KRAS and NRAS) mutation status: Patients with codons 12 and 13 (exon 2), codons 59 and 61 (exon 3), or codons 117 and 146 (exon 4) RAS (KRAS or NRAS) mutations are unlikely to benefit from EGFR inhibitor therapy. Panitumumab is not indicated in patients with RAS mutation-positive metastatic colorectal cancer or patients in which RAS mutation status is unknown. Utilizing an anti-EGFR-directed antibody in patients whose tumors contain RAS mutations resulted in increased toxicity without clinical benefit. In a study of FOLFOX4 (fluorouracil, leucovorin and oxaliplatin) ± panitumumab, patients with a KRAS mutation who received panitumumab with FOLFOX4 experienced a significantly shortened progression-free survival (Douillard, 2010). In addition, a subset analysis of patients with wild-type KRAS identified additional RAS (KRAS [exons 3 and 4] or NRAS [exons 2, 3, 4]) mutations; progression-free survival and overall survival were significantly shortened in patients with RAS mutations who received FOLFOX4 in combination with panitumumab (Douillard, 2013). The American Society of Clinical Oncology (ASCO) provisional clinical opinion (Allegra, 2009) recommends genotyping tumor tissue for KRAS mutation in all patients with metastatic colorectal cancer (genotyping may be done on archived specimens). An updated ASCO provisional clinical opinion recommends that all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy should be tested (in a certified lab) for mutations in both KRAS and NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146); anti-EGFR monoclonal antibody therapy should only be considered in patients whose tumors lack mutations after extended RAS testing (Allegra, 2015). Panitumumab is also reported to be ineffective in patients with BRAF V600E mutation (Di Nicolantonio, 2008).

Concurrent drug therapy issues:

• Bevacizumab and combination chemotherapy: In a study of bevacizumab with combination chemotherapy ± panitumumab, the use of panitumumab resulted in decreased progression-free and overall survival and significantly increased toxicity compared to regimens without panitumumab (Hecht, 2009). Toxicities included rash/acneiform dermatitis, diarrhea/dehydration, electrolyte disturbances, mucositis/stomatitis, and an increased incidence of pulmonary embolism.

Special populations:

• Elderly: Patients >65 years of age receiving panitumumab plus FOLFOX experienced a higher incidence of serious adverse events including severe diarrhea.

Monitoring Parameters

KRAS genotyping of tumor tissue. Monitor serum electrolytes, including magnesium and calcium (periodically during and for at least 8 weeks after therapy), and potassium. Monitor vital signs and temperature before, during, and after infusion. Monitor for skin toxicity, for evidence of ocular toxicity, and for acute onset or worsening pulmonary symptoms.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have demonstrated adverse fetal effects. Based on animal studies, panitumumab may disrupt normal menstrual cycles. IgG is known to cross the placenta; therefore, it is possible the developing fetus may be exposed to panitumumab. Because panitumumab inhibits epidermal growth factor (EGF), a component of fetal development, adverse effects on pregnancy would be expected. Men and women of childbearing potential should use effective contraception during and for 6 months after treatment. In the US and Canada, women who become pregnant during panitumumab treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program (US: 1-800-772-6436; Canada: 1-866-512-6436).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dyspepsia or eyelash growth. Have patient report immediately to prescriber signs of hypomagnesemia, considerable nausea, significant diarrhea, vision changes, ophthalmalgia, intolerable eye irritation, urinary retention, oliguria, angina, hemoptysis, xerostomia, stomatitis, injection site irritation, considerable constipation, significant asthenia, edema of hands or feet, skin or nail changes, or signs of severe pulmonary disorder (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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