Panitumumab

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)

Pharmacology

Mechanism of Action

Panitumumab is a 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.

Pharmacokinetics/Pharmacodynamics

Half-Life Elimination

~7.5 days (range: 4 to 11 days)

Use: Labeled Indications

Colorectal cancer (metastatic): Treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an approved test) 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

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: Off Label

Colorectal cancer, metastatic, KRAS wild-type (in combination with other chemotherapy agents)a

Data from an open-label, randomized, multicenter, phase III study supports the use of panitumumab (based on an improvement in progression-free survival) for the treatment of metastatic colorectal cancer (KRAS wild-type) in combination with other chemotherapy (FOLFIRI) Peeters 2010.

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 and Administration

Dosing: Adult

Note: Establish RAS mutation status (to confirm RAS wild-type) prior to treatment initiation.

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

Dosing: Geriatric

Refer to adult dosing.

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 initial dose.

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

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

Reconstitution

Inspect vial prior to use; solution is colorless but may contain a small amount of translucent to white amorphous panitumumab protein particles. Do not shake vial. Use a 21-gauge (or larger gauge/smaller bore) needle to withdraw appropriate volume from vial; do not use needle-free devices or vial adapters to withdraw vial contents. The manufacturer recommends diluting to a total volume of 100 mL (for doses ≤1,000 mg) or 150 mL (doses >1,000 mg) of NS. The final concentration should not exceed 10 mg/mL. Gently invert to mix; do not shake. Discard any unused portion remaining in the vial.

Administration

IV: For IV infusion only; do not administer IV push or as a bolus. Administer via infusion pump through a low protein-binding 0.2 or 0.22 micrometer in-line filter. Doses ≤1,000 mg, infuse over 1 hour; if first infusion is tolerated, subsequent doses may be administered over 30 to 60 minutes. Doses >1,000 mg, infuse over 90 minutes. 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.

Storage

Store intact vials in the original carton 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. Solutions diluted in NS 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

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

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 (mono- and combination therapy): Abscess, angioedema, bullous skin disease (mucocutaneous), corneal ulcer, keratitis, necrotizing fasciitis, sepsis, skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis

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 mutation status: Confirm absence of RAS mutation prior to treatment; 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 whom 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 update 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 2016). Information on tests approved for detection of RAS mutation is available at www.fda.gov/CompanionDiagnostics. 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.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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

RAS genotyping of tumor tissue to establish RAS mutation status and confirm RAS wild-type (prior to treatment initiation). 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

Pregnancy Considerations

Based on animal reproduction studies and on the mechanism of action, panitumumab may cause fetal harm if administered during pregnancy. Panitumumab is a humanized monoclonal antibody (IgG₂). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Because panitumumab inhibits epidermal growth factor (EGF), a component of fetal development, adverse effects on pregnancy would be expected. Females of reproductive potential should use effective contraception during treatment and for at least 2 months after the last dose.

Patient Education

What is this drug used for?

• It is used to treat colorectal cancer.

Frequently reported side effects of this drug

• Loss of strength and energy
• Nausea
• Vomiting
• Weight loss
• Lack of appetite
• Hair loss
• Acne
• Itching
• Dry skin
• Eyelash growth

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Chills
• Severe skin irritation
• Severe diarrhea
• Vision changes
• Eye pain
• Severe eye irritation
• Chest pain
• Coughing up blood
• Severe abdominal pain
• Mouth irritation
• Mouth sores
• Skin or nail changes
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.