Important safety information1
Safety data are available from 15 clinical trials in which 1,467 patients received Vectibix®; of these, 1,293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.
WARNINGS
Dermatologic Toxicity: Dermatologic toxicities related to Vectibix® blockade of EGF binding and subsequent inhibition of EGFR-mediated signaling pathways were reported in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Severe dermatologic toxicities were complicated by infection, including sepsis, septic death, and abscesses requiring incision and drainage. Withhold or discontinue Vectibix® and monitor for inflammatory or infectious sequelae in patients with severe dermatologic toxicities.
Infustion Reactions: Severe infusion reactions occurred with the administration of Vectibix® in approximately 1% of patients. Severe infusion reactions were identified by reports of anaphylactic reaction, bronchospasm, fever, chills, and hypotension. Although fatal infusion reactions have not been reported with Vectibix®, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.
Mucosal, Ocular, and Nail Toxicities
In the randomized, controlled clinical trial, eye-related toxicities occurred in 15% of patients and included, but were not limited to: conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Other nail disorders were observed in 9% of patients.
Increased Toxicity with Combination Chemotherapy
Vectibix® is not indicated for use in combination with chemotherapy with or without bevacizumab. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased progression-free survival (n=947) and increased incidence of NCI-CTC grade 3-5 (87% vs. 72%) adverse reactions (n=926). All patients received bevacizumab; 86% received an oxaliplatin fluoropyrimidine-based regimen and 14% received an irinotecan fluoropyrimidine-based regimen. NCI-CTC grade 3-4 adverse drug reactions occurring at a higher rate in Vectibix® treated patients included rash/dermatitis/acneiform (26% vs. 1%), diarrhea (23% vs. 12%), dehydration, primarily occurring in patients with diarrhea (16% vs. 5%), hypokalemia (10% vs. 4%), stomatitis/mucositis (4% vs. <1%) and hypomagnesemia (4% vs. 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix® treated patients (7% vs. 4%) and included fatal events in 3 (<1%) Vectibix® treated patients.
In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.
Pulmonary Fibrosis
Pulmonary fibrosis occurred in less than 1% (2/1,467) of patients in clinical trials of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.
Electrolyte Depletion and Monitoring
In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, hypomagnesemia was associated with hypocalcemia. Patients should be periodically monitored for hypomagnesemia and accompanying hypocalcemia during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment, eg, oral or IV electrolyte repletion, as needed.
Photosensitivity
It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®, since sunlight can exacerbate any skin reactions that may occur.
Pregnancy Category C
In women of childbearing potential, appropriate contraceptive measures must be used during, and for 6 months after, treatment with Vectibix®.
General Safety
The most common adverse events observed in clinical studies of Vectibix® (n=1,467) were skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events observed were pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.
Pivotal trial safety
Incidence of adverse events in the randomized, controlled study occurring in >5% of patients with a between group difference of >5% (Vectibix® plus BSC, n=229; BSC, n=234).*
|
|
Vectibix® + BSC |
Vectibix® + BSC |
BSC |
BSC |
|
Body as a Whole |
| |||
|
Fatigue |
26 |
4 |
15 |
3 |
|
General Deterioration |
11 |
8 |
4 |
3 |
|
Digestive |
| |||
|
Abdominal Pain |
25 |
7 |
17 |
5 |
|
Nausea |
23 |
1 |
16 |
< 1 |
|
Diarrhea |
21 |
2 |
11 |
0 |
|
Constipation |
21 |
3 |
9 |
1 |
|
Vomiting |
19 |
2 |
12 |
1 |
|
Stomatitis |
7 |
0 |
1 |
0 |
|
Mucosal Inflammation |
6 |
< 1 |
1 |
0 |
|
Metabolic/Nutritional |
| |||
|
Peripheral Edema |
12 |
1 |
6 |
< 1 |
|
Hypomagnesemia (Lab) |
39 |
4 |
2 |
0 |
|
Respiratory |
|
|
|
|
|
Cough |
14 |
< 1 |
7 |
0 |
|
Skin/Appendages |
| |||
|
All Skin/Integument Toxicity |
90 |
16 |
9 |
0 |
|
Skin |
90 |
14 |
6 |
0 |
|
Erythema |
65 |
5 |
1 |
0 |
|
Acneiform Dermatitis |
57 |
7 |
1 |
0 |
|
Pruritus |
57 |
2 |
2 |
0 |
|
Skin Exfoliation |
25 |
2 |
0 |
0 |
|
Rash |
22 |
1 |
1 |
0 |
|
Skin Fissures |
20 |
1 |
< 1 |
0 |
|
Dry Skin |
10 |
0 |
0 |
0 |
|
Acne |
13 |
1 |
0 |
0 |
|
Nail |
29 |
2 |
0 |
0 |
|
Paronychia |
25 |
2 |
0 |
0 |
|
Other Nail Disorder |
9 |
0 |
0 |
0 |
|
Hair |
9 |
0 |
1 |
0 |
|
Growth of Eyelashes |
6 |
0 |
0 |
0 |
|
Eye |
15 |
< 1 |
2 |
0 |
|
*Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0. | ||||
References
1. Vectibix® (panitumumab) package insert. Amgen; 2007.
_______________________________________________
Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently no data are available that demonstrate an improvement in disease related symptoms or increased survival with Vectibix®.
Important Safety Information
Safety data are available from 15 clinical trials in which 1,467 patients received Vectibix®; of these, 1,293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.
WARNING Infusion Reactions: Severe infusion reactions occurred with the administration of Vectibix® in approximately 1% of patients. Severe infusion reactions were identified by reports of anaphylactic reaction, bronchospasm, fever, chills, and hypotension. Although fatal infusion reactions have not been reported with Vectibix®, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.
Dermatologic Toxicity:Dermatologic toxicities, related to Vectibix® blockade of EGF binding and subsequent inhibition of EGFR-mediated signaling pathways, were reported in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Severe dermatologic toxicities were complicated by infection including sepsis, septic death, and abscesses requiring incisions and drainage. Withhold or discontinue Vectibix® and monitor for inflammatory or infectious sequelae in patients with severe dermatologic toxicities.
Vectibix® is not indicated for use in combination with chemotherapy with or without bevacizumab. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased progression-free survival (n=947) and increased incidence of NCI-CTC grade 3-5 (87% vs. 72%) adverse reactions (n=926).
In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.
Pulmonary fibrosis occurred in less than 1% (2/1,467) of patients in clinical trials of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, and evidence of interstitial pneumonitis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.
In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of Vectibix®. In some patients, hypomagnesemia was associated with hypocalcemia. Patients should be periodically monitored, and treated appropriately, for hypomagnesemia and hypocalcemia during and for 8 weeks after the completion of Vectibix® therapy.
It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®, since sunlight can exacerbate any skin reactions that may occur.
In women of childbearing potential, appropriate contraceptive measures must be used during, and for 6 months after, treatment with Vectibix®.
The most common adverse events observed in clinical studies of Vectibix® (n = 1,467) were skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events observed were pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.
