Erbitux 100 Mg 20 Ml Iv Vial Merck Sharp & Dohme

Erbitux 100 Mg 20 Ml Iv Vial Merck Sharp & Dohme

Brand:MSD Pharmaceuticals
Product Code:63
Availability:In Stock

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST

1    INDICATIONS AND USAGE

1.1   Squamous Cell Carcinoma of the Head and Neck (SCCHN)

1.2   K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer

2    DOSAGE AND ADMINISTRATION

2.1   Squamous Cell Carcinoma of the Head and Neck

2.2   Colorectal Cancer

2.3   Recommended Premedication

2.4   Dose Modifications

2.5   Preparation for Administration

3    DOSAGE FORMS AND STRENGTHS

4    CONTRAINDICATIONS

5    WARNINGS AND PRECAUTIONS

5.1   Infusion Reactions

5.2   Cardiopulmonary Arrest

5.3   Pulmonary Toxicity

5.4   Dermatologic Toxicity

5.5   Use of Erbitux in Combination With Radiation and Cisplatin

5.6   Hypomagnesemia and Electrolyte Abnormalities

5.7   K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients

5.8   Epidermal Growth Factor Receptor (EGFR) Expression and Response

6.2   Immunogenicity

6.3   Postmarketing Experience

7    DRUG INTERACTIONS

8    USE IN SPECIFIC POPULATIONS

8.1   Pregnancy

8.3   Nursing Mothers

8.4   Pediatric Use

8.5   Geriatric Use

10    OVERDOSAGE

11    DESCRIPTION

12    CLINICAL PHARMACOLOGY

12.1   Mechanism of Action

12.2   Pharmacodynamics

12.3   Pharmacokinetics

13    NONCLINICAL TOXICOLOGY

13.1   Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2   Animal Pharmacology and/or Toxicology

14    CLINICAL STUDIES

14.1   Squamous Cell Carcinoma of the Head and Neck (SCCHN)

14.2   Colorectal Cancer

16    HOW SUPPLIED/STORAGE AND HANDLING

17    PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

6    ADVERSE REACTIONS

6.1   Clinical Trials Experience

 
FULL PRESCRIBING INFORMATION

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions (5.1), Adverse Reactions (6).] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions (5.2, 5.6), Clinical Studies (14.1).]

1    INDICATIONS AND USAGE

1.1   Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Erbitux® is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1).]

Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1).]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1).]

1.2   K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer

Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2), Warnings and Precautions (5.7), Clinical Studies (14.2)]

in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for the first-line treatment,
in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy,
as a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions (5.7), Clinical Pharmacology (12.1), Clinical Studies (14.2).]
Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions (5.7), Clinical Studies (14.2)].

2    DOSAGE AND ADMINISTRATION

2.1   Squamous Cell Carcinoma of the Head and Neck

Erbitux in combination with radiation therapy or in combination with platinum-based therapy with 5-FU:

The recommended initial dose is 400 mg/m2 administered one week prior to initiation of a course of radiation therapy or on the day of initiation of platinum-based therapy with 5-FU as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min). Complete Erbitux administration 1 hour prior to platinum-based therapy with 5-FU.
The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) for the duration of radiation therapy (6–7 weeks) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-FU. Complete Erbitux administration 1 hour prior to radiation therapy or platinum-based therapy with 5-FU.
Erbitux monotherapy:

The recommended initial dose is 400 mg/m2 administered as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min).
The recommended subsequent weekly dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity.
2.2   Colorectal Cancer

Determine K-Ras mutation and EGFR-expression status using FDA-approved tests prior to initiating treatment. Only patients whose tumors are K-Ras mutation-negative (wild-type) should receive Erbitux.
The recommended initial dose, either as monotherapy or in combination with irinotecan or FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), is 400 mg/m2 administered as a 120-minute intravenous infusion (maximum infusion rate 10 mg/min). Complete Erbitux administration 1 hour prior to FOLFIRI.
The recommended subsequent weekly dose, either as monotherapy or in combination with irinotecan or FOLFIRI, is 250 mg/m2 infused over 60 minutes (maximum infusion rate 10 mg/min) until disease progression or unacceptable toxicity. Complete Erbitux administration 1 hour prior to FOLFIRI.
2.3   Recommended Premedication

Premedicate with an H1 antagonist (eg, 50 mg of diphenhydramine) intravenously 30–60 minutes prior to the first dose; premedication should be administered for subsequent Erbitux doses based upon clinical judgment and presence/severity of prior infusion reactions.

2.4   Dose Modifications

Infusion Reactions

Reduce the infusion rate by 50% for NCI CTC Grade 1 or 2 and non-serious NCI CTC Grade 3 infusion reaction.

Immediately and permanently discontinue Erbitux for serious infusion reactions, requiring medical intervention and/or hospitalization.

2.5   Preparation for Administration

Do not administer Erbitux as an intravenous push or bolus.

Administer via infusion pump or syringe pump. Do not exceed an infusion rate of 10 mg/min.

Administer through a low protein binding 0.22-micrometer in-line filter.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The solution should be clear and colorless and may contain a small amount of easily visible, white, amorphous, cetuximab particulates. Do not shake or dilute.

3    DOSAGE FORMS AND STRENGTHS

100 mg/50 mL, single-use vial

200 mg/100 mL, single-use vial

4    CONTRAINDICATIONS

None.

5    WARNINGS AND PRECAUTIONS

5.1   Infusion Reactions

Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1,14.2).]

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4).]

5.2   Cardiopulmonary Arrest

Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions (5.6).]

5.3   Pulmonary Toxicity

Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD.

5.4   Dermatologic Toxicity

Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients.

Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4).]

5.5   Use of Erbitux in Combination With Radiation and Cisplatin

In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Erbitux in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone. The addition of Erbitux resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone. Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Erbitux combination arm and 14 patients (3.0%) in the control arm. Nine patients in the Erbitux arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm. The main efficacy outcome of the study was progression-free survival (PFS). The addition of Erbitux to radiation and cisplatin did not improve PFS.

5.6   Hypomagnesemia and Electrolyte Abnormalities

In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%.

In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

5.7   K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients

Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2), Clinical Pharmacology (12.1), Clinical Studies (14.2).]

Perform the assesment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results.

Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux.

5.8   Epidermal Growth Factor Receptor (EGFR) Expression and Response

Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDxTM test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

6    ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

Infusion reactions [See Boxed Warning, Warnings and Precautions (5.1).]
Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions (5.2).]
Pulmonary toxicity [See Warnings and Precautions (5.3).]
Dermatologic toxicity [See Warnings and Precautions (5.4).]
Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions (5.6).]
The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

6.1   Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14).]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck

Erbitux in Combination with Radiation Therapy

Table 2 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

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