Drug Safety-related Labeling Changes (SrLC)

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ERBITUX (BLA-125084)

(CETUXIMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/23/2019 (SUPPL-273)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Addition of the following prior to Table 4

Serious adverse reactions included pulmonary embolism, which was reported in 4.4% of patients treated with cetuximab with FOLFIRI as compared to 3.4% of patients treated with FOLFIRI alone.

06/05/2018 (SUPPL-269)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: INFUSION REACTIONS and CARDIOPULMONARY ARREST

Infusion Reactions: ERBITUX can cause serious and fatal infusion reactions. Immediately interrupt and permanently discontinue ERBITUX for serious infusion reactions.

Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving ERBITUX with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration.

5 Warnings and Precautions

Additions and/or revisions underlined in the following subsections:

5.1 Infusion Reactions

ERBITUX can cause serious and fatal infusion reactions. Infusion reactions of any grade occurred in 8.4% of 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients.  Signs and symptoms included rapid onset …

The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies directed against galactose-?-1,3-galactose (alpha-gal).

… with the first infusion despite premedication with antihistamines. Infusion reactions may occur during or several hours following completion of the infusion.

Premedicate with a histamine-1(H1) receptor antagonist as recommended. Monitor patients for at least 1 hour following each ERBITUX infusion, in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. In patients requiring treatment for infusion reactions, monitor for more than 1 hour to confirm resolution of the reaction. Interrupt the infusion and upon recovery, resume the infusion at a slower rate or permanently discontinue ERBITUX based on severity.

5.2 Cardiopulmonary Arrest

ERBITUX can cause cardiopulmonary arrest. Cardiopulmonary arrest or sudden death …

BONNER replaces Study 1

EXTREME replaces Study 2

… of 219 patients treated with a cetuximab product in combination with platinum-based therapy and fluorouracil.

… or platinum-based therapy with fluorouracil in patients with SCCHN with a history of coronary …

5.3 Pulmonary Toxicity

ERBITUX can cause interstitial lung disease … ERBITUX in clinical trials.

Monitor patients for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue ERBITUX for acute onset …

5.4 Dermatologic Toxicity

Acneiform rash occurred in 82% of the 1373 patients who received ERBITUX across clinical trials. Severe (Grades 3 or 4) acneiform rash occurred in 9.7% of patients. Acneiform rash usually developed within the first two weeks of therapy; the rash lasted more than 28 days after stopping ERBITUX in most patients.

… Instruct patients to limit sun exposure during ERBITUX therapy. Withhold, reduce dose or permanently discontinue ERBITUX based on severity of acneiform rash or mucocutaneous disease.

5.5 Risks Associated with Use in Combination with Radiation and Cisplatin

… Adverse reactions with fatal outcome were reported in 4% of patients in the ERBITUX combination arm … The addition of ERBITUX to radiation and cisplatin did not improve PFS. ERBITUX is not indicated for the treatment of SCCHN in combination with radiation and cisplatin.

5.6 Hypomagnesemia and Accompanying Electrolyte Abnormalities

ERBITUX can cause hypomagnesemia … receiving ERBITUX in Study CA225-025 and two other clinical trials in patients with colorectal cancer (CRC) or head and neck cancer, including Grades 3 and 4 in 6% to 17%.

In EXTREME, where a cetuximab product was administered in combination … resulted in an increased incidence of hypomagnesemia of any grade (14%) and of Grade 3 or 4 hypomagnesemia (7%). Hypomagnesemia of any grade occurred in 4% of patients who received cetuximab, carboplatin, and fluorouracil.

Hypomagnesemia and accompanying electrolyte abnormalities can occur days to months after initiating ERBITUX. Monitor patients weekly during treatment for hypomagnesemia.

5.7 Increased Tumor Progression, Increased Mortality, or Lack of Benefit in Patients with Ras-Mutant mCRC

… hereafter is referred to as “Ras” or when the Ras status is unknown.

CRYSTAL replaces Study 4

… resulted in no clinical benefit with treatment related toxicity. Confirm Ras mutation status in tumor specimens prior to initiating ERBITUX.

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information.

6.2 Immunogenicity

Additions and/or revisions underlined:

… For these reasons, comparison of the incidence of antibodies to cetuximab in the studies below with the incidence of antibodies to cetuximab in other studies or to other products may be misleading.

An ELISA methodology was used to characterize the incidence of anti-cetuximab antibodies. The incidence of anti- cetuximab binding antibodies in 105 patients (from studies I4E-MC-JXBA, I4E-MC-JXBB, and I4E-MC-JXBD) with at least one post-baseline blood sample (greater than or equal to4 weeks post first ERBITUX administration) was less than 5%.

6.3 Postmarketing Experience

Additions and/or revisions underlined:

Because these reactions are reported voluntarily from a population of uncertain size … to drug exposure.

  • Neurologic: Aseptic meningitis

  • Gastrointestinal: Mucosal inflammation

  • Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis …

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Addition of the following:

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating ERBITUX.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 1662 patients with advanced colorectal cancer who received ERBITUX with irinotecan, with FOLFIRI or as monotherapy in six studies (BOND, IMCL-CP02-9923, IMCL-CP02-0141, IMCL-CP02-0144, CA225-025 and CRYSTAL), 35% of patients were 65 years of age or older …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Extensively changed; please refer to label for complete information.

05/03/2018 (SUPPL-268)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Embryo-Fetal Toxicity

(Newly added subsection)

Based on animal data and its mechanism of action, ERBITUX can cause fetal harm when administered to a pregnant woman. There are no available data for ERBITUX exposure in pregnant women. In an animal reproduction study, intravenous administration of cetuximab once weekly to pregnant cynomolgus monkeys during the period of organogenesis resulted in an increased incidence of embryolethality and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ERBITUX and for 2 months after the last dose of ERBITUX.

6 Adverse Reactions

6.2 Immunogenicity

(Additions and/or revisions are underlined)

As with all therapeutic proteins, there is potential for immunogenicity. An ELISA methodology was used to characterize the incidence of anti-cetuximab antibodies. In total, 105 ERBITUX-treated patients with at least one post-baseline blood sample (?4 weeks post first administration) were assessed for the development of anti-cetuximab binding antibodies and the incidence of treatment-emergent anti-cetuximab binding antibodies and the incidence of treatment-emergent anti- cetuximab binding antibodies was <5%.

…                            

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], ERBITUX can cause fetal harm when administered to a pregnant woman. There are no available data for ERBITUX exposure in pregnant women. In an animal reproduction study, intravenous administration of cetuximab once weekly to pregnant cynomolgus monkeys during the period of organogenesis resulted in an increased incidence of embryolethality and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. Human IgG is known to cross the placental barrier; therefore, cetuximab may be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.


Data

Animal Data

Pregnant cynomolgus monkeys were administered cetuximab intravenously once weekly during the period of organogenesis (gestation day [GD] 20-48) at dose levels 0.4 to 4 times the recommended human dose of cetuximab based on body surface area (BSA). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams on GD 49. While no fetal malformations occurred in offspring, there was an increased incidence of embryolethality and abortions at doses approximately 1 to 4 times the recommended human dose of cetuximab, based on BSA.

In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Thhere is no information regarding the presence of ERBITUX in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG antibodies can be excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants from ERBITUX, advise women not to breast-feed during treatment with ERBITUX and for 2 months following the last dose of ERBITUX.

 

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

Contraception

Based on its mechanism of action, ERBITUX can cause harm to the fetus when administered to a pregnant woman [see Use in Specific Populations (8.1)].


Females

Advise females of reproductive potential to use effective contraception during treatment with ERBITUX and for 2 months following the last dose of ERBITUX.


Infertility

Females

Based on animal studies, ERBITUX may impair fertility in females of reproductive potential.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

 (Additions and/or revisions are underlined)

 Advise patients:

  • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

  • Of the potential risks of using ERBITUX during pregnancy or breastfeeding and to use adequate contraception in females of reproductive potential during treatment with ERBITUX and for 2 months following the last dose of ERBITUX.

  • ThatTo discontinue breastfeeding during treatment with ERBITUX and for 2 months following the last dose of ERBITUX.

  • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of ERBITUX.

     

10/11/2016 (SUPPL-265)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity (addition underlined)

As with all therapeutic proteins, there is potential for immunogenicity. An ELISA methodology was used to characterize the incidence of anti-cetuximab antibodies. In total, 105 Erbitux-treated patients with at least one post-baseline blood sample (?4 weeks post first administration) were assessed for the development of anti-cetuximab binding antibodies and the incidence of treatment-emergent anti-cetuximab binding antibodies was <5%.

 

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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