PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 7 mL Vial Carton. NDC 57894-501-01Rybrevant(R) (amivantamab-vmjw)Injection350 mg/7 mL(50 mg/mL)For Intravenous Infusion OnlyDilute Before UseRx only7 mL VialjanssenSingle-dose vial.Discard unused portion.. PRINCIPAL DISPLAY PANEL 7 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of RYBREVANT have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR exon 20 insertion mutations.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Infusion-Related ReactionsAdvise patients that RYBREVANT can cause infusion-related reactions, the majority of which may occur with the first infusion. Advise patients to alert their healthcare provider immediately for any signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.1)].. Interstitial Lung Disease/PneumonitisAdvise patients of the risks of interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Warnings and Precautions (5.2)].. Dermatologic Adverse ReactionsAdvise patients of the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure, to use broad spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with RYBREVANT [see Warnings and Precautions (5.3)]. Advise patients to apply alcohol free emollient cream to dry skin.. Ocular ToxicityAdvise patients of the risk of ocular toxicity. Advise patients to contact their ophthalmologist if they develop eye symptoms and advise discontinuation of contact lenses until symptoms are evaluated [see Warnings and Precautions (5.4)].. ParonychiaAdvise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Adverse Reactions (6.1)]. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus, to use effective contraception during treatment with RYBREVANT and for months after the final dose, and to inform their healthcare provider of known or suspected pregnancy. see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)]. LactationAdvise women not to breastfeed during treatment with RYBREVANT and for months after the final dose [see Use in Specific Populations (8.2)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:Infusion-Related Reactions [see Warnings and Precautions (5.1)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)] Ocular Toxicity [see Warnings and Precautions (5.4)] Infusion-Related Reactions [see Warnings and Precautions (5.1)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] Dermatologic Adverse Reactions [see Warnings and Precautions (5.3)] Ocular Toxicity [see Warnings and Precautions (5.4)] The most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. (6.1)The most common Grade or laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. (6.1). The most common Grade or laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT as single agent in the CHRYSALIS study in 302 patients with locally advanced or metastatic NSCLC who received dose of 1050 mg (for patients <80 kg) or 1400 mg (for patients >=80 kg) once weekly for weeks, then every weeks thereafter. Among 302 patients who received RYBREVANT, 36% were exposed for months or longer and 12% were exposed for greater than one year. In the safety population, the most common (>= 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased phosphate, decreased albumin, increased glucose, increased gamma glutamyl transferase, decreased sodium, decreased potassium, and increased alkaline phosphatase.The data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for months or longer and 12% were exposed for greater than one year.The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight <80 kg.Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in >= 2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in patients (1.5%) due to pneumonia and patient (0.8%) due to sudden death.Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in >=1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in >=5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.Dose reductions of RYBREVANT due to an adverse reaction occurred in 15% of patients. Adverse reactions requiring dose reductions in >= 2% of patients included rash and paronychia.The most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.Table summarizes the adverse reactions in CHRYSALIS.Table 7:Adverse Reactions (>= 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALISAdverse ReactionsRYBREVANT(N=129)All Grades (%)Grades or (%)Skin and subcutaneous tissue disorders RashRash: acne, dermatitis, dermatitis acneiform, eczema, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome, perineal rash, rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular, skin exfoliation, toxic epidermal necrolysis 843.9 Pruritus180 Dry skin140General disorders and administration site conditions Infusion related reaction643.1 FatigueFatigue: asthenia, fatigue 332.3 EdemaEdema: eyelid edema, face edema, generalized edema, lip edema, edema, edema peripheral, periorbital edema, peripheral swelling 270.8 Pyrexia130Infections and infestations Paronychia503.1 PneumoniaPneumonia: atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, and pulmonary sepsis 100.8Musculoskeletal and connective tissue disorders Musculoskeletal painMusculoskeletal pain: arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain 470Respiratory, thoracic and mediastinal disorders DyspneaDyspnea: dyspnea, dyspnea exertional 372.3 CoughCough: cough, productive cough, upper airway cough syndrome 250Gastrointestinal disorders Nausea360 StomatitisStomatitis: aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, stomatitis 260.8 Constipation230 Vomiting220 Diarrhea163.1 Abdominal PainAbdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort 110.8Vascular disorders HemorrhageHemorrhage: epistaxis, gingival bleeding, hematuria, hemoptysis, hemorrhage, mouth hemorrhage, mucosal hemorrhage 190Metabolism and nutrition disorders Decreased appetite150Nervous system disorders Peripheral neuropathyPeripheral neuropathy: hypoesthesia, neuralgia, paresthesia, peripheral sensory neuropathy 130 Dizziness120.8 HeadacheHeadache: headache, migraine 100.8Clinically relevant adverse reactions in <10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).Table summarizes the laboratory abnormalities in CHRYSALIS.Table 8: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT in CHRYSALISLaboratory AbnormalityRYBREVANTThe denominator used to calculate the rate was 126 based on the number of patients with baseline value and at least one post-treatment value. (N=129)All Grades (%)Grades or (%)Chemistry Decreased albumin798 Increased glucose564 Increased alkaline phosphatase534.8 Increased creatinine460 Increased alanine aminotransferase381.6 Decreased phosphate338 Increased aspartate aminotransferase330 Decreased magnesium270 Increased gamma-glutamyl transferase274 Decreased sodium274 Decreased potassium266Hematology Decreased lymphocytes368. 6.2 Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other amivantamab products may be misleading.In CHRYSALIS, of the 286 (1%) patients who were treated with RYBREVANT and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab-vmjw antibodies (one at 27 days, one at 59 days and one at 168 days after the first dose) with titers of 1:40 or less. There are insufficient data to evaluate the effect of ADA on the pharmacokinetics, safety, or efficacy of RYBREVANT.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Amivantamab-vmjw is bispecific antibody that binds to the extracellular domains of EGFR and MET.In in vitro and in vivo studies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.. 12.2 Pharmacodynamics. The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR exon 20 insertion mutations.. 12.3 Pharmacokinetics. Amivantamab-vmjw exposures increased proportionally over dosage range from 350 to 1750 mg (0.25 to 1.25 times the maximum approved recommended dosage). Steady state of amivantamab-vmjw concentrations was achieved by the 9th infusion. The accumulation ratio at steady state was 2.4.. DistributionThe amivantamab-vmjw mean (+- SD) volume of distribution is 5.13 (+- 1.78) L.. EliminationThe mean (+- SD) clearance of amivantamab-vmjw is 360 (+- 144) mL/day and the terminal half-life is 11.3 (+- 4.53) days.. Specific PopulationsNo clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 32-87 years), sex, race, creatinine clearance (CLcr 29 to 276 mL/min), or mild hepatic impairment [(total bilirubin <= ULN and AST ULN) or (ULN total bilirubin <= 1.5 times ULN)]. The pharmacokinetics of amivantamab-vmjw have not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or patients with moderate (total bilirubin 1.5 to times ULN) to severe (total bilirubin 3 times ULN) hepatic impairment.. Body WeightIncreases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30-40% lower in patients who weighed >= 80 kg compared to patients with body weight 80 kg at the same dose. Exposures of amivantamab-vmjw were comparable between patients who weighed 80 kg and received 1050 mg dose and patients who weighed >= 80 kg and received 1400 mg dose.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of amivantamab-vmjw in human milk on milk production, or its effects on the breastfed child. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed infants, advise women not to breast-feed during treatment with RYBREVANT and for months after the final dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Amivantamab-vmjw is bispecific antibody that binds to the extracellular domains of EGFR and MET.In in vitro and in vivo studies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of RYBREVANT was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in multicenter, open-label, multi-cohort clinical trial (CHRYSALIS, NCT02609776). The study included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients with untreated brain metastases and patients with history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last years were not eligible for the study.In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations, plasma samples from 96% of patients were tested retrospectively using Guardant360(R) CDx. While 76% of patients had an EGFR exon 20 insertion mutation identified in plasma specimen, 20% did not have an EGFR exon 20 insertion mutation identified in plasma specimen, and 3.7% did not have plasma samples for testing.Patients received RYBREVANT at 1050 mg (for patient baseline body weight 80 kg) or 1400 mg (for patient baseline body weight >=80 kg) once weekly for weeks, then every weeks thereafter until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.The efficacy population included 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who were previously treated with platinum-based chemotherapy. The median age was 62 (range: 42 to 84) years, 59% were female; 49% were Asian, 37% were White, 2.5% were Black; 74% had baseline body weight <80 kg; 95% had adenocarcinoma; and 46% had received prior immunotherapy. The median number of prior therapies was (range: to 7). At baseline, 67% had Eastern Cooperative Oncology Group (ECOG) performance status of 1; 53% never smoked; all patients had metastatic disease; and 22% had previously treated brain metastases.Efficacy results are summarized in Table 9.Table 9: Efficacy Results for CHRYSALISPrior Platinum-based Chemotherapy Treated(N=81)Based on Kaplan-Meier estimates.NE=Not Estimable, CI=confidence interval.Overall Response Rate (95% CI)40% (29%, 51%) Complete response (CR)3.7% Partial response (PR)36%Duration of Response (DOR) Median, months (95% CI), months11.1 (6.9, NE) Patients with DOR >=6 months63%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT as single agent in the CHRYSALIS study in 302 patients with locally advanced or metastatic NSCLC who received dose of 1050 mg (for patients <80 kg) or 1400 mg (for patients >=80 kg) once weekly for weeks, then every weeks thereafter. Among 302 patients who received RYBREVANT, 36% were exposed for months or longer and 12% were exposed for greater than one year. In the safety population, the most common (>= 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased phosphate, decreased albumin, increased glucose, increased gamma glutamyl transferase, decreased sodium, decreased potassium, and increased alkaline phosphatase.The data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for months or longer and 12% were exposed for greater than one year.The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight <80 kg.Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in >= 2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in patients (1.5%) due to pneumonia and patient (0.8%) due to sudden death.Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in >=1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in >=5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.Dose reductions of RYBREVANT due to an adverse reaction occurred in 15% of patients. Adverse reactions requiring dose reductions in >= 2% of patients included rash and paronychia.The most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.Table summarizes the adverse reactions in CHRYSALIS.Table 7:Adverse Reactions (>= 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALISAdverse ReactionsRYBREVANT(N=129)All Grades (%)Grades or (%)Skin and subcutaneous tissue disorders RashRash: acne, dermatitis, dermatitis acneiform, eczema, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome, perineal rash, rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular, skin exfoliation, toxic epidermal necrolysis 843.9 Pruritus180 Dry skin140General disorders and administration site conditions Infusion related reaction643.1 FatigueFatigue: asthenia, fatigue 332.3 EdemaEdema: eyelid edema, face edema, generalized edema, lip edema, edema, edema peripheral, periorbital edema, peripheral swelling 270.8 Pyrexia130Infections and infestations Paronychia503.1 PneumoniaPneumonia: atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, and pulmonary sepsis 100.8Musculoskeletal and connective tissue disorders Musculoskeletal painMusculoskeletal pain: arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain 470Respiratory, thoracic and mediastinal disorders DyspneaDyspnea: dyspnea, dyspnea exertional 372.3 CoughCough: cough, productive cough, upper airway cough syndrome 250Gastrointestinal disorders Nausea360 StomatitisStomatitis: aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, stomatitis 260.8 Constipation230 Vomiting220 Diarrhea163.1 Abdominal PainAbdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort 110.8Vascular disorders HemorrhageHemorrhage: epistaxis, gingival bleeding, hematuria, hemoptysis, hemorrhage, mouth hemorrhage, mucosal hemorrhage 190Metabolism and nutrition disorders Decreased appetite150Nervous system disorders Peripheral neuropathyPeripheral neuropathy: hypoesthesia, neuralgia, paresthesia, peripheral sensory neuropathy 130 Dizziness120.8 HeadacheHeadache: headache, migraine 100.8Clinically relevant adverse reactions in <10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).Table summarizes the laboratory abnormalities in CHRYSALIS.Table 8: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT in CHRYSALISLaboratory AbnormalityRYBREVANTThe denominator used to calculate the rate was 126 based on the number of patients with baseline value and at least one post-treatment value. (N=129)All Grades (%)Grades or (%)Chemistry Decreased albumin798 Increased glucose564 Increased alkaline phosphatase534.8 Increased creatinine460 Increased alanine aminotransferase381.6 Decreased phosphate338 Increased aspartate aminotransferase330 Decreased magnesium270 Increased gamma-glutamyl transferase274 Decreased sodium274 Decreased potassium266Hematology Decreased lymphocytes368.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Amivantamab-vmjw is low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has molecular weight of approximately 148 kDa. RYBREVANT (amivantamab-vmjw) injection for intravenous infusion is sterile, preservative-free, colorless to pale yellow solution in single-dose vials. The pH is 5.7.Each RYBREVANT vial contains 350 mg (50 mg/mL) amivantamab-vmjw, EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. (2.2, 2.5, 2.6) Administer premedications as recommended. (2.3) Administer via peripheral line on Week and Week 2. (2.6) Administer RYBREVANT weekly for weeks, with the initial dose as split infusion in Week on Day and Day 2, then administer every weeks starting at Week 5. (2.2) Administer diluted RYBREVANT intravenously according to the infusion rates in Table 6. (2.5, 2.6)Body Weight (at Baseline)Recommended DoseLess than 80 kg1050 mg (3 vials)Greater than or equal to 80 kg1400 mg (4 vials). The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. (2.2, 2.5, 2.6). Administer premedications as recommended. (2.3). Administer via peripheral line on Week and Week 2. (2.6). Administer RYBREVANT weekly for weeks, with the initial dose as split infusion in Week on Day and Day 2, then administer every weeks starting at Week 5. (2.2). Administer diluted RYBREVANT intravenously according to the infusion rates in Table 6. (2.5, 2.6). 2.1Patient Selection. Select patients for treatment with RYBREVANT based on the presence of EGFR exon 20 insertion mutations [see Clinical Studies (14)]. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2Recommended Dosage. The recommended doses of RYBREVANT, based on baseline body weight, are provided in Table 1, and the dosing schedule is provided in Table 2.Table 1: Recommended Dose of RYBREVANT Based on Baseline Body WeightBody Weight at BaselineDose adjustments not required for subsequent body weight changes. Recommended DoseNumber of 350 mg/7 mL RYBREVANT VialsLess than 80 kg1050 mg3Greater than or equal to 80 kg1400 mg4Table 2:Dosing schedule for RYBREVANTWeeksScheduleWeeks to 4Weekly (total of doses) Week - split infusion on Day and Day Weeks to - infusion on Day 1Week onwardsEvery weeks starting at Week 5Administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.3)]. Administer diluted RYBREVANT intravenously according to the infusion rates in Table 6, with the initial dose as split infusion on Week on Day and Day [see Dosage and Administration (2.5), (2.6)]. Administer RYBREVANT until disease progression or unacceptable toxicity.. 2.3Recommended Premedications. Prior to initial infusion of RYBREVANT (Week 1, Days and 2), administer premedication as described in Table to reduce the risk of infusion-related reactions: [see Warnings and Precautions (5.1)] Table 3: PremedicationsMedicationDoseRoute of AdministrationDosing Window Prior to RYBREVANT AdministrationAntihistamineRequired at all doses. Diphenhydramine (25 to 50 mg) or equivalentIntravenous15 to 30 minutesOral30 to 60 minutesAntipyretic Acetaminophen (650 to 1,000 mg)Intravenous15 to 30 minutesOral30 to 60 minutesGlucocorticoidRequired at initial dose (Week 1, Days and 2); optional for subsequent doses. Dexamethasone (10 mg) or Methylprednisolone (40 mg) or equivalentIntravenous45 to 60 minutesAdminister both antihistamine and antipyretic prior to all infusions. Glucocorticoid administration required for Week 1, Days and doses only and as necessary for subsequent infusions.. 2.4Dosage Modifications for Adverse Reactions. The recommended RYBREVANT dose reductions for adverse reactions (see Table 5) are listed in Table 4.Table 4: RYBREVANT Dose Reductions for Adverse ReactionsBody Weight at BaselineInitial Dose1st Dose Reduction2nd Dose Reduction3rd Dose ReductionLess than 80 kg1050 mg700 mg350 mgDiscontinue RYBREVANTGreater than or equal to 80 kg1400 mg1050 mg700 mgThe recommended RYBREVANT dosage modifications for adverse reactions are provided in Table 5.Table 5: Recommended RYBREVANT Dosage Modifications for Adverse ReactionsAdverse ReactionSeverityDosage ModificationsInfusion-related reactions (IRR) [see Warnings and Precautions (5.1)] Grade to 2Interrupt RYBREVANT infusion if IRR is suspected and monitor patient until reaction symptoms resolve.Resume the infusion at 50% of the infusion rate at which the reaction occurred.If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Table 6).Include corticosteroid with premedications for subsequent dose (see Table 3).Grade 3Interrupt RYBREVANT infusion and administer supportive care medications. Monitor patient until reaction symptoms resolve. Resume the infusion at 50% of the infusion rate at which the reaction occurred.If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Table 6). Include corticosteroid with premedications for subsequent dose (see Table 3). For recurrent Grade 3, permanently discontinue RYBREVANT.Grade 4Permanently discontinue RYBREVANT.Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2)]. Any GradeWithhold RYBREVANT if ILD/pneumonitis is suspected.Permanently discontinue RYBREVANT if ILD/pneumonitis is confirmed.Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see Warnings and Precautions (5.3)] Grade 2Initiate supportive care management.Reassess after weeks; if rash does not improve, consider dose reduction.Grade 3Withhold RYBREVANT and initiate supportive care management.Upon recovery to <= Grade 2, resume RYBREVANT at reduced dose.If no improvement within weeks, permanently discontinue treatment.Grade 4Permanently discontinue RYBREVANTSevere bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN)Permanently discontinue RYBREVANT.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3Withhold RYBREVANT until recovery to <= Grade or baseline.Resume at the same dose if recovery occurs within week.Resume at reduced dose if recovery occurs after week but within weeks.Permanently discontinue if recovery does not occur within weeks.Grade 4Withhold RYBREVANT until recovery to <=Grade or baseline.Resume at reduced dose if recovery occurs within weeks.Permanently discontinue if recovery does not occur within weeks.Permanently discontinue for recurrent Grade reactions.. Interrupt RYBREVANT infusion if IRR is suspected and monitor patient until reaction symptoms resolve.. Resume the infusion at 50% of the infusion rate at which the reaction occurred.. If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Table 6).. Include corticosteroid with premedications for subsequent dose (see Table 3).. Interrupt RYBREVANT infusion and administer supportive care medications. Monitor patient until reaction symptoms resolve.. Resume the infusion at 50% of the infusion rate at which the reaction occurred.. If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Table 6).. Include corticosteroid with premedications for subsequent dose (see Table 3). For recurrent Grade 3, permanently discontinue RYBREVANT.. Permanently discontinue RYBREVANT.. Withhold RYBREVANT if ILD/pneumonitis is suspected.. Permanently discontinue RYBREVANT if ILD/pneumonitis is confirmed.. Initiate supportive care management.. Reassess after weeks; if rash does not improve, consider dose reduction.. Withhold RYBREVANT and initiate supportive care management.. Upon recovery to <= Grade 2, resume RYBREVANT at reduced dose.. If no improvement within weeks, permanently discontinue treatment.. Permanently discontinue RYBREVANT. Permanently discontinue RYBREVANT.. Withhold RYBREVANT until recovery to <= Grade or baseline.. Resume at the same dose if recovery occurs within week.. Resume at reduced dose if recovery occurs after week but within weeks.. Permanently discontinue if recovery does not occur within weeks.. Withhold RYBREVANT until recovery to <=Grade or baseline.. Resume at reduced dose if recovery occurs within weeks.. Permanently discontinue if recovery does not occur within weeks.. Permanently discontinue for recurrent Grade reactions.. 2.5Preparation. Dilute and prepare RYBREVANT for intravenous infusion before administration.Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.Determine the dose required (either 1050 mg or 1400 mg) and number of RYBREVANT vials needed based on patients baseline weight [see Dosage and Administration (2.2)]. Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.Withdraw and then discard volume of either 5% dextrose solution or 0.9% sodium chloride solution from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).Withdraw mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.Gently invert the bag to mix the solution. Do not shake.Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 59F to 77F (15C to 25C).. Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.. Determine the dose required (either 1050 mg or 1400 mg) and number of RYBREVANT vials needed based on patients baseline weight [see Dosage and Administration (2.2)]. Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.. Withdraw and then discard volume of either 5% dextrose solution or 0.9% sodium chloride solution from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).. Withdraw mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.. Gently invert the bag to mix the solution. Do not shake.. Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 59F to 77F (15C to 25C).. 2.6Administration. Administer the diluted solution [see Dosage and Administration (2.5)] by intravenous infusion using an infusion set fitted with flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer) primed with diluent only. Administration sets must be made of either polyurethane (PU), polybutadiene (PBD) PVC, PP, or PE.Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.Administer RYBREVANT via peripheral line on Week and Week given the high incidence of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)]. RYBREVANT may be administered via central line for subsequent weeks. For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.Administer RYBREVANT infusion intravenously according to the infusion rates in Table 6.Table 6: Infusion Rates for RYBREVANT Administration1050 mg DoseWeekDose(per 250 mL bag)Initial Infusion RateSubsequent Infusion RateIncrease the initial infusion rate to the subsequent infusion rate after hours in the absence of infusion-related reactions.Week (split dose infusion) Week Day 350 mg50 mL/hr75 mL/hr Week Day 700 mg50 mL/hr75 mL/hrWeek 21050 mg85 mL/hrWeek 31050 mg125 mL/hrWeek 41050 mg125 mL/hrSubsequent weeksStarting at Week 5, patients are dosed every weeks. 1050 mg125 mL/hr1400 mg DoseWeekDose(per 250 mL bag)Initial Infusion RateSubsequent Infusion RateWeek (split dose infusion) Week Day 350 mg50 mL/hr75 mL/hr Week Day 1050 mg35 mL/hr50 mL/hrWeek 21400 mg65 mL/hrWeek 31400 mg85 mL/hrWeek 41400 mg125 mL/hrSubsequent weeks1400 mg125 mL/hr.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in single-dose vial.. Injection: 350 mg/7 mL (50 mg/mL) solution in single-dose vial (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. RYBREVANT can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment and for months after the final dose of RYBREVANT.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 129 patients treated with RYBREVANT, 41% were 65 years of age or older, and 9% were 75 years of age or older. No clinically important differences in safety or efficacy were observed between patients who were >=65 years of age and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedRYBREVANT(TM) (amivantamab-vmjw) injection is sterile, preservative-free, colorless to pale yellow solution for intravenous infusion. Each single-dose vial contains 350 mg/7 mL (50 mg/mL) RYBREVANT. Each vial is individually packed in single carton. (NDC 57894-501-01).. Storage and HandlingStore in refrigerator at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other amivantamab products may be misleading.In CHRYSALIS, of the 286 (1%) patients who were treated with RYBREVANT and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab-vmjw antibodies (one at 27 days, one at 59 days and one at 168 days after the first dose) with titers of 1:40 or less. There are insufficient data to evaluate the effect of ADA on the pharmacokinetics, safety, or efficacy of RYBREVANT.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. RYBREVANT is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1)], whose disease has progressed on or after platinum-based chemotherapy.This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.. RYBREVANT is bispecific EGF receptor-directed and MET receptor-directed antibody indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. (1, 2.1)This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Amivantamab-vmjw exposures increased proportionally over dosage range from 350 to 1750 mg (0.25 to 1.25 times the maximum approved recommended dosage). Steady state of amivantamab-vmjw concentrations was achieved by the 9th infusion. The accumulation ratio at steady state was 2.4.. DistributionThe amivantamab-vmjw mean (+- SD) volume of distribution is 5.13 (+- 1.78) L.. EliminationThe mean (+- SD) clearance of amivantamab-vmjw is 360 (+- 144) mL/day and the terminal half-life is 11.3 (+- 4.53) days.. Specific PopulationsNo clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 32-87 years), sex, race, creatinine clearance (CLcr 29 to 276 mL/min), or mild hepatic impairment [(total bilirubin <= ULN and AST ULN) or (ULN total bilirubin <= 1.5 times ULN)]. The pharmacokinetics of amivantamab-vmjw have not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or patients with moderate (total bilirubin 1.5 to times ULN) to severe (total bilirubin 3 times ULN) hepatic impairment.. Body WeightIncreases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30-40% lower in patients who weighed >= 80 kg compared to patients with body weight 80 kg at the same dose. Exposures of amivantamab-vmjw were comparable between patients who weighed 80 kg and received 1050 mg dose and patients who weighed >= 80 kg and received 1400 mg dose.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryolethality, malformations, and post-natal death in animals (see Data ). Advise pregnant women of the potential risk to 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 DataNo animal studies have been conducted to evaluate the effects of amivantamab-vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. 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. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab-vmjw has the potential to be transmitted from the mother to the developing fetus.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)12/2021.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONRYBREVANT (RYE-breh-vant)(amivantamab-vmjw)Injection, for intravenous useThis Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 05/2021What is RYBREVANTRYBREVANT is prescription medicine used to treat adults with non-small cell lung cancer (NSCLC) that:has spread to other parts of the body (metastatic) or cannot be removed by surgery, and has certain abnormal epidermal growth factor receptor EGFR gene(s) and whose disease has worsened while on or after chemotherapy that contains platinum.Your healthcare provider will perform test to make sure that RYBREVANT is right for you.It is not known if RYBREVANT is safe and effective in children.Before you receive RYBREVANT, tell your healthcare provider about all of your medical conditions, including if you:have history of lung or breathing problemsare pregnant or plan to become pregnant. RYBREVANT can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with RYBREVANT.You should use effective birth control (contraception) during treatment and for months after your final dose of RYBREVANT.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RYBREVANT. are breastfeeding or plan to breastfeed. It is not known if RYBREVANT passes into your breast milk. Do not breastfeed during treatment and for months after your final dose of RYBREVANT.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive RYBREVANTRYBREVANT will be given to you by your healthcare provider by intravenous infusion into your vein.Your healthcare provider will decide the time between doses as well as how many treatments you will receive.Your healthcare provider will give you medicines before each dose of RYBREVANT to help reduce the risk of infusion-related reactions.If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What should avoid while receiving RYBREVANT RYBREVANT can cause skin reactions. You should limit your time in the sun during and for months after your treatment with RYBREVANT. Wear protective clothing and use sunscreen during treatment with RYBREVANT.What are the possible side effects of RYBREVANTRYBREVANT may cause serious side effects, including:infusion-related reactions. Infusion-related reactions are common with RYBREVANT and can be severe or serious. Tell your healthcare provider right away if you get any of the following symptoms during your infusion of RYBREVANT:shortness of breathfeverchillsnauseaflushingchest discomfortlightheadednessvomitinglung problems. RYBREVANT may cause lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you get any new or worsening lung symptoms, including shortness of breath, cough, or fever.skin problems. RYBREVANT may cause rash, itching, and dry skin. You may use alcohol-free moisturizing cream for dry skin. Tell your healthcare provider right away if you get any skin reactions. Your healthcare provider may treat you with medicine(s) or send you to see skin specialist (dermatologist) if you get skin reactions during treatment with RYBREVANT. See What should avoid while receiving RYBREVANTeye problems. RYBREVANT may cause eye problems. Tell your healthcare provider right away if you get symptoms of eye problems which may include: eye paindry eyeseye rednessblurred visionchanges in visionitchy eyesexcessive tearingsensitivity to lightYour healthcare provider may send you to see an eye specialist (ophthalmologist) if you get eye problems during treatment with RYBREVANT. You should not use contact lenses until your eye symptoms are checked by healthcare provider.The most common side effects of RYBREVANT include:rashinfusion-related reactionsinfected skin around the nailmuscle and joint painshortness of breathnauseafeeling very tiredswelling of hands, ankles, feet, face, or all of your bodysores in the mouth coughconstipationvomitingchanges in certain blood testsYour healthcare provider may temporarily stop, decrease your dose or completely stop your treatment with RYBREVANT if you have serious side effects. These are not all of the possible side effects of RYBREVANT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about safe and effective use of RYBREVANTMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about RYBREVANT that is written for health professionals.What are the ingredients of RYBREVANTActive ingredient: amivantamab-vmjwInactive ingredients: EDTA disodium salt dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injection.Product of IrelandManufactured by: Janssen Biotech, Inc., Horsham, PA 19044.U.S. License Number 1864(C) 2021 Janssen Pharmaceutical CompaniesFor more information, call Janssen Products, LP at 1-800-526-7736 (1-800-JANSSEN) or go to www.RYBREVANT.com.. has spread to other parts of the body (metastatic) or cannot be removed by surgery, and has certain abnormal epidermal growth factor receptor EGFR gene(s) and whose disease has worsened while on or after chemotherapy that contains platinum.. have history of lung or breathing problems. are pregnant or plan to become pregnant. RYBREVANT can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with RYBREVANT.You should use effective birth control (contraception) during treatment and for months after your final dose of RYBREVANT.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RYBREVANT. Your healthcare provider should do pregnancy test before you start treatment with RYBREVANT.. You should use effective birth control (contraception) during treatment and for months after your final dose of RYBREVANT.. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RYBREVANT.. are breastfeeding or plan to breastfeed. It is not known if RYBREVANT passes into your breast milk. Do not breastfeed during treatment and for months after your final dose of RYBREVANT.. RYBREVANT will be given to you by your healthcare provider by intravenous infusion into your vein.. Your healthcare provider will decide the time between doses as well as how many treatments you will receive.. Your healthcare provider will give you medicines before each dose of RYBREVANT to help reduce the risk of infusion-related reactions.. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.. infusion-related reactions. Infusion-related reactions are common with RYBREVANT and can be severe or serious. Tell your healthcare provider right away if you get any of the following symptoms during your infusion of RYBREVANT:. shortness of breath. fever. chills. nausea. flushing. chest discomfort. lightheadedness. vomiting. lung problems. RYBREVANT may cause lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you get any new or worsening lung symptoms, including shortness of breath, cough, or fever.. skin problems. RYBREVANT may cause rash, itching, and dry skin. You may use alcohol-free moisturizing cream for dry skin. Tell your healthcare provider right away if you get any skin reactions. Your healthcare provider may treat you with medicine(s) or send you to see skin specialist (dermatologist) if you get skin reactions during treatment with RYBREVANT. See What should avoid while receiving RYBREVANT. eye problems. RYBREVANT may cause eye problems. Tell your healthcare provider right away if you get symptoms of eye problems which may include: eye pain. dry eyes. eye redness. blurred vision. changes in vision. itchy eyes. excessive tearing. sensitivity to light. rash. infusion-related reactions. infected skin around the nail. muscle and joint pain. shortness of breath. nausea. feeling very tired. swelling of hands, ankles, feet, face, or all of your body. sores in the mouth cough. constipation. vomiting. changes in certain blood tests.

SPL UNCLASSIFIED SECTION.

2.1Patient Selection. Select patients for treatment with RYBREVANT based on the presence of EGFR exon 20 insertion mutations [see Clinical Studies (14)]. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.

STORAGE AND HANDLING SECTION.

Storage and HandlingStore in refrigerator at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryolethality, malformations, and post-natal death in animals (see Data ). Advise pregnant women of the potential risk to 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 DataNo animal studies have been conducted to evaluate the effects of amivantamab-vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. 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. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab-vmjw has the potential to be transmitted from the mother to the developing fetus.. 8.2 Lactation. Risk SummaryThere are no data on the presence of amivantamab-vmjw in human milk on milk production, or its effects on the breastfed child. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed infants, advise women not to breast-feed during treatment with RYBREVANT and for months after the final dose.. 8.3 Females and Males of Reproductive Potential. RYBREVANT can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment and for months after the final dose of RYBREVANT.. 8.4 Pediatric Use. The safety and efficacy of RYBREVANT have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 129 patients treated with RYBREVANT, 41% were 65 years of age or older, and 9% were 75 years of age or older. No clinically important differences in safety or efficacy were observed between patients who were >=65 years of age and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infusion-Related Reactions (IRR): Interrupt infusion at the first sign of IRRs. Reduce infusion rate or permanently discontinue RYBREVANT based on severity. (2.4, 5.1)Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. (2.4, 5.2)Dermatologic Adverse Reactions: May cause rash including acneiform dermatitis and toxic epidermal necrolysis. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity. (2.4, 5.3)Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity. (5.4)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.5, 8.1, 8.3). Infusion-Related Reactions (IRR): Interrupt infusion at the first sign of IRRs. Reduce infusion rate or permanently discontinue RYBREVANT based on severity. (2.4, 5.1). Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. (2.4, 5.2). Dermatologic Adverse Reactions: May cause rash including acneiform dermatitis and toxic epidermal necrolysis. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity. (2.4, 5.3). Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity. (5.4). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.5, 8.1, 8.3). 5.1Infusion-Related Reactions. RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.Based on the safety population [see Adverse Reactions (6.1)], IRR occurred in 66% of patients treated with RYBREVANT. Among patients receiving treatment on Week Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day infusion, 0.4% with the Week infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT due to IRR. Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended [see Dosage and Administration (2.3)]. Administer RYBREVANT via peripheral line on Week and Week [see Dosage and Administration (2.6)].Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)]. 5.2Interstitial Lung Disease/Pneumonitis. RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed [see Dosage and Administration (2.4)].. 5.3Dermatologic Adverse Reactions. RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population [see Adverse Reactions (6.1)], rash occurred in 74% of patients treated with RYBREVANT, including Grade rash in 3.3% of patients. The median time to onset of rash was 14 days (range: to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients [see Adverse Reactions (6.1)]. Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT.Instruct patients to limit sun exposure during and for months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within weeks to dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)].. 5.4Ocular Toxicity. RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population [see Adverse Reactions (6.1)], keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)].. 5.5Embryo-Fetal Toxicity. Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryolethality, and abortion. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for months after the final dose of RYBREVANT. [see Use in Specific Populations (8.1, 8.3)].