WARNINGS & PRECAUTIONS
RYBREVANT® + LAZCLUZE™1,2
Infusion-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. The median time to IRR onset is approximately 1 hour.
RYBREVANT® in combination with LAZCLUZE™ can cause infusion-related reactions. In MARIPOSA, IRRs occurred in 63% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 5% and Grade 4 in 1% of patients. The incidence of infusion modifications due to IRR was 54%, and IRRs leading to dose reduction of RYBREVANT® occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT® occurred in 4.5% of patients receiving RYBREVANT® in combination with LAZCLUZE™.
Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT® as recommended. Administer RYBREVANT® via a peripheral line on Week 1 and Week 2 to reduce the risk of IRRs.
Monitor patients for signs and symptoms of infusion reactions during RYBREVANT® infusion in a 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.
Interstitial Lung Disease/Pneumonitis
RYBREVANT® in combination with LAZCLUZE™ can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.
In MARIPOSA, ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was 1 fatal case of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT® and LAZCLUZE™ due to ILD/pneumonitis.
Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold RYBREVANT® and LAZCLUZE™ in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.
Venous Thromboembolic (VTE) Events With Concomitant Use of RYBREVANT® and LAZCLUZE™
RYBREVANT® in combination with LAZCLUZE™ can cause serious and fatal venous thromboembolic (VTEs) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first 4 months of therapy.
In MARIPOSA, VTEs occurred in 36% of patients receiving RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were 2 fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT®, 1% of patients had VTE leading to dose reductions of RYBREVANT®, and 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT®. 7% of patients had VTE leading to dose interruptions of LAZCLUZE™, 0.5% of patients had VTE leading to dose reductions of LAZCLUZE™, and 1.9% of patients permanently discontinued LAZCLUZE™ due to VTE. The median time to onset of VTEs was 84 days (range, 6 to 777). Administer prophylactic anticoagulation for the first 4 months of treatment. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.
Withhold RYBREVANT® and LAZCLUZE™ based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT® and LAZCLUZE™ at the same dose level at the discretion of the healthcare provider. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT®. Treatment can continue with LAZCLUZE™ at the same dose level at the discretion of the healthcare provider.
Dermatologic Adverse Reactions
RYBREVANT® in combination with LAZCLUZE™ can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus and dry skin.
In MARIPOSA, rash occurred in 86% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range, 1 to 556 days). Rash leading to dose interruptions of RYBREVANT® occurred in 37% of patients, rash leading to dose reductions of RYBREVANT® occurred in 23% of patients, and rash leading to permanent discontinuation of RYBREVANT® occurred in 5% of patients. Rash leading to dose reduction of LAZCLUZE™ occurred in 19% of patients, rash leading to dose interruption of LAZCLUZE™ occurred in 30% of patients, and LAZCLUZE™ was permanently discontinued due to rash in 1.7% of patients.
Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT® in combination with LAZCLUZE™. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (eg, isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.
When initiating treatment with RYBREVANT® in combination with LAZCLUZE™, administer alcohol-free (eg, isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (eg, use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT® and LAZCLUZE™ based on severity.
Ocular Toxicity
RYBREVANT® can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus and uveitis. LAZCLUZE™, in combination with RYBREVANT®, can cause ocular toxicity, including keratitis.
In MARIPOSA, ocular toxicity occurred in 16% of patients treated with RYBREVANT® in combination with LAZCLUZE™, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT® and continue LAZCLUZE™ based on severity.
Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT® and continue LAZCLUZE™ based on severity.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal models, RYBREVANT® and LAZCLUZE™ can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Advise patients of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT®.
Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE™ and for 3 weeks after the last dose.
RYBREVANT® + Chemotherapy1*
Infusion-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. The median time to IRR onset is approximately 1 hour.
Based on the pooled safety population (N=281), IRR occurred in 50% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed, including Grade 3 (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT® due to IRR.
Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT® as recommended. Administer RYBREVANT® via a peripheral line on Week 1 and Week 2 to reduce the risk of IRRs.
Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT® infusion in a 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.
Interstitial Lung Disease/Pneumonitis
RYBREVANT® can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.
Based on the pooled safety population (N=281), ILD/pneumonitis occurred in 2.1% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed with 1.8% of patients experiencing Grade 3 ILD/pneumonitis. 2.1% discontinued RYBREVANT® due to ILD/pneumonitis.
Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold RYBREVANT® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.
Dermatologic Adverse Reactions
RYBREVANT® can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.
Based on the pooled safety population (N=281), rash occurred in 82% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT® and 3.1% discontinued pemetrexed.
Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT®. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (eg, isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.
When initiating treatment with RYBREVANT®, administer alcohol-free (eg, isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (eg, use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT® based on severity.
Ocular Toxicity
RYBREVANT® can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.
Based on the pooled safety population (N=281), ocular toxicity occurred in 16% of patients treated with RYBREVANT® in combination with carboplatin and pemetrexed. All events were Grade 1 or 2.
Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT® based on severity.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal models, RYBREVANT® can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, 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 3 months after the last dose of RYBREVANT®.
*The pooled safety population described in Warnings and Precautions reflects exposure to RYBREVANT® in combination with carboplatin and pemetrexed in 281 patients in both the MARIPOSA-2 (n=130) and the PAPILLON (n=151) studies.
RYBREVANT® Monotherapy1
Infusion-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. The median time to IRR onset is approximately 1 hour.
In CHRYSALIS, IRR occurred in 66% of patients treated with RYBREVANT® as a single agent. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1 to 2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 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. Administer RYBREVANT® via a peripheral line on Week 1 and Week 2 to reduce the risk of IRR.
Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT® infusion in a 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.
Interstitial Lung Disease/Pneumonitis
RYBREVANT® can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.
In CHRYSALIS, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT® as a single agent, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) permanently discontinued RYBREVANT® due to ILD/pneumonitis.
Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Immediately withhold RYBREVANT® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.
Dermatologic Adverse Reactions
RYBREVANT® can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritis, and dry skin.
In CHRYSALIS, rash occurred in 74% of patients treated with RYBREVANT® as a single agent, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 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.
Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT® as a single agent.
Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT®. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (eg, isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.
When initiating treatment with RYBREVANT®, administer alcohol-free (eg, isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (eg, use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT® based on severity.
Ocular Toxicity
RYBREVANT® can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.
In CHRYSALIS, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT®. All events were Grade 1 to 2.
Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT® based on severity.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal models, RYBREVANT® can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, 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 3 months after the last dose of RYBREVANT®.