Rybrevant
(amivantamab-vmjw)Dosage & Administration
| Body Weight (at Baseline) | Dosage | Recommended Dose |
|---|---|---|
| RYBREVANT in Combination with Carboplatin and Pemetrexed | ||
| Less than 80 kg | Weeks 1–4 | 1,400 mg |
| Week 7 onwards | 1,750 mg | |
| Greater than or equal to 80 kg | Weeks 1–4 | 1,750 mg |
| Week 7 onwards | 2,100 mg | |
| RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent | ||
| Less than 80 kg | Weeks 1–5 Week 7 onwards | 1,050 mg |
| Greater than or equal to 80 kg | Weeks 1–5 Week 7 onwards | 1,400 mg |
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Rybrevant Prescribing Information
First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations
RYBREVANT, in combination with lazertinib, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] .
Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations
RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor [see Dosage and Administration (2.2)] .
First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations
RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] .
Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations
RYBREVANT is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] , whose disease has progressed on or after platinum-based chemotherapy.
Important Dosage Information
- Administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5)].
- Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Dosage and Administration (2.8)].
- Administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)].
- When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.8)].
- When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.8)].
- When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Dosage and Administration (2.4)].
Patient Selection
Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by an FDA-approved test.
| Indication | Treatment Regimen | Source for Testing |
|---|---|---|
| Information on FDA approved tests is available at: http://www.fda.gov/CompanionDiagnostics. | ||
| First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations [see Indications and Usage (1.1)] | RYBREVANT in combination with lazertinib |
|
| Previously treated locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (progressive disease on an EGFR tyrosine kinase inhibitor) [see Indications and Usage (1.2)] | RYBREVANT in combination with carboplatin and pemetrexed | |
| First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.3)] | RYBREVANT in combination with carboplatin and pemetrexed | |
| Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.4)] | RYBREVANT as a single agent | |
Recommended Dosage of RYBREVANT in Combination with Carboplatin and Pemetrexed for the Treatment of NSCLC – Every 3-week dosing
The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 2.
| Body weight at Baseline * | Recommended Dose | Dosing Schedule |
|---|---|---|
| ||
| Less than 80 kg | 1,400 mg | Weekly (total of 4 doses) from Weeks 1 to 4
|
1,750 mg | Every 3 weeks starting at Week 7 onwards | |
| Greater than or equal to 80 kg | 1,750 mg | Weekly (total of 4 doses) from Weeks 1 to 4
|
2,100 mg | Every 3 weeks starting at Week 7 onwards | |
The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 3.
| RYBREVANT in Combination with Carboplatin and Pemetrexed | ||
|---|---|---|
| Administer the regimen in the following order: pemetrexed first, carboplatin second, and RYBREVANT last. | ||
| Drug | Dose | Duration/Timing of Treatment |
| Pemetrexed | Pemetrexed 500 mg/m 2 intravenously Refer to the pemetrexed Full Prescribing Information for complete information. | Every 3 weeks, continue until disease progression or unacceptable toxicity. |
| Carboplatin | Carboplatin AUC 5 intravenously Refer to the carboplatin Full Prescribing Information for complete information. | Every 3 weeks for up to 12 weeks. |
| RYBREVANT | RYBREVANT intravenously See Table 2. | Every 3 weeks, continue until disease progression or unacceptable toxicity. |
Recommended Dosage of RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent - Every 2-week dosing
The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 4. Administer RYBREVANT until disease progression or unacceptable toxicity.
| Body weight at Baseline * | Recommended Dose | Dosing Schedule |
|---|---|---|
| ||
| Less than 80 kg | 1,050 mg | Weekly (total of 5 doses) from Weeks 1 to 5
|
| Every 2 weeks starting at Week 7 onwards | ||
| Greater than or equal to 80 kg | 1,400 mg | Weekly (total of 5 doses) from Weeks 1 to 5
|
| Every 2 weeks starting at Week 7 onwards | ||
RYBREVANT in Combination with Lazertinib
Order of Administration
When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day. Refer to the lazertinib prescribing information for recommended lazertinib dosing information. Administer RYBREVANT in combination with lazertinib until disease progression or unacceptable toxicity.
Concomitant Medications
When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Warnings and Precautions (5.3)]. If there are no signs or symptoms of VTE during the first four months of treatment, consider discontinuation of anticoagulant prophylaxis at the discretion of the healthcare provider. Refer to the lazertinib prescribing information for information about concomitant medications.
When initiating treatment with RYBREVANT in combination with lazertinib, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream and encourage patients to limit sun exposure during and for 2 months after treatment, to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions [see Warnings and Precautions (5.4)]. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Refer to the lazertinib prescribing information for information about concomitant medications.
Recommended Premedications
Prior to the initial infusion of RYBREVANT (Week 1, Day 1 and 2), administer premedications as described in Table 5 to reduce the risk of infusion-related reactions [see Warnings and Precautions (5.1)].
Glucocorticoid administration is required for Week 1, Day 1 and 2 dose only and upon re-initiation after prolonged dose interruptions, then as necessary for subsequent infusions (see Table 5) .Administer both antihistamine and antipyretic prior to all infusions.
| Medication | Dose | Route of Administration | Dosing Window Prior to RYBREVANT Administration |
|---|---|---|---|
| |||
| Antihistamine * | Diphenhydramine (25 to 50 mg) or equivalent | Intravenous | 15 to 30 minutes |
Oral | 30 to 60 minutes | ||
| Antipyretic * | Acetaminophen (650 to 1,000 mg) | Intravenous | 15 to 30 minutes |
Oral | 30 to 60 minutes | ||
| Glucocorticoid † | Dexamethasone (20 mg) or equivalent | Intravenous | 45 to 60 minutes |
| Glucocorticoid ‡ | Dexamethasone (10 mg) or equivalent | Intravenous | 45 to 60 minutes |
Dosage Modifications for Adverse Reactions
The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 6.
| Dose at which the adverse reaction occurred | 1 st Dose Reduction | 2 nd Dose Reduction | 3 rd Dose Reduction |
|---|---|---|---|
| 1,050 mg | 700 mg | 350 mg | Discontinue RYBREVANT |
| 1,400 mg | 1,050 mg | 700 mg | |
| 1,750 mg | 1,400 mg | 1,050 mg | |
| 2,100 mg | 1,750 mg | 1,400 mg |
The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 7.
| Adverse Reaction | Severity | Dosage Modifications |
|---|---|---|
| Infusion-related reactions (IRR) [see Warnings and Precautions (5.1)] | Grade 1 to 2 |
|
| Grade 3 |
| |
| Grade 4 or any Grade anaphylaxis / anaphylactic reactions |
| |
| Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2)] | Any Grade |
|
| Venous Thromboembolic (VTE) Events [Applies to the combination with lazertinib, see Warnings and Precautions (5.3)] | Grade 2 or 3 |
|
| Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation |
| |
| Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see Warnings and Precautions (5.4)] | Grade 1 or Grade 2 |
|
| Grade 3 |
| |
| Grade 4 |
| |
| Severe bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN) |
| |
| Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 3 |
|
| Grade 4 |
|
Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Lazertinib
When administering RYBREVANT in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT first.
Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib.
Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Carboplatin and Pemetrexed
When administering RYBREVANT in combination with carboplatin and pemetrexed, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT as shown in Table 7. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.
Preparation
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 and number of RYBREVANT vials needed based on patient's baseline weight [see Dosage and Administration (2.3)] . Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.
- Withdraw and then discard a volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard 7 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 7 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 15°C to 25°C (59°F to 77°F).
Administration
- Administer the diluted RYBREVANT solution [see Dosage and Administration (2.7)] by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer).
- Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.
- The administration set with filter, mustbe primed with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion.
- Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.
RYBREVANT in Combination with Carboplatin and Pemetrexed
- Administer RYBREVANT in combination with carboplatin and pemetrexed infusions every 3 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 8.
- Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk 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 the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last.
| |||
| Body Weight Less Than 80 kg | |||
| Week | Dose (per 250 mL bag) | Initial Infusion Rate (mL/hr) | Subsequent Infusion Rate * (mL/hr) |
| Week 1 (split dose infusion) | |||
| Week 1 Day 1 | 350 mg | 50 | 75 |
| Week 1 Day 2 | 1,050 mg | 33 | 50 |
| Week 2 | 1,400 mg | 65 | |
| Week 3 | 1,400 mg | 85 | |
| Week 4 | 1,400 mg | 125 | |
| Weeks 5 and 6 | No dose | ||
| Week 7 and every 3 weeks thereafter | 1,750 mg | 125 | |
| Body Weight Greater Than or Equal to 80 kg | |||
| Week | Dose (per 250 mL bag) | Initial Infusion Rate (mL/hr) | Subsequent Infusion Rate (mL/hr) |
| Week 1 (split dose infusion) | |||
| Week 1 Day 1 | 350 mg | 50 | 75 |
| Week 1 Day 2 | 1,400 mg | 25 | 50 |
| Week 2 | 1,750 mg | 65 | |
| Week 3 | 1,750 mg | 85 | |
| Week 4 | 1,750 mg | 125 | |
| Week 5 and 6 | No dose | ||
| Week 7 and every 3 weeks thereafter | 2,100 mg | 125 | |
RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent
- Administer RYBREVANT as a single agent infusion every 2 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9.
- Administer RYBREVANT via a peripheral line on Week 1 and Week 2, to reduce the risk 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.
- When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day.
| |||
| Body Weight Less Than 80 kg | |||
| Week | Dose (per 250 mL bag) | Initial Infusion Rate (mL/hr) | Subsequent Infusion Rate * (mL/hr) |
| Week 1 (split dose infusion) | |||
| Week 1 Day 1 | 350 mg | 50 | 75 |
| Week 1 Day 2 | 700 mg | 50 | 75 |
| Week 2 | 1,050 mg | 85 | |
| Week 3 | 1,050 mg | 125 | |
| Week 4 | 1,050 mg | 125 | |
| Week 5 | 1,050 mg | 125 | |
| Week 6 | No dose | ||
| Week 7 and every 2 weeks thereafter | 1,050 mg | 125 | |
| Body Weight Greater Than or Equal to 80 kg | |||
| Week | Dose (per 250 mL bag) | Initial Infusion Rate (mL/hr) | Subsequent Infusion Rate * (mL/hr) |
| Week 1 (split dose infusion) | |||
| Week 1 Day 1 | 350 mg | 50 | 75 |
| Week 1 Day 2 | 1,050 mg | 35 | 50 |
| Week 2 | 1,400 mg | 65 | |
| Week 3 | 1,400 mg | 85 | |
| Week 4 | 1,400 mg | 125 | |
| Week 5 | 1,400 mg | 125 | |
| Week 6 | No dose | ||
| Week 7 and every 2 weeks thereafter | 1,400 mg | 125 | |
Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in a single-dose vial.
Pregnancy
Risk Summary
Based on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to a 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 embryo lethality, malformations, and post-natal death in animals ( see Data) .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
No 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.
Lactation
Risk Summary
There are no data on the presence of amivantamab-vmjw in human milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed children, advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose.
Females and Males of Reproductive Potential
RYBREVANT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.
Pediatric Use
The safety and efficacy of RYBREVANT have not been established in pediatric patients.
Geriatric Use
- Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were ≥ 65 years of age and 12% were ≥ 75 years of age.
- Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were ≥ 65 years of age and 10% were ≥ 75 years of age.
- Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were ≥ 65 years of age and 8% were ≥ 75 years of age.
- Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as a single agent in the CHRYSALIS study, 39% were ≥ 65 years of age and 11% were ≥ 75 years of age.
No clinically important differences in safety or efficacy were observed between patients who were ≥ 65 years of age and younger patients.
None.
Infusion-Related Reactions
RYBREVANT can cause infusion-related reactions (IRR) including anaphylaxis; 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 with Lazertinib
RYBREVANT in combination with lazertinib can cause infusion-related reactions. In MARIPOSA, [see Adverse Reactions (6.1)] , IRRs occurred in 63% of patients treated with RYBREVANT in combination with lazertinib, 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 lazertinib.
RYBREVANT with Carboplatin and Pemetrexed
Based on the pooled safety population [see Adverse Reactions (6.1)] , 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.
RYBREVANT as a Single Agent
In CHRYSALIS, [see Adverse Reactions (6.1)], 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 1–2, 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 [see Dosage and Administration (2.5)] . Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)] .
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 [see Dosage and Administration (2.6)]. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT.
Interstitial Lung Disease/Pneumonitis
RYBREVANT can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.
RYBREVANT with Lazertinib
In MARIPOSA [see Adverse Reactions (6.1)] , ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 1% and Grade 4 in 0.2% of patients. There was one fatal case of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT and lazertinib due to ILD/pneumonitis [see Adverse Reactions (6.1)].
RYBREVANT with Carboplatin and Pemetrexed
Based on the pooled safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 2.1% 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.
RYBREVANT as a Single Agent
In CHRYSALIS, [see Adverse Reactions (6.1)] , 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 (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 (2.6)] .
Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and Lazertinib
RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of therapy [see Adverse Reactions (6.1)] .
In MARIPOSA [see Adverse Reactions (6.1)], VTEs occurred in 36% of patients receiving RYBREVANT in combination with lazertinib, 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 two 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. The median time to onset of VTEs was 84 days (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment [see Dosage and Administration (2.4)]. 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 lazertinib based on severity [see Dosage and Administration (2.6)] . Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.4)]. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.6)]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification.
Dermatologic Adverse Reactions
RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.
RYBREVANT with Lazertinib
In MARIPOSA, [see Adverse Reactions (6.1)] , rash occurred in 86% of patients treated with RYBREVANT in combination with lazertinib, 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.
RYBREVANT with Carboplatin and Pemetrexed
Based on the pooled safety population [see Adverse Reactions (6.1)] , 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.
RYBREVANT as a Single Agent
In CHRYSALIS, [see Adverse Reactions (6.1)] , 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 [see Adverse Reactions (6.1)].
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 (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.
When initiating treatment with RYBREVANT, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g., 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 [see Dosage and Administration (2.6)] .
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.
RYBREVANT with Lazertinib
In MARIPOSA [see Adverse Reactions (6.1)] , ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT and continue lazertinib based on severity [see Dosage and Administration (2.4)] .
RYBREVANT with Carboplatin and Pemetrexed
Based on the pooled safety population [see Adverse Reactions (6.1)], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All events were Grade 1 or 2.
RYBREVANT as a Single Agent
In CHRYSALIS, [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 with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)] .
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. [see Use in Specific Populations (8.1, 8.3)] .