In-office dosing and administration

Recommended dosage and pre-infusion medications

Administer RYBREVANT^® weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter, starting at Week 5, until disease progression or unacceptable toxicity¹

Weeks	Schedule
Weeks 1 to 4	Weekly (total of 4 doses) Week 1 – split infusion on Day 1 and Day 2 Weeks 2 to 4 – infusion on Day 1
Week 5 onwards	Every 2 weeks starting at Week 5

Weeks

Schedule

Weeks 1 to 4

Weekly (total of 4 doses)

Week 1 – split infusion on Day 1 and Day 2

Weeks 2 to 4 – infusion on Day 1

Week 5 onwards

Every 2 weeks starting at Week 5

Recommended Dose of RYBREVANT^®

Body Weight of Patient at Baseline*	Recommended Dose	Number of 350 mg/7 mL RYBREVANT^® Vials
Less than 80 kg	1050 mg	3
Greater than or equal to 80 kg	1400 mg	4


Body Weight of Patient at Baseline*	Recommended Dose	Number of 350 mg/7 mL RYBREVANT^® Vials
Less than 80 kg	1050 mg	3
Greater than or equal to 80 kg	1400 mg	4

*Dose adjustments not required for subsequent body weight changes.

Administer both antihistamine and antipyretic prior to all infusions. Glucocorticoid administration required for Week 1, Days 1 and 2 doses only and as necessary for subsequent infusions.¹

Medication	Dose	Route of Administration	Dosing Window Prior to RYBREVANT^® Administration
Antihistamine^†	Diphenhydramine (25 to 50 mg) or equivalent	IV	15 to 30 minutes
Antihistamine^†	Diphenhydramine (25 to 50 mg) or equivalent	Oral	30 to 60 minutes
Antipyretic^†	Acetaminophen (650 to 1,000 mg)	IV	15 to 30 minutes
Antipyretic^†	Acetaminophen (650 to 1,000 mg)	Oral	30 to 60 minutes
Glucocorticoid^‡	Dexamethasone (10 mg) or Methylprednisolone (40 mg) or equivalent	IV	45 to 60 minutes

Medication
Dose	Route of Administration	Dosing Window Prior to RYBREVANT^® Administration
Antihistamine^†
Diphenhydramine (25 to 50 mg) or equivalent	IV	15 to 30 minutes
Diphenhydramine (25 to 50 mg) or equivalent	Oral	30 to 60 minutes
Antipyretic^†
Acetaminophen (650 to 1,000 mg)	IV	15 to 30 minutes
Acetaminophen (650 to 1,000 mg)	Oral	30 to 60 minutes
Glucocorticoid^‡
Dexamethasone (10 mg) or Methylprednisolone (40 mg) or equivalent	IV	45 to 60 minutes

^†Required at all doses.

^‡Required at initial dose (Week 1, Days 1 and 2); optional for subsequent doses.

Dose modification for adverse reactions

Dose reductions or temporary interruptions may help to manage adverse reactions.

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
Dose reductions of RYBREVANT^® due to an adverse reaction occurred in 15% of patients

Body Weight at Baseline	Initial Dose	1st Dose Modification	2nd Dose Modification	3rd Dose Modification
Less than 80 kg	1050 mg	700 mg	350 mg	Discontinue RYBREVANT^®
Greater than or equal to 80 kg	1400 mg	1050 mg	700 mg	Discontinue RYBREVANT^®

Body Weight at Baseline
Initial Dose	1st Dose Modification	2nd Dose Modification	3rd Dose Modification
Less than 80 kg
1050 mg	700 mg	350 mg	Discontinue RYBREVANT^®
Greater than or equal to 80 kg
1400 mg	1050 mg	700 mg	Discontinue RYBREVANT^®

Preparation and Administration

Preparation of RYBREVANT^®

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 patient’s baseline weight. Each vial of RYBREVANT^® contains 350 mg of amivantamab-vmjw.
Withdraw and then discard a 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 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 59°F to 77°F (15°C to 25°C).

Administration of RYBREVANT^®

Administer the diluted solution 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) 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 a peripheral line on Week 1 and Week 2 given the high incidence of infusion-related reactions during initial treatment. 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 the table below.

Infusion Rates for RYBREVANT^® Administration¹

1050 mg Dose
Week	Dose (per 250 mL bag)	Initial Infusion Rate	Subsequent Infusion Rate^¶
Week 1 (split dose infusion)
Week 1 Day 1	350 mg	50 mL/hr	75 mL/hr
Week 1 Day 2	700 mg	50 mL/hr	75 mL/hr
Week 2	1050 mg	85 mL/hr
Week 3	1050 mg	125 mL/hr
Week 4	1050 mg	125 mL/hr
Subsequent weeks^§	1050 mg	125 mL/hr

1050 mg Dose
Week	Dose (per 250 mL bag)	Initial Infusion Rate	Subsequent Infusion Rate^¶
Week 1 (split dose infusion)
Week 1 Day 1	350 mg	50 mL/hr	75 mL/hr
Week 1 Day 2	700 mg	50 mL/hr	75 mL/hr
Week 2
	1050 mg	85 mL/hr
Week 3
	1050 mg	125 mL/hr
Week 4
	1050 mg	125 mL/hr
Subsequent weeks^§
	1050 mg	125 mL/hr

1400 mg Dose
Week	Dose (per 250 mL bag)	Initial Infusion Rate	Subsequent Infusion Rate^¶
Week 1 (split dose infusion)
Week 1 Day 1	350 mg	50 mL/hr	75 mL/hr
Week 1 Day 2	1050 mg	35 mL/hr	50 mL/hr
Week 2	1400 mg	65 mL/hr
Week 3	1400 mg	85 mL/hr
Week 4	1400 mg	125 mL/hr
Subsequent weeks^§	1400 mg	125 mL/hr

1400 mg Dose
Week	Dose (per 250 mL bag)	Initial Infusion Rate	Subsequent Infusion Rate^¶
Week 1 (split dose infusion)
Week 1 Day 1	350 mg	50 mL/hr	75 mL/hr
Week 1 Day 2	1050 mg	35 mL/hr	50 mL/hr
Week 2
	1400 mg	65 mL/hr
Week 3
	1400 mg	85 mL/hr
Week 4
	1400 mg	125 mL/hr
Subsequent weeks^§
	1400 mg	125 mL/hr

^§Starting at Week 5, patients are dosed every 2 weeks.

^¶Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions.

Infusion duration

Clinical trial median infusion times by hours²^||

^||Based on the safety population (N=302). Recommended phase 2 dose: 1050 mg if baseline weight <80 kg, and 1400 mg if baseline weight ≥80 kg.

ILD, interstitial lung disease; IRR, infusion-related reaction.

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References

1. RYBREVANT^® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
2. Data on file. Janssen Biotech, Inc. 2021.

WARNINGS AND PRECAUTIONS

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.

Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT^®. 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. Administer RYBREVANT^® via a peripheral line on Week 1 and Week 2. 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 interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT^®, with 0.7% of patients experiencing Grade 3 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.

Dermatologic Adverse Reactions

RYBREVANT^® can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT^®, 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 occurred in one patient (0.3%) treated with RYBREVANT^®.

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 emollient cream is recommended for dry skin.

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, dose reduce or permanently discontinue RYBREVANT^® based on severity.

Ocular 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, 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.

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. 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 final dose of RYBREVANT^®.

Adverse Reactions

The most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

Please read full Prescribing Information for RYBREVANT^®.

cp-213274v2

In-office dosing and administration

Recommended dosage and pre-infusion medications

Administer RYBREVANT® weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter, starting at Week 5, until disease progression or unacceptable toxicity1

Dose modification for adverse reactions

Dose reductions or temporary interruptions may help to manage adverse reactions.

Preparation and Administration

Infusion duration

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Administer RYBREVANT^® weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter, starting at Week 5, until disease progression or unacceptable toxicity¹

You are leaving the RYBREVANT^® website