Rybrevant Dosage/Direction for Use

Treatment with Rybrevant should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Rybrevant should be administered by a healthcare professional with access to appropriate medical support to manage infusion-related reactions (IRRs) if they occur.
Before initiation of Rybrevant therapy, EGFR mutation status in tumour tissue or plasma specimens must be established using a validated test method. If no mutation is detected in a plasma specimen, tumour tissue should be tested if available in sufficient amount and quality due to the potential for false negative results using a plasma-test. Testing may be performed at any time from initial diagnosis until the initiation of therapy; testing does not need to be repeated once EGFR mutation status has been established (see Pharmacology: Pharmacodynamics under Actions).
Posology: Premedications should be administered to reduce the risk of IRRs with Rybrevant (see "Dose modifications" and "Recommended concomitant medicinal products" as follows).
Every 3 weeks: The recommended dosages of Rybrevant, when used in combination with carboplatin and pemetrexed, is provided in Table 6 (see "Infusion rates" and Table 10 as follows). (See Table 6.)

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When used in combination with carboplatin and pemetrexed, Rybrevant should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. See Pharmacology: Pharmacodynamics under Actions and the manufacturer's prescribing information for dosing instructions for carboplatin and pemetrexed.
Every 2 weeks: The recommended dosages of Rybrevant monotherapy or in combination with lazertinib is provided in Table 7 (see "Infusion rates" and Table 11 as follows). (See Table 7.)

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When given in combination with lazertinib, it is recommended to administer Rybrevant any time after lazertinib when given on the same day. Refer to Dosage & Administration of this monograph for recommended lazertinib dosing information.
Duration of treatment: It is recommended that patients are treated with Rybrevant until disease progression or unacceptable toxicity.
Missed dose: If a planned dose is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.
Dose modifications: Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 8. See also specific dose modifications for specific adverse reactions following Table 8.
If used in combination with lazertinib, refer to this section of the monograph for information about dose modifications. (See Table 8.)

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Infusion-related reactions: Infusion should be interrupted at the first sign of IRRs. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see Precautions).
Grade 1-3 (mild-severe): Upon recovery from symptoms, resume infusion at 50% of the previous rate. If there are no additional symptoms, the rate may be increased per the recommended infusion rate (see Tables 10 and 11). Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent (see Table 9).
Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant.
Venous thromboembolic (VTE) events with concomitant use with lazertinib: At the initiation of treatment, prophylactic anticoagulants should be administered to prevent VTE events in patients receiving Rybrevant in combination with lazertinib. Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.
For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction), both drugs should be withheld until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, discontinue Rybrevant. Treatment can continue with lazertinib at the same dose.
Skin and nail reactions: Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Alcohol-free emollient cream is recommended for dry areas. For further information about prophylaxis for skin and nail reactions, see Precautions. If the patient develops a Grade 1-2 skin or nail reaction, supportive care should be initiated; if there is no improvement after 2 weeks, dose reduction should be considered for persistent Grade 2 rash (see Table 8). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated, and interruption of Rybrevant should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see Precautions).
Interstitial lung disease: Rybrevant should be withheld if interstitial lung disease (ILD) or ILD-like adverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD-like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see Precautions).
Recommended concomitant medicinal products: Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 9). For subsequent doses, antihistamines and antipyretics are required to be administered. Glucocorticoids should also be re-initiated after prolonged dose interruptions. Antiemetics should be administered as needed. (See Table 9.)

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Special populations: Paediatric population: There is no relevant use of amivantamab in the paediatric population in the treatment of non-small cell lung cancer.
Elderly: No dose adjustments are necessary (see Adverse Reactions, and Pharmacodynamics and Pharmacokinetics under Actions).
Renal impairment: No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see Pharmacology: Pharmacokinetics under Actions). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations as previously mentioned.
Hepatic impairment: No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment. Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population (see Pharmacology: Pharmacokinetics under Actions). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations as previously mentioned.
Method of administration: Rybrevant is for intravenous use. It is administered as an intravenous infusion following dilution with sterile 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution for injection. Rybrevant must be administered with in-line filtration.
For instructions on dilution of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.
Infusion rates: Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 10 or 11 as follows. Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower (see Special precautions for disposal and other handling under Cautions for Usage). It is recommended for the first dose to be prepared as close to administration as possible to maximise the likelihood of completing the infusion in the event of an IRR. (See Tables 10 and 11.)

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