RYBREVANT Concentrate for solution for infusion Ref.[28354] Active ingredients: Amivantamab

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 Exon 20 insertion mutation-positive status must be established using a validated test method (see section 5.1).

Posology

Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dose modifications” and “Recommended concomitant medicinal products”).

The recommended dose of Rybrevant is provided in Table 1, and the dosing schedule is provided in Table 2 (see below “Infusion rates”).

Table 1. Recommended dose of Rybrevant:

^* Dose adjustments not required for subsequent body weight changes

Table 2. Dosing schedule for Rybrevant:

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 3. See also specific dose modifications for specific adverse reactions below Table 3.

Table 3. Recommended dose modifications for adverse reactions:

Infusion-related reactions

Interrupt infusion 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 section 4.4).

• Grade 1-3 (mild-severe): Upon recovery of 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 Table 5). Concomitant medicinal products should be administered at the next dose (see Table 4).
• Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant.

Skin and nail reactions

If the patient develops a Grade 2 skin or nail reaction, supportive care should be initiated; if there is no improvement after 2 weeks, dose reduction should be considered (see Table 3). 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 (including toxic epidermal necrolysis (TEN)), permanently discontinue Rybrevant (see section 4.4).

Interstitial lung disease

If the patient develops interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4).

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 4). For subsequent doses, antihistamines and antipyretics are required to be administered. Antiemetics should be administered as needed.

Table 4. Dosing schedule of premedications:

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

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 section 4.8, section 5.1, and section 5.2).

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 section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

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 section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

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 section 6.6.

Infusion rates

Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 5 below. 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 section 6.6). 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.

Table 5. Infusion rates for Rybrevant administration:

^* After 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 IRRs.

No maximum tolerated dose has been determined in a clinical study in which patients received up to 1,750 mg administered intravenously. There is no known specific antidote for amivantamab overdose. In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved.

Unopened vial:

24 months.

After dilution:

Chemical and physical in-use stability has been demonstrated for 10 hours at 15°C to 25°C in room light. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

7 mL concentrate in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-off cap containing 350 mg amivantamab. Pack size of 1 vial.

Prepare the solution for intravenous infusion using aseptic technique as follows:

Preparation:

• Determine the dose required (either 1,050 mg for patients <80 kg or 1,400 mg for patients ≥80 kg) and the number of Rybrevant vials needed based on patient’s baseline weight (see section 4.2). Each vial contains 350 mg of amivantamab.
• Check that the Rybrevant solution is colourless to pale yellow. Do not use if discolouration or visible particles are present.
• Withdraw and then discard a volume of either 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution for injection from the 250 mL infusion bag that is equal to the required volume of Rybrevant solution to be added (discard 7 mL diluent from the infusion bag for each vial). Infusion bags must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).
• Withdraw 7 mL of Rybrevant from each vial needed then add it to the infusion bag. Each vial contains a 0.5 mL overfill to ensure sufficient extractable volume. 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.
• Visually inspect for particulate matter and discolouration prior to administration. Do not use if discolouration or visible particles are observed.

Administration:

• 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 0.22 or 0.2 micrometer). 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.
• The diluted solution should be administered within 10 hours (including infusion time) at room temperature (15°C to 25°C) and in room light.
• 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 infusion rates in section 4.2.

Disposal

This medicinal product is for single use only and any unused medicinal product that is not administered within 10 hours should be disposed of in accordance with local requirements.