RYBREVANT Solution for injection Ref.[115919] Active ingredients: Amivantamab

Treatment with Rybrevant subcutaneous formulation should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Before initiation of Rybrevant subcutaneous formulation, 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. Once EGFR mutation status has been established, testing does not need to be repeated (see section 5.1).

Rybrevant subcutaneous formulation should be administered by a healthcare professional with access to appropriate medical support to manage administration-related reactions if they occur.

Posology

Premedications should be administered to reduce the risk of administration-related reactions with Rybrevant subcutaneous formulation (see below "Dose modifications" and "Recommended concomitant medicinal products").

The recommended dosages of Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy based on baseline body weight, are provided in Table 1.

Table 1. Recommended dosage of Rybrevant subcutaneous formulation:

^* Dose adjustments not required for subsequent body weight changes.

When given in combination with lazertinib, it is recommended to administer Rybrevant subcutaneous formulation any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib Summary of Product Characteristics for recommended lazertinib dosing information.

Duration of treatment

It is recommended that patients are treated with Rybrevant subcutaneous formulation until disease progression or unacceptable toxicity.

Missed dose

If a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 4, it should be administered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 5 onward, it should be administered within 7 days. Otherwise, the missed dose should not be administered and the next dose should be administered per the usual dosing schedule.

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 2. See also specific dose modifications for specific adverse reactions below Table 2.

If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product Characteristics for information about dose modifications.

Table 2. Recommended dose modifications for adverse reactions:

^* Dose at which the adverse reaction occurred

Administration-related reactions

Premedications should be administered to reduce the risk of administration-related reactions with Rybrevant subcutaneous formulation (see "Recommended concomitant medicinal products"). Injections should be interrupted at the first sign of administration-related reactions. 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 Rybrevant subcutaneous formulation injections. Concomitant medicinal products should be administered at the next dose, including dexamethasone (20 mg) or equivalent (see Table 3).
• 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 subcutaneous formulation 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 (see section 4.4).

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 section 4.4. 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 2). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated, and interruption of Rybrevant subcutaneous formulation should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant subcutaneous formulation should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4).

Interstitial lung disease

Rybrevant subcutaneous formulation 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 section 4.4).

Recommended concomitant medicinal products

Prior to the initial dose (Week 1, Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions (see Table 3). 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.

Table 3. Dosing schedule of premedications:

^* Required at all doses.
^† Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an administration-related reaction.
^‡ Optional for subsequent doses.

Special populations

Paediatric population

There is no relevant use of amivantamab in the paediatric population in the treatment of NSCLC.

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 solution for injection is for subcutaneous use only.

Rybrevant subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. See section 6.6 for instructions on handling of the medicinal product before administration.

Inject the required volume of Rybrevant subcutaneous formulation into the subcutaneous tissue of the abdomen over approximately 5 minutes. Do not administer at other sites of the body as no data are available.

Pause or slow delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

If administering with a subcutaneous infusion set, ensure that the full dose is delivered through the infusion set. Sodium chloride 9 mg/mL (0.9%) solution may be utilised to flush remaining medicinal product through the line.

Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact or within 5 cm around the periumbilical area.

Injection sites should be rotated for successive injections.

There is no information on overdose with Rybrevant subcutaneous formulation and no known specific antidote for 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:

2 years.

Prepared syringe:

Chemical and physical in-use stability has been demonstrated up to 24 hours at 2°C to 8°C followed by up to 24 hours at 15°C to 30°C. From a microbiological point of view, unless the method of dose preparation 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 preparing the syringe, see section 6.3.

10 mL solution in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-off cap containing 1600 mg amivantamab. Pack size of 1 vial.

14 mL solution in a Type 1 glass vial with an elastomeric closure and an aluminium seal with a flip-off cap containing 2240 mg amivantamab. Pack size of 1 vial.

Rybrevant subcutaneous formulation is for single use only and is ready to use.

The solution for injection should be prepared using aseptic technique as follows:

Preparation:

• Determine the dose required and the appropriate Rybrevant subcutaneous formulation vial needed based on the patient's baseline weight (see section 4.2).
• Patients <80 kg receive 1600 mg and for patients ≥80 kg, 2240 mg weekly from Weeks 1 to 4 and then every 2 weeks starting at Week 5 onwards.
• Remove the appropriate Rybrevant subcutaneous formulation vial from refrigerated storage (2°C to 8°C).
• Check that the Rybrevant solution is colourless to pale yellow. Do not use if opaque particles, discolouration or other foreign particles are present.
• Equilibrate Rybrevant subcutaneous formulation to room temperature (15°C to 30°C) for at least 15 minutes. Do not warm Rybrevant subcutaneous formulation in any other way. Do not shake.
• Withdraw the required injection volume of Rybrevant subcutaneous formulation from the vial into an appropriately sized syringe using a transfer needle. Smaller syringes require less force during preparation and administration.
• Rybrevant subcutaneous formulation is compatible with stainless steel injection needles, polypropolene and polycarbonate syringes, and polyethylene, polyurethane, and polyvinylchloride subcutaneous infusion sets. A sodium chloride 9 mg/mL (0.9%) solution may also be used to flush an infusion set if needed.
• Replace the transfer needle with the approriate ancillaries for transport or administration. Use of a 21G to 23G needle or infusion set is recommended to ensure ease of administration.

Storage of prepared syringe:

The prepared syringe should be administered immediately. If immediate administration is not possible, store the prepared syringe refrigerated at 2°C to 8°C for up to 24 hours followed by at room temperature of 15°C to 30°C for up to 24 hours. The prepared syringe should be discarded if stored for more than 24 hours refrigerated or more than 24 hours at room temperature. If stored in the refrigerator, the solution should come up to room temperature before administration.

Disposal:

This medicinal product is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.