Version May 2024
Note: Dose is based on baseline body weight (dose adjustments are not required for subsequent changes in body weight). Premedications are recommended prior to infusion (to reduce the risk of infusion reaction).
Non–small cell lung cancer, locally advanced or metastatic, with epidermal growth factor receptor exon 20 insertion mutation (Ref):
Patients <80 kg:
Week 1: IV: 1,050 mg split over days 1 and 2 (350 mg on day 1 and 700 mg on day 2).
Weeks 2 to 4: IV: 1,050 mg once weekly.
Subsequent infusions: IV: 1,050 mg once every 2 weeks (starting at week 5) until disease progression or unacceptable toxicity.
Patients ≥80 kg:
Week 1: IV: 1,400 mg split over days 1 and 2 (350 mg on day 1 and 1,050 mg on day 2).
Weeks 2 to 4: IV: 1,400 mg once weekly.
Subsequent infusions: IV: 1,400 mg once every 2 weeks (starting at week 5) until disease progression or unacceptable toxicity.
Premedication:
|
Medication |
Dose |
Administration route |
Dosing window (prior to amivantamab) |
|---|---|---|---|
|
Antihistamine (administer prior to all amivantamab doses) |
Diphenhydramine (25 to 50 mg) or equivalent |
IV |
15 to 30 minutes |
|
Oral |
30 to 60 minutes | ||
|
Antipyretic (administer prior to all amivantamab doses) |
Acetaminophen 650 to 1,000 mg |
IV |
15 to 30 minutes |
|
Oral |
30 to 60 minutes | ||
|
Glucocorticoid (administer prior to week 1, days 1 and 2 doses; optional [as needed] for subsequent doses) |
Dexamethasone (10 mg) or methylprednisolone (40 mg) or equivalent |
IV |
45 to 60 minutes |
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥29 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling; however, CrCl 29 to 276 mL/minute had no clinically meaningful difference on amivantamab pharmacokinetics.
CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin ≤1.5 times ULN): There are no dosage adjustments provided in the manufacturer’s labeling; however, mild impairment had no clinically meaningful difference on amivantamab pharmacokinetics.
Moderate (total bilirubin >1.5 to ≤3 times ULN) or severe (total bilirubin >3 times ULN) impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
|
Patient baseline body weight |
<80 kg |
≥80 kg |
|---|---|---|
|
Initial dose |
1,050 mg |
1,400 mg |
|
1st dose reduction |
700 mg |
1,050 mg |
|
2nd dose reduction |
350 mg |
700 mg |
|
3rd dose reduction |
Discontinue amivantamab | |
|
Adverse reaction |
Severity |
Dosage modification |
|---|---|---|
|
Dermatologic toxicity |
General recommendations |
If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. |
|
Dry skin |
Apply alcohol-free emollient cream. | |
|
Grade 2 |
Initiate supportive care management. Reassess after 2 weeks; if rash does not improve, consider amivantamab dose reduction. | |
|
Grade 3 |
Withhold amivantamab and initiate supportive care management. Add oral steroids and consider dermatologic consultation. Upon recovery to ≤ grade 2, resume amivantamab at reduced dose. If no improvement within 2 weeks, permanently discontinue amivantamab. | |
|
Grade 4 |
Permanently discontinue amivantamab. | |
|
Severe bullous, blistering, or exfoliating skin conditions (including toxic epidermal necrolysis) |
Permanently discontinue amivantamab. | |
|
Ocular toxicity |
Any grade |
Promptly refer patients presenting with eye symptoms to an ophthalmologist. Based on the severity, withhold, dose reduce, or permanently discontinue amivantamab. |
|
Pulmonary toxicity: Interstitial lung disease (ILD)/pneumonitis |
Any grade |
Withhold amivantamab for suspected ILD/pneumonitis. Permanently discontinue amivantamab if ILD/pneumonitis is confirmed. |
|
Infusion-related reaction (IRR) |
Grade 1 or 2 |
Interrupt amivantamab infusion for suspected IRR and monitor until reaction symptoms resolve. Resume the infusion at 50% of the infusion rate at which the reaction occurred. If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Administration). Include corticosteroid with premedications for subsequent doses. |
|
Grade 3 |
Interrupt amivantamab infusion and administer supportive care medications. Monitor until reaction symptoms resolve. Resume the infusion at 50% of the infusion rate at which the reaction occurred. If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Administration). Include corticosteroid with premedications for subsequent doses. For recurrent grade 3 IRR, permanently discontinue amivantamab. | |
|
Grade 4 |
Permanently discontinue amivantamab. | |
|
Other adverse reactions |
Grade 3 |
Withhold amivantamab until recovery to ≤ grade 1 or baseline. Resume at the same dose if recovery occurs within 1 week. Resume at reduced dose if recovery occurs after 1 week but within 4 weeks. Permanently discontinue amivantamab if recovery does not occur within 4 weeks. |
|
Grade 4 |
Withhold amivantamab until recovery to ≤ grade 1 or baseline. Resume at reduced dose if recovery occurs within 4 weeks. Permanently discontinue amivantamab if recovery does not occur within 4 weeks or for recurrent grade 4 reactions. |
Refer to adult dosing.
Amivantamab may cause skin rash (including acneiform dermatitis), pruritus, and xeroderma. Rash is commonly observed in patients treated with amivantamab, including grade 3 rash, frequently. Paronychia has also been commonly reported. Toxic epidermal necrolysis was observed rarely (Ref).
Onset: Varied; median time to rash onset was 14 days (range: 1 to 276 days)
Risk factors:
• Dosage (potential risk factor)
Amivantamab commonly causes an infusion-related reaction (IRR). IRRs occurred in approximately two-thirds of patients treated with amivantamab, particularly with the first infusion. Most IRRs were grade 1 or 2; however, grade 3 and 4 infusion related reactions have been reported.
Mechanism: Non–dose-related; immunologic
Onset: Rapid; the median time to onset was 1 hour (range: 0.1 to 18 hours) after start of infusion. The vast majority of IRRs occurred with the week 1 day 1 infusion, with a much smaller incidence occurring on week 1 day 2 and only a small percentage occurring with subsequent infusions.
Risk factors:
• Rate of infusion
• Omission of premedication (potential risk factor)
Amivantamab may rarely cause ocular toxicity, including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. All reported ocular adverse events were grade 1 or 2.
Risk factors:
• Dosage (potential risk factor)
Interstitial pulmonary disease/pneumonitis, including grade 3 events, have been reported. Symptoms of interstitial lung disease (ILD)/pneumonitis typically present as cough, dyspnea, and fever; permanent discontinuation is warranted if ILD/pneumonitis is confirmed.
Risk factors:
• Dosage (potential risk factor)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (27%)
Dermatologic: Paronychia (50%), pruritus (18%), skin rash (84%), xeroderma (14%)
Endocrine & metabolic: Decreased serum albumin (79%), decreased serum magnesium (27%), decreased serum phosphate (33%), decreased serum potassium (26%), decreased serum sodium (27%), increased gamma-glutamyl transferase (27%), increased serum glucose (56%)
Gastrointestinal: Abdominal pain (11%), constipation (23%), decreased appetite (15%), diarrhea (16%; grades 3/4: 3%), nausea (36%), stomatitis (26%; grades 3/4: <1%), vomiting (22%)
Hematologic & oncologic: Hemorrhage (19%), lymphocytopenia (36%; grades 3/4: 8%)
Hepatic: Increased serum alanine aminotransferase (38%), increased serum alkaline phosphatase (53%), increased serum aspartate aminotransferase (33%)
Nervous system: Dizziness (12%), fatigue (33%), peripheral neuropathy (13%)
Neuromuscular & skeletal: Musculoskeletal pain (47%)
Renal: Increased serum creatinine (46%)
Respiratory: Cough (25%), dyspnea (37%)
Miscellaneous: Fever (13%), infusion related reaction (64%)
1% to 10%:
Dermatologic: Toxic epidermal necrolysis (<10%)
Nervous system: Headache (10%)
Ophthalmic: Ocular toxicity (<10%)
Respiratory: Interstitial pulmonary disease (<10%), pneumonia (10%), pneumonitis (<10%)
Frequency not defined:
Cardiovascular: Pulmonary embolism
Immunologic: Antibody development
Neuromuscular & skeletal: Myasthenia
Ophthalmic: Keratitis, uveitis
Respiratory: Pleural effusion
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to amivantamab or any component of the formulation.
Concerns related to adverse effects:
• Photosensitivity: Patients should limit sun exposure during and for 2 months after amivantamab treatment. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Select patients for amivantamab treatment based on the presence of epidermal growth factor receptor exon 20 insertion mutations. Information on approved tests is available at http://www.FDA.gov/CompanionDiagnostics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Rybrevant: Amivantamab-vmjw 350 mg/7 mL (7 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]
No
Solution (Rybrevant Intravenous)
350 mg/7 mL (per mL): $574.06
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Rybrevant: Amivantamab-vmjw 350 mg/7 mL (7 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]
IV: Administer according to the infusion rate(s) in the Amivantamab Recommended Administration Rate table. Administer via an infusion set fitted with a flow regulator and with an in-line, sterile, nonpyrogenic, low protein-binding polyethersulfone 0.2 micron filter primed with diluent only. Use administration sets made of either polyurethane, polybutadiene, PVC, polypropylene, or polyethylene.
In week 1 and week 2, administer via a peripheral line (due to the high incidence of infusion-related reactions during initial treatment). Subsequent infusions (after week 2) may be administered via central line. Prepare the initial amivantamab infusion as close to administration time as possible to allow for potential extended infusion times if an infusion-related reaction occurs. Do not infuse amivantamab concomitantly in the same IV line with other medications.
|
a Increase the infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions. | |||||||||||||||||||||||||
|
1,050 mg dose | |||||||||||||||||||||||||
|
Week |
Dose (per 250 mL bag) |
Initial infusion rate |
Subsequent infusion ratea | ||||||||||||||||||||||
|
Week 1, day 1 (split dose infusion) |
350 mg |
50 mL/hour |
75 mL/hour | ||||||||||||||||||||||
|
Week 1, day 2 (split dose infusion) |
700 mg |
50 mL/hour |
75 mL/hour | ||||||||||||||||||||||
|
Week 2 |
1,050 mg |
85 mL/hour | |||||||||||||||||||||||
|
Week 3 |
1,050 mg |
125 mL/hour | |||||||||||||||||||||||
|
Week 4 |
1,050 mg |
125 mL/hour | |||||||||||||||||||||||
|
Subsequent infusions (dosed every 2 weeks) |
1,050 mg |
125 mL/hour | |||||||||||||||||||||||
|
1,400 mg dose | |||||||||||||||||||||||||
|
Week |
Dose (per 250 mL bag) |
Initial infusion rate |
Subsequent infusion ratea | ||||||||||||||||||||||
|
Week 1, day 1 (split dose infusion) |
350 mg |
50 mL/hour |
75 mL/hour | ||||||||||||||||||||||
|
Week 1, day 2 (split dose infusion) |
1,050 mg |
35 mL/hour |
50 mL/hour | ||||||||||||||||||||||
|
Week 2 |
1,400 mg |
65 mL/hour | |||||||||||||||||||||||
|
Week 3 |
1,400 mg |
85 mL/hour | |||||||||||||||||||||||
|
Week 4 |
1,400 mg |
125 mL/hour | |||||||||||||||||||||||
|
Subsequent infusions (dosed every 2 weeks) |
1,400 mg |
125 mL/hour | |||||||||||||||||||||||
Non–small cell lung cancer, locally advanced or metastatic: Treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) in adults with epidermal growth factor receptor (EGFR) exon 20 insertion mutations (as detected by an approved test) with disease progression on or after platinum-based chemotherapy.
Amivantamab may be confused with afatinib, avapritinib, naxitamab, tafasitamab.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Verify pregnancy status prior to treatment initiation.
Patients who may become pregnant should use effective contraception during therapy and for 3 months after the last amivantamab dose.
Based on the mechanism of action and data from animal models, in utero exposure to amivantamab may cause fetal harm.
Amivantamab is a humanized monoclonal antibody (IgG1). Human IgG is known to cross the placenta; exposure is dependent upon the IgG subclass, maternal serum concentrations, newborn birth weight, and GA, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).
It is not known if amivantamab is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 3 months after the last amivantamab dose.
EGFR exon 20 insertion mutation status. Evaluate pregnancy status prior to treatment (in patients who could become pregnant). Monitor for signs/symptoms of dermatologic toxicity, ocular toxicity, and for new or worsening symptoms (eg, dyspnea, cough, fever) indicative of interstitial lung disease/pneumonitis. Monitor (in a setting where cardiopulmonary resuscitation medication and equipment are available) for signs/symptoms of infusion reactions during infusion (eg, dyspnea, flushing, fever, chills, nausea, vomiting, chest discomfort, hypotension); monitor until resolved if a reaction occurs.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]; ESC [Lyon 2022]).
Amivantamab is a bispecific antibody that targets both epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET). Amivantamab binds to the EGFR and MET extracellular domains and disrupts EGFR and MET signaling by blocking ligand binding and, in exon 20 insertion mutation models, degrading EGFR and MET. The presence of EGFR and MET on tumor cell surfaces also allows for targeted cell destruction by immune effector cells, such as natural killer cells and macrophages, via antibody-dependent cellular cytotoxicity and trogocytosis mechanisms, respectively.
Distribution: Vd: 5.13 L.
Half-life elimination: 11.3 days.
Excretion: Clearance: 360 mL/day.
Body weight: Increases in body weight increased the amivantamab Vd and clearance. Amivantamab exposures are 30% to 40% lower in patients weighing ≥80 kg, compared to patients weighting <80 kg (at the same dose). Amivantamab exposures were comparable between patients who weighed <80 kg and received a 1,050 mg dose and patients who weighed ≥80 kg and received a 1,400 mg dose.
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