阿维鲁单抗(Avelumab)详细说明书

Avelumab is a PD-L1 inhibitor jointly developed by Pfizer and Merck. It was approved by the FDA in 2017. It activates the body's immune system to kill tumor cells by blocking the PD-1/PD-L1 pathway between cancer cells and immune cells.

1. Indications

1. Metastatic Merkel cell carcinoma

Avelumab (avelumab) is suitable for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC).

2. Locally advanced or metastatic urothelial carcinoma

(1) Avelumab is suitable for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have not progressed on first-line platinum-containing chemotherapy.

(2) Avelumab is suitable for the treatment of patients with previously treated locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or after platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

3. Advanced renal cell carcinoma

Avelumab combined with axitinib is suitable for first-line treatment of patients with advanced renal cell carcinoma (RCC).

2. Usage and dosage

1. Preoperative medication

Before the first 4 infusions of avelumab, the patient was premedicated with antihistamines and acetaminophen. Premedication for subsequent avelumab doses should be based on clinical judgment and the presence/severity of prior infusion reactions.

2. Recommended dose for metastatic Merkel cell carcinoma

The recommended dose of avelumab is 800 mg, administered intravenously for 60 minutes every 2 weeks until disease progression or unacceptable toxicity occurs.

3. Recommended dose for locally advanced or metastatic urothelial carcinoma

The recommended dose of avelumab is 800 mg, administered as a 60-minute intravenous infusion every 2 weeks until disease progression or unacceptable toxicity occurs.

4. Recommended dose of advanced renal cell carcinoma

The recommended dose of avelumab is 800 mg, intravenous infusion, 60 minutes every 2 weeks, combined with axitinib 5 mg, orally, twice a day (12 hours apart), with food or alone, until disease progression or unacceptable toxicity occurs.

When axitinib is used in combination with avelumab, consideration may be given to escalating the axitinib dose above the initial 5 mg dose every two weeks or more. View full prescribing information for axitinib before starting.

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3. Dose adjustment

1. Adverse reaction dose adjustment

It is not recommended to reduce the dose of avelumab. For serious (Grade 3) immune-mediated adverse reactions, dosing is usually suspended. Avelumab needs to be permanently discontinued if life-threatening (Grade 4) immune-mediated adverse reactions occur, recurrent severe (Grade 3) immune-mediated reactions requiring systemic immunosuppressive therapy, or if the dose cannot be reduced to prednisone ≤ 10 mg/day (or equivalent) within 12 weeks of starting corticosteroid therapy.

2. Adverse reaction dose adjustment in combination with axitinib

(1) If ALT or AST ≥ 3 times ULN and < 10 times ULN and total bilirubin ≥ 2 times ULN, the combination of avelumab and axitinib needs to be suspended until the adverse reactions return to grade 0-1 † . The following strategies may be considered after recovery: rechallenge with avelumab or axitinib alone, or sequential rechallenge.

(2) When ALT or AST is at least 10 times the ULN or exceeds 3 times the ULN, and total bilirubin is at least 2 times the ULN, permanently discontinue avelumab and axitinib.

3. Specifications and properties

Injection, 200mg/10mL (20mg/mL), transparent, colorless to slightly yellow solution, packed in single-dose vial.

IV. Adverse reactions

1. Metastatic Merkel cell carcinoma

Fatigue, musculoskeletal pain, diarrhea, infusion-related reactions, nausea, rash, loss of appetite, peripheral edema, cough, constipation, abdominal pain, arthralgia, weight loss, dizziness, hypertension, vomiting, dyspnea, headache, pruritus, lymphopenia, anemia, elevated ALT and AST concentrations, thrombocytopenia, elevated lipase concentration.

2. Locally advanced or metastatic urothelial carcinoma

Fatigue, infusion-related reactions, musculoskeletal pain, nausea, loss of appetite, urinary tract infection, abdominal pain, weight loss, constipation, diarrhea, dyspnea (including exertional dyspnea), peripheral edema, elevated S chromium concentration/kidney Failure, fever, rash, cough, vomiting/retching, hypertension (including hypertensive crisis), pruritus, hyponatremia, elevated gamma-glutamyl transferase (γ-glutamyl transpeptidase, GGT, GGTP) concentrations, lymphopenia, hyperglycemia, elevated alkaline phosphatase concentrations, anemia, elevated lipase concentrations.

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5. Precautions

1. Serious and fatal immune-mediated adverse reactions

(1) Immune-mediated pneumonia

Avelumab can cause immune-mediated pneumonia. When other PD-1/PD-L1 blocking antibodies were used, the incidence of pneumonia was higher in patients who had previously received chest radiation therapy.

(2) Immune-mediated colitis

Avelumab can cause immune-mediated colitis. A major component of immune-mediated colitis includes diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In the setting of corticosteroid-refractory colitis, consider repeating infectious workup to rule out other causes.

(3) Hepatotoxicity and immune-mediated hepatitis

Avelumab can cause immune-mediated hepatitis. Includes fatal, grade 3 and grade 2 adverse reactions. Hepatitis resulted in permanent discontinuation of avelumab in 0.6% of patients and discontinuation of avelumab in 0.2% of patients. Avelumab in combination with axitinib was associated with hepatotoxicity, with grade 3 and 4 ALT and AST elevations occurring more frequently than expected compared with avelumab alone. Consider monitoring liver enzymes more frequently than with monotherapy. For elevated liver enzymes, interrupt avelumab and axitinib and consider administering corticosteroids as needed.

(4) Immune-mediated endocrinopathy

Avelumab can cause primary or secondary adrenocortical insufficiency. For grade 2 or higher adrenocorticism, initiate symptomatic treatment, including hormone replacement therapy, as clinically indicated. Discontinue avelumab based on severity. Avelumab can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms related to mass effect, such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Start hormone replacement therapy as clinically indicated. Discontinue or permanently discontinue avelumab based on severity.

(5) Thyroid disease

Avelumab can cause immune-mediated thyroid disease. Thyroiditis may be associated with or without endocrine pathology. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or medical management of hyperthyroidism as clinically indicated. Discontinue or permanently discontinue avelumab based on severity.

(6) Immune-mediated type I diabetes

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate insulin therapy as clinically indicated. Discontinue avelumab based on severity.

(7) Immune-mediated nephritis with renal insufficiency

Avelumab can cause immune-mediated nephritis. Immune-mediated nephritis with renal insufficiency, including Grade 3 and 2 adverse reactions, occurred in 0.1% of patients receiving avelumab. Nephritis with renal insufficiency resulted in permanent discontinuation of avelumab in 0.1% of patients. Nephritis did not cause any patient to discontinue avelumab.

(8) Immune-mediated dermatological adverse reactions

Avelumab can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, DRESS, and toxic epidermal necrolysis (TEN), has occurred in response to PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be sufficient to treat mild to moderate nonexfoliative rashes. Discontinue or permanently discontinue avelumab based on severity.

(9) Other immune-mediated adverse reactions

In PD-1/PD-L1 inhibitor treatment, immune-mediated adverse reactions with an incidence rate of <1% but potentially fatal include cardiovascular, gastrointestinal, nervous system, ocular toxicity, musculoskeletal, endocrine, and blood/immune system. Systemic immunosuppressive therapy is required, and ophthalmic emergencies may require urgent intervention to prevent permanent visual impairment.

2. Infusion-related reactions

Avelumab can cause serious or life-threatening infusion-related reactions. Premedicate with antihistamines and acetaminophen before the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions, including fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. For mild or moderate infusion-related reactions, interrupt or slow the infusion rate. For serious (Grade 3) or life-threatening (Grade 4) infusion-related reactions, discontinue the infusion and permanently discontinue avelumab.

3. Complications of allogeneic hematopoietic stem cell transplantation

Patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after receiving PD-1/PD-L1 blocking antibody therapy may develop fatal and other serious complications. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and febrile syndrome requiring steroids (without an identified infectious cause). These complications may occur despite therapeutic intervention between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefits and risks of using PD-1/PD-L1 blocking antibody therapy before or after allogeneic hematopoietic stem cell transplantation.

4. Major adverse cardiovascular events

The combined use of avelumab and axitinib can cause serious and fatal cardiovascular events. Consider baseline and periodic assessment of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Avelumab and axitinib were discontinued for grade 3-4 cardiovascular events.

5. Embryo-fetal toxicity

According to its mechanism of action, avelumab can cause harm to the fetus when administered to pregnant women. Animal studies have shown that inhibition of the PD-1/PD-L1 pathway can lead to an increased risk of immune-mediated rejection of the developing fetus, leading to fetal death. If this medication is used during pregnancy, or if the patient becomes pregnant while taking avelumab, inform the patient of the potential risk to the fetus. Advise females of childbearing potential to use effective contraception during treatment with avelumab and for at least one month after the last dose of avelumab.

VI. Medication for Special Populations

1. Pregnancy

According to its mechanism of action, avelumab will cause harm to the fetus when administered to pregnant women. There are no data available on the use of avelumab in pregnant women. Animal studies have shown that inhibition of the PD-1/PD-L1 pathway leads to an increased risk of immune-mediated rejection of the developing fetus, leading to fetal death. Human IgG1 immunoglobulin (IgG1) is known to cross the placenta. Avelumab has the potential to be transmitted from mother to the developing fetus. If this medication is used during pregnancy, or if the patient becomes pregnant while taking this medication, inform the patient of the potential risk to the fetus.

2. Lactation

There is no information on the presence of avelumab in breast milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs, including antibodies, are excreted in breast milk, lactating women are advised not to breastfeed during treatment and for at least one month after the last dose of avelumab because breastfed infants may develop serious adverse reactions.

3. People with childbearing potential

Based on its mechanism of action, avelumab can cause fetal harm when administered to pregnant women. Advise females of childbearing potential to use effective contraception during treatment with avelumab and for at least 1 month after the last dose of avelumab.

4. Pediatric patients

The safety and effectiveness of avelumab in pediatric patients under 12 years of age have not yet been determined.

5. Elderly patients

There is no overall difference in safety or effectiveness between elderly patients aged 65 or above and younger patients.

7. Contraindications

The instructions are not yet clear.

8. Drug Interactions

The instructions indicate that there is no formal drug interaction study.

9. Validity period

24 months

10. Storage conditions

Avelumab should be refrigerated in the original packaging at 36°F to 46°F (2°C to 8°C) to protect from light. Do not freeze or shake vial.

11. Pharmacokinetics

Distribution

The average volume of distribution at steady state after patients received a dose of 10 mg/kg was 4.7L (coefficient of variation (%CV) was 44%).

Elimination

The primary elimination mechanism of avelumab is proteolytic degradation. In patients receiving the 10 mg/kg dose every 2 weeks, the total systemic clearance (%CV) was 0.59 L/day (25%) and the terminal half-life (%CV) was 6.1 days (92%).