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Avelumab

Pronunciation

(a VEL ue mab)

Index Terms

  • Anti-PD-L1 Monoclonal Antibody MSB0010718C
  • Bavencio
  • MSB0010718C

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Bavencio: 200 mg/10 mL (10 mL)

Brand Names: U.S.

  • Bavencio

Pharmacologic Category

  • Antineoplastic Agent, Anti-PD-L1 Monoclonal Antibody
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Avelumab is a fully human monoclonal antibody that binds to programmed death ligand 1 (PD-L1) to selectively prevent the interaction between the programmed cell death-1 (PD-1) and B7.1 receptors, while still allowing interaction between PD-L2 and PD-1 (Kaufman 2016). PD-L1 is an immune check point protein expressed on tumor cells and tumor infiltrating cells and down regulates anti-tumor t-cell function by binding to PD-1 and B7.1; blocking PD-1 and B7.1 interactions restores antitumor t-cell function (Fehrenbacher 2016, Rosenberg 2016).

Distribution

Vdss: 4.72 L (10 mg/kg dose)

Excretion

Total systemic clearance was 0.59 L/day in patients receiving a 10 mg/kg dose.

Half-Life Elimination

6.1 days

Special Populations Note

Body weight positively correlates with total systemic clearance.

Use: Labeled Indications

Merkel cell carcinoma, metastatic: Treatment of metastatic Merkel cell carcinoma (MCC) in adults and children ≥12 years of age.

Urothelial carcinoma, locally advanced or metastatic: Treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Note: Premedicate with an antihistamine and acetaminophen prior to the first 4 infusions; consider premedication for subsequent infusions based on clinical judgment and the presence and/or severity of infusion-related reactions with previous infusions.

Merkel cell carcinoma, metastatic: IV: 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicity (Kaufman 2016).

Urothelial carcinoma, locally advanced or metastatic: IV: 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Premedicate with an antihistamine and acetaminophen prior to the first 4 infusions; consider premedication for subsequent infusions based on clinical judgment and the presence and/or severity of infusion-related reactions with previous infusions.

Merkel cell carcinoma, metastatic: Children ≥12 years and Adolescents: IV: 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

Dosing: Renal Impairment

Renal impairment prior to treatment initiation: There are no dosage adjustments provided in the manufacturer’s labeling; however, no clinically meaningful differences were observed in a population pharmacokinetic analysis in patients with CrCl 15 to 89 mL/minute.

Renal toxicity during treatment (nephritis and renal dysfunction):

Serum creatinine >1.5 to 6 times ULN: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent, followed by a taper). Resume avelumab treatment if symptoms improve to grade 0 or 1 after corticosteroid taper.

Serum creatinine >6 times ULN: Discontinue permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Dosing: Hepatic Impairment

Hepatic impairment prior to treatment: There are no dosage adjustments provided in the manufacturer’s labeling; however, no clinically meaningful differences were observed in a population pharmacokinetic analysis in patients with mild (bilirubin ≤ ULN and AST > ULN or bilirubin between 1 to 1.5 times ULN) or moderate (bilirubin between 1.5 to 3 times ULN) impairment. Limited data is available in patients with severe (bilirubin >3 times ULN) impairment.

Hepatotoxicity during treatment:

AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent, followed by a taper). Resume avelumab treatment if hepatitis symptoms improve to grade 0 or 1 after corticosteroid taper.

AST or ALT >5 times ULN or total bilirubin >3 times ULN: Discontinue permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Dosing: Adjustment for Toxicity

Endocrinopathies:

Adrenal insufficiency, grade 3 or 4: Withhold treatment; administer corticosteroids as appropriate. Resume avelumab treatment if symptoms improve to grade 0 or 1 after corticosteroid taper.

Hyperglycemia, grade 3 or 4: Withhold treatment. May require insulin or other anti-hyperglycemic treatment. Resume avelumab once metabolic control has been achieved.

Hyperthyroidism or hypothyroidism, grade 3 or 4: Withhold treatment. Initiate medical management for hyperthyroidism; manage hypothyroidism with hormone replacement therapy.

Other endocrinopathies, grade 3 or 4: Withhold treatment; administer corticosteroids as appropriate. Resume avelumab treatment if symptoms improve to grade 0 or 1 after corticosteroid taper.

Gastrointestinal toxicity:

Diarrhea or colitis, grade 2 or 3: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. May resume avelumab treatment if symptoms improve to grade 0 or 1 after corticosteroid taper.

Diarrhea or colitis, grade 4 or recurrent grade 3: Discontinue permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Infusion-related reaction:

Grade 1 or 2: Interrupt or slow the rate of infusion.

Grade 3 or 4: Permanently discontinue.

Pulmonary toxicities:

Pneumonitis, grade 2: Withhold treatment. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper. May resume avelumab treatment if symptoms improve to grade 0 or 1 after corticosteroid taper.

Pneumonitis, grade 3 or 4, or recurrent grade 2: Discontinue permanently. Administer high-dose systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a corticosteroid taper.

Other immune-mediated toxicities (eg, arthritis, bullous dermatitis, demyelination, encephalitis, erythema multiforme, exfoliative dermatitis, Guillain-Barré syndrome, hemolytic anemia, histiocytic necrotizing lymphadenitis, hypophysitis, hypopituitarism, iritis, myasthenia gravis, myocarditis, myositis, pancreatitis, pemphigoid, psoriasis, rhabdomyolysis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), uveitis, vasculitis):

Immune-mediated toxicities, moderate or severe (not described previously): Withhold treatment and evaluate. Administer high-dose systemic corticosteroids, and if appropriate, initiate hormone replacement therapy. When toxicity improves to grade 1 or less, initiate a corticosteroid taper. May resume avelumab treatment if symptoms improve to grade 0 or 1 after corticosteroid taper.

Life-threatening reactions (excluding endocrinopathies), recurrent severe immune-mediated reactions, or persistent grade 2 or 3 immune-mediated reactions lasting 12 weeks or longer, or requirement for ≥10 mg/day prednisone (or equivalent) for >12 weeks: Discontinue permanently. If appropriate, administer high-dose systemic corticosteroids followed by a corticosteroid taper.

Reconstitution

Withdraw appropriate volume from vial and transfer to IV bag containing 250 mL NS or ½ NS. Mix by gently inverting bag (do not shake); avoid foaming or excessive shearing. Discard unused portion of the vial.

Administration

IV: Infuse over 60 minutes through a 0.2 micron sterile, nonpyrogenic, low-protein binding inline filter. Do not infuse other medications through the same infusion line.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect vials from light (store in original packaging). Do not shake. Solutions diluted for infusion should be protected from light and may be stored at room temperature for up to 4 hours or refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. Do not freeze or shake diluted solution. If refrigerated, allow to reach room temperature prior to administration.

Drug Interactions

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (20%), hypertension (13%)

Central nervous system: Fatigue (50%), dizziness (14%)

Dermatologic: Skin rash (22%)

Endocrine & metabolic: Weight loss (15%)

Gastrointestinal: Diarrhea (23%), nausea (22%), decreased appetite (20%), constipation (17%), abdominal pain (16%), increased serum lipase (14%), vomiting (13%)

Hematologic & oncologic: Lymphocytopenia (49%; grades 3/4: 19%), anemia (35%; grades 3/4: 9%), thrombocytopenia (27%; grades 3/4: 1%)

Hepatic: Increased serum AST (34%), increased serum ALT (20%)

Neuromuscular & skeletal: Musculoskeletal pain (32%), arthralgia (16%)

Respiratory: Cough (18%), dyspnea (11%)

Miscellaneous: Infusion-related reaction (22% to 25%)

1% to 10%:

Central nervous system: Headache (10%)

Dermatologic: Pruritus (10%), cellulitis (>1%)

Endocrine & metabolic: Increased amylase (8%), hypothyroidism (immune-mediated: 5%)

Gastrointestinal: Colitis (immune-mediated: 2%), intestinal obstruction (>1%)

Hematologic & oncologic: Neutropenia (6%; grades 3/4: 1%)

Hepatic: Increased serum bilirubin (6%)

Immunologic: Antibody development (4%)

Neuromuscular & skeletal: Weakness (>1%)

Renal: Acute renal failure (>1%)

Respiratory: Pneumonitis (immune-mediated: 1%)

Frequency not defined:

Cardiovascular: Pericardial effusion

Neuromuscular & skeletal: Increased creatine phosphokinase

<1% (Limited to important of life-threatening): Adrenocortical insufficiency (immune-mediated), arthritis (immune-mediated), erythema multiforme (immune-mediated), exfoliative dermatitis (immune-mediated), Guillain-Barré syndrome (immune-mediated), hepatitis (immune-mediated), hyperthyroidism (immune-mediated), myocarditis (immune-mediated), myositis (immune-mediated), nephritis (immune-mediated), pemphigoid (immune-mediated), pituitary insufficiency (immune-mediated), psoriasis (immune-mediated), sepsis (systemic inflammatory response; immune-mediated), thyroiditis (immune-mediated), type 1 diabetes mellitus (immune-mediated), uveitis (immune-mediated)

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Adrenal insufficiency may occur. The median time to onset was 2.5 months (range: 1 day to 8 months). In clinical studies, all patients received corticosteroid therapy for adrenal insufficiency; in patients who received high-dose corticosteroids, the median duration of high-dose systemic corticosteroid therapy was 1 day (range: 1 day to 24 days). Monitor for signs/symptoms of adrenal insufficiency both during and after treatment. Administer corticosteroids as appropriate. Withhold avelumab for severe (grade 3) or life-threatening (grade 4) toxicity.

• Diabetes mellitus: Type 1 diabetes mellitus has occurred (including diabetic ketoacidosis). Monitor closely for hyperglycemia and other signs/symptoms of diabetes. Insulin or other anti-hyperglycemic therapy may be required; if severe hyperglycemia is observed, administer antihyperglycemics or insulin and withhold avelumab treatment until glucose control has been accomplished.

• Gastrointestinal toxicity: Immune-mediated colitis has occurred. The median time to onset of colitis was 2.1 months (range: 2 days to 11 months) and the median duration was 6 weeks (range: 1 day to over 14 months). In many patients, colitis was managed with high-dose systemic corticosteroids for a median duration of 19 days (range: 1 day to 2.3 months), followed by a corticosteroid taper. More than two-thirds of patients with colitis experienced resolution. May require treatment interruption, systemic corticosteroid therapy, and/or permanent discontinuation. Monitor for signs and symptoms of colitis; administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent] followed by a taper) for grade 2 or higher colitis.

• Hepatotoxicity: Immune-mediated hepatitis has occurred, including fatal cases. The median onset for hepatitis was 3.2 months (range: 7 days to 15 months); the median duration was 2.5 months (range: 1 day to over 7 months). Hepatitis resolved in approximately half of the patients. Administer corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent] followed by a taper for grade 2 or higher hepatitis), and withhold or discontinue therapy based on the severity of liver enzyme elevations. Systemic corticosteroids were used to manage immune-mediated hepatitis; the median duration of high-dose corticosteroid therapy was 14 days (range: 1 day to 2.5 months). Monitor for liver function changes. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.

• Infusion-related reactions: Infusion-related reactions (including severe and life-threatening cases) have occurred. Prior to the initial four infusions, premedicate with an antihistamine and acetaminophen. Monitor for signs/symptoms of a reaction (eg, pyrexia, chills, wheezing, flushing, hypotension, dyspnea, back pain, abdominal pain, urticaria). Some infusion-related reactions occurred after completion of the infusion. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop infusion and permanently discontinue for severe (grade 3) or life-threatening (grade 4) infusion-related reactions.

• Nephrotoxicity: Immune-mediated nephritis has occurred. Grade 2 or higher nephritis should be managed with systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent], followed by a taper). Monitor serum creatinine at baseline and periodically during therapy. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.

• Pulmonary toxicity: Immune-mediated pneumonitis has been observed, including fatal cases. The median time to development was 2.5 months (range: 3 days to 11 months) and the median duration was 7 weeks (range: 4 days to over 4 months). Pneumonitis was managed with systemic corticosteroids; the median duration of initial corticosteroid therapy was 8 days (range: 1 day to 2.3 months) followed by a corticosteroid taper. Pneumonitis resolved in approximately half of the affected patients. May require treatment interruption, corticosteroid therapy (prednisone initial dose of 1 to 2 mg/kg /day [or equivalent] followed by a taper, for grade 2 or higher pneumonitis), and/or permanent discontinuation. Monitor for signs and symptoms of pneumonitis; if pneumonitis is suspected, evaluate with radiographic imaging; administer systemic corticosteroids for grade 2 or higher pneumonitis.

• Thyroid disorders: Immune-mediated hyperthyroidism, hypothyroidism, and thyroiditis have occurred; and may develop at any time during avelumab treatment. The median onset for immune-mediated thyroid disorders was 2.8 months (range: 2 weeks to 13 months). Monitor for changes in thyroid function (at baseline, periodically during treatment, and as clinically indicated) and for signs/symptoms of thyroid disorders. Administer medical management for hyperthyroidism as appropriate; may require treatment interruption and/or permanent discontinuation. Manage hypothyroidism with replacement therapy. Immune-mediated thyroid disorders may require treatment interruption.

• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been observed rarely with avelumab use and may affect any organ system (may be fatal), including myocarditis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response. May occur during treatment or following discontinuation. Other immune-mediated disorders have been observed with other similar medications (same class), including bullous dermatitis, Stevens Johnson syndrome/toxic epidermal necrolysis, pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis. If an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes; based on severity of reaction, withhold treatment and administer systemic corticosteroids and (if appropriate) hormone replacement therapy. Upon resolution to grade 0 or 1, initiate corticosteroid taper. When reaction remains at grade 1 or less during taper may reinitiate avelumab. Discontinue permanently for severe grade 3 immune-mediated adverse event that is recurrent or for life-threatening reactions.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Liver (AST, ALT, and total bilirubin), renal, and thyroid function tests (at baseline, periodically during treatment and as clinically indicated); blood glucose; signs/symptoms of colitis, thyroid disorders, pneumonitis, adrenal insufficiency, hepatitis, hyperglycemia, monitor for infusion reactions.

Pregnancy Considerations

Immunoglobulins are known to cross the placenta and fetal exposure to avelumab is expected. Based on the mechanism of action, avelumab may cause fetal harm. Immune-mediated fetal rejection causing increased abortion or stillbirth was observed in animal reproduction studies. Women of reproductive potential should use effective contraception during therapy and for at least 1 month after treatment is complete.

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