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Bavencio

Generic Name: Avelumab
Class: Antineoplastic Agents
Chemical Name: Immunoglobulin G1-λ1, anti-[Homo sapiens CD274 (programmed death ligand 1, PDL1, PD-L1, B7 homolog 1, B7H1)], Homo sapiens monoclonal antibody
Molecular Formula: C6374H9898N1694O2010S44
CAS Number: 1537032-82-8

Medically reviewed on Feb 5, 2018

Introduction

Antineoplastic agent; fully human anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody.1 3

Uses for Bavencio

Merkel Cell Carcinoma

Treatment of metastatic Merkel cell carcinoma1 3 (designated an orphan drug by FDA for this use).12

Accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Urothelial Carcinoma

Treatment of locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-containing therapy or within 12 months of platinum-containing therapy in the neoadjuvant or adjuvant setting.1 11

Accelerated approval based on objective response rate and duration of response.1 Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.1

Bavencio Dosage and Administration

General

  • Premedicate with an antihistamine and acetaminophen prior to initial 4 infusions of avelumab.1 Premedicate prior to subsequent infusions as clinically indicated based on occurrence and severity of previous infusion reactions.1

  • In JAVELIN Solid Tumor study, diphenhydramine hydrochloride 25–50 mg and IV acetaminophen 500–650 mg (or oral equivalent) were administered 30–60 minutes prior to each infusion of avelumab.5 11

Restricted Distribution Program

  • Obtain avelumab through a limited network of specialty distributors.4

  • Consult Bavencio website for specific availability information ([Web]).4

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Avelumab injection concentrate must be diluted prior to administration.1

Do not infuse simultaneously through the same IV line with other drugs.1

Administer using a sterile, nonpyrogenic, low-protein-binding 0.2-μm inline filter.1

Dilution

Undiluted solution should be clear and colorless to pale yellow.1 Do not use if it is cloudy or discolored or contains a precipitate.1

Withdraw appropriate dose (10 mg/kg) of avelumab injection concentrate (containing 20 mg/mL) and dilute in infusion bag containing 250 mL of 0.45 or 0.9% sodium chloride injection.1 Mix the diluted solution by gentle inversion; do not shake.1 Discard any partially used vial.1

Rate of Administration

Administer by IV infusion over 60 minutes.1

Dosage

Pediatric Patients

Merkel Cell Carcinoma
IV

Adolescents ≥12 years of age: 10 mg/kg every 2 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Therapy Interruption for Toxicity
IV

Follow recommendations for therapy interruption in adults.1

Adults

Merkel Cell Carcinoma
IV

10 mg/kg every 2 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Urothelial Carcinoma
IV

10 mg/kg every 2 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Therapy Interruption for Toxicity
Immune-mediated Pneumonitis
IV

If grade 2 immune-mediated pneumonitis occurs, interrupt avelumab therapy.1 Once pneumonitis resolves to grade 0 or 1 and corticosteroid taper is completed, may resume therapy.1 If pneumonitis recurs, permanently discontinue drug.1 (See Immune-mediated Pneumonitis under Cautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs, permanently discontinue drug.1

Immune-mediated Hepatic Effects
IV

For serum ALT or AST elevations >3 times but ≤5 times the ULN or total bilirubin concentrations >1.5 times but ≤3 times the ULN, interrupt avelumab therapy.1 Once toxicity resolves to grade 0 or 1 and corticosteroid taper is completed, may resume therapy.1 (See Immune-mediated Hepatic Effects under Cautions.)

For serum ALT or AST elevations >5 times the ULN or total bilirubin concentrations >3 times the ULN, permanently discontinue drug.1

Immune-mediated GI Effects
IV

If grade 2 or 3 immune-mediated colitis or diarrhea occurs, interrupt avelumab therapy.1 Once colitis or diarrhea resolves to grade 0 or 1 and corticosteroid taper is completed, may resume therapy.1 If colitis or diarrhea recurs, permanently discontinue drug.1 (See Immune-mediated GI Effects under Cautions.)

If grade 4 immune-mediated colitis or diarrhea occurs, permanently discontinue drug.1

Immune-mediated Endocrine Effects
IV

If grade 3 or 4 immune-mediated endocrinopathies (e.g., hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes mellitus) occur, interrupt avelumab therapy.1 Once toxicity resolves to grade 0 or 1 and corticosteroid taper is completed, may resume therapy.1 (See Immune-mediated Endocrine Effects under Cautions.)

Immune-mediated Renal Effects
IV

For Scr concentrations >1.5 times but ≤6 times the ULN, interrupt avelumab therapy.1 Once toxicity resolves to grade 0 or 1 and corticosteroid taper is completed, may resume therapy.1 (See Immune-mediated Renal Effects under Cautions.)

For Scr concentrations >6 times the ULN, permanently discontinue drug.1

Other Immune-mediated Adverse Effects
IV

If any other immune-mediated adverse effects with moderate or severe signs or symptoms occur, interrupt avelumab therapy and exclude other causes.1 Once toxicity resolves to grade 0 or 1 and corticosteroid taper is completed, may resume therapy.1 (See Other Immune-mediated Effects under Cautions.)

If grade 2 or 3 immune-mediated adverse effects last ≥12 weeks or corticosteroid dosage cannot be tapered to <10 mg of prednisone daily (or equivalent) within 12 weeks, permanently discontinue drug.1

For life-threatening immune-mediated adverse effects (except for endocrinopathies) or for recurrent severe immune-mediated adverse effects, permanently discontinue drug.1

Infusion-related Reactions
IV

If grade 1 or 2 infusion-related reactions occur, interrupt infusion or reduce infusion rate.1 (See Infusion-related Effects under Cautions.)

If grade 3 or 4 infusion-related reactions occur, permanently discontinue drug.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Bavencio

Contraindications

  • No known contraindications.1

Warnings/Precautions

Immune-mediated Pneumonitis

Immune-mediated pneumonitis, sometimes fatal, reported.1

Monitor patients for manifestations of pneumonitis.1 If pneumonitis is suspected, evaluate with radiographic imaging.1

If immune-mediated pneumonitis occurs, temporarily withhold or discontinue avelumab.1 (See Immune-mediated Pneumonitis under Dosage and Administration.) If grade 2 or greater pneumonitis occurs, initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.1

Immune-mediated Hepatic Effects

Immune-mediated hepatitis, sometimes fatal, reported.1

Monitor patients for manifestations of hepatitis.1 Evaluate liver function tests (i.e., ALT, AST, total bilirubin) prior to initiation of and periodically during therapy.1

If immune-mediated hepatitis occurs, temporarily withhold or discontinue avelumab.1 (See Immune-mediated Hepatic Effects under Dosage and Administration.) If grade 2 or greater hepatitis occurs, initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.1

Immune-mediated GI Effects

Immune-mediated colitis reported.1

Monitor patients for manifestations of colitis.1

If immune-mediated colitis occurs, temporarily withhold or discontinue avelumab.1 (See Immune-mediated GI Effects under Dosage and Administration.) If grade 2 or greater colitis occurs, initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.1

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies, such as thyroid dysfunction (i.e., hypothyroidism, hyperthyroidism), adrenal insufficiency, and diabetes mellitus (including ketoacidosis), reported.1

Adrenal Insufficiency

Monitor for manifestations of adrenal insufficiency.1

If grade 3 or 4 immune-mediated adrenal insufficiency occurs, temporarily withhold avelumab.1 (See Immune-mediated Endocrine Effects under Dosage and Administration.) Initiate systemic corticosteroid therapy as clinically indicated.1

Thyroid Dysfunction

Monitor for manifestations of thyroid dysfunction.1 Evaluate thyroid function prior to initiation of and periodically during therapy, then as clinically indicated.1

If grade 3 or 4 immune-mediated thyroid dysfunction occurs, temporarily withhold avelumab.1 (See Immune-mediated Endocrine Effects under Dosage and Administration.)

If immune-mediated hypothyroidism occurs, initiate thyroid hormone replacement therapy.1

If immune-mediated hyperthyroidism occurs, initiate appropriate medical therapy as clinically indicated.1

Diabetes Mellitus

Monitor for manifestations of type 1 diabetes mellitus.1 If grade 3 or greater type 1 diabetes mellitus occurs, temporarily withhold avelumab and initiate antidiabetic therapy (i.e., insulin).1 Once blood glucose concentrations have stabilized on antidiabetic therapy, resume avelumab.1

Immune-mediated Renal Effects

Immune-mediated nephritis reported.1

Monitor patients for manifestations of nephritis.1 Evaluate Scr concentrations prior to initiation of and periodically during therapy.1

If immune-mediated nephritis occurs, temporarily withhold or discontinue avelumab.1 (See Immune-mediated Renal Effects under Dosage and Administration.) If grade 2 or greater nephritis occurs, initiate systemic corticosteroid therapy (1–2 mg/kg of prednisone daily [or equivalent]) followed by tapering of the corticosteroid dosage.1

Other Immune-mediated Effects

Other immune-mediated adverse effects (i.e., myocarditis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, systemic inflammatory responses), sometimes severe or fatal, reported with avelumab.1

Additional immune-mediated adverse effects (e.g., bullous dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, encephalitis) reported with other anti-programmed-death 1 (anti-PD-1) and anti-PD-L1 antibodies.1

If immune-mediated adverse effect suspected, temporarily withhold or discontinue avelumab.1 Depending on severity, initiate high-dose corticosteroid therapy followed by tapering of the corticosteroid dosage; if indicated, initiate hormone replacement therapy.1 (See Other Immune-mediated Effects under Dosage and Administration.)

Infusion-related Effects

Infusion-related reactions, sometimes severe or life-threatening, reported.1

Premedicate with acetaminophen and an antihistamine prior to initial 4 avelumab infusions.1 (See General under Dosage and Administration.)

Monitor patients for manifestations of infusion-related reactions.1 If infusion-related reactions occur, interrupt infusion, reduce infusion rate, or permanently discontinue avelumab.1 (See Infusion-related Reactions under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 May disrupt maternal immune tolerance to the fetus and increase risk of fetal loss (abortion, stillbirth); also may increase risk of immune-mediated disorders.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use an effective contraceptive method while receiving avelumab and for ≥1 month after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Immunogenicity

Potential for immunogenicity.1 Development of binding antibodies to avelumab reported.1 3 5 Effects on safety (including infusion-related reactions) or pharmacokinetics of the drug not observed.1 2

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether avelumab is distributed into milk.1 Discontinue nursing during therapy and for ≥1 month after drug discontinuance.1

Pediatric Use

Safety and efficacy not established in pediatric patients <12 years of age.1

Because of similarity in clinical course and treatment of Merkel cell carcinoma in adults and pediatric patients, safety and efficacy of avelumab for treatment of metastatic Merkel cell carcinoma in adolescents ≥12 years of age are supported by extrapolation of data from clinical studies of the drug in adults, population pharmacokinetic analyses indicating that age (range of 20–91 years)2 and body weight (range of 30–90 kg)2 do not affect exposure to avelumab, and evidence that exposure to monoclonal antibodies generally is similar in adults and adolescents.1

Pain, nausea, and vomiting during and following avelumab therapy reported in a 10-year-old girl with metastatic Merkel cell carcinoma who received 3 doses of avelumab 10 mg/kg following prior therapy with cisplatin and etoposide; the child subsequently experienced disease progression.2

Geriatric Use

Insufficient experience in patients ≥65 years of age with Merkel cell carcinoma to determine whether they respond differently than younger adults.1

In JAVELIN Solid Tumor study, 68% of patients with locally advanced or metastatic urothelial carcinoma were ≥65 years of age and 29% were ≥75 years of age.1 Among 153 patients ≥65 years of age assessed for ≥13 weeks, 14% responded to avelumab and 58% experienced a grade 3 or 4 adverse effect; no overall differences in safety and efficacy compared with younger adults.1

Hepatic Impairment

Pharmacokinetics not affected by mild or moderate hepatic impairment.1 Limited data in patients with severe hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not affected by mild, moderate, or severe renal impairment.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Metastatic Merkel cell carcinoma: Fatigue,1 3 musculoskeletal pain,1 diarrhea,1 infusion-related reactions,1 3 nausea,1 rash,1 loss of appetite,1 peripheral edema,1 cough,1 constipation,1 abdominal pain,1 arthralgia,1 decreased weight,1 dizziness,1 hypertension,1 vomiting,1 dyspnea,1 headache,1 pruritus,1 lymphopenia,1 anemia,1 elevated ALT and AST concentrations,1 thrombocytopenia,1 elevated lipase concentrations.1

Locally advanced or metastatic urothelial carcinoma: Fatigue,1 infusion-related reactions,1 musculoskeletal pain,1 nausea,1 loss of appetite,1 urinary tract infection,1 abdominal pain,1 decreased weight,1 constipation,1 diarrhea,1 dyspnea (including dyspnea on exertion),1 peripheral edema,1 elevated Scr concentrations/renal failure,1 pyrexia,1 rash,1 cough,1 vomiting/retching,1 hypertension (including hypertensive crisis),1 pruritus,1 hyponatremia,1 elevated γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations,1 lymphopenia,1 hyperglycemia,1 elevated alkaline phosphatase concentrations,1 anemia,1 elevated lipase concentrations.1

Interactions for Bavencio

No formal drug interaction studies to date.1

Bavencio Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations achieved within 4–6 weeks when administered every 2 weeks.1

Systemic exposure is dose proportional over the dosage range of 3–20 mg/kg every 2 weeks;1 5 systemic accumulation is approximately 1.3-fold when administered every 2 weeks.1

Peak plasma concentrations achieved within 1 hour following completion of 1-hour IV infusion.5

Distribution

Extent

Not known whether avelumab is distributed into milk.1

Elimination

Metabolism

Proteolytic degradation.1

Half-life

6.1 days.1

Special Populations

Mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration between 1–1.5 times the ULN) or moderate (total bilirubin concentration between 1.5–3 times the ULN) hepatic impairment does not affect pharmacokinetics.1 Limited data available for severe hepatic impairment (total bilirubin concentration >3 times the ULN).1

Mild, moderate, or severe renal impairment (Clcr 15–89 mL/minute) does not affect pharmacokinetics.1

Age (range of 20–91 years), gender, race, PD-L1 status, and tumor burden do not have meaningful effects on pharmacokinetics of avelumab.1 2

Stability

Storage

Parenteral

Injection

2–8°C.1 Do not freeze; protect from light.1

Diluted solution: Room temperature for ≤4 hours or 2–8°C for ≤24 hours.1 Do not freeze; protect from light.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1

Compatible

Sodium chloride 0.45 or 0.9%

Actions

  • An IgG1 lambda immunoglobulin that is selective for PD-L1.1 3

  • Overexpression of PD-1 ligands on surface of tumor cells results in activation of PD-1 and B7.1 and suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production.1 8 9 10

  • Blocks interaction between PD-L1 and the receptors PD-1 and B7.1, resulting in restoration of immune responses (i.e., activation of antitumor immune response).1

  • In vitro, induces antibody-dependent cell-mediated cytotoxicity (ADCC).1

  • Reduces tumor growth in syngeneic mouse tumor models.1

Advice to Patients

  • Importance of reading the manufacturer's medication guide.1

  • Risk of immune-mediated pneumonitis.1 Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.1

  • Risk of immune-mediated hepatitis.1 Importance of informing clinician immediately if signs and symptoms of liver damage (e.g., jaundice, severe nausea or vomiting, abdominal pain [particularly in the right upper quadrant], lethargy, easy bruising or bleeding) occur.1

  • Risk of immune-mediated colitis.1 Importance of informing clinician immediately if diarrhea or severe abdominal pain occurs.1

  • Risk of immune-mediated endocrinopathies.1 Importance of informing clinician immediately if signs and symptoms of adrenal insufficiency, hypothyroidism, hyperthyroidism, or diabetes mellitus occur.1

  • Risk of immune-mediated nephritis or renal dysfunction.1 Importance of informing clinician immediately if signs and symptoms of nephritis (e.g., decreased urine output, hematuria, peripheral edema, lack of appetite) occur.1

  • Risk of infusion-related reactions.1 Importance of informing clinician if signs and symptoms of such reactions, including chills, fever, breathing difficulty (i.e., shortness of breath, wheezing), urticaria, flushing, hypotension, and back or abdominal pain, occur.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential that they should use a highly effective method of contraception while receiving the drug and for ≥1 month after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of advising women to avoid breast-feeding while receiving the drug and for ≥1 month after discontinuance of therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of avelumab is restricted.4 (See Restricted Distribution Program under Dosage and Administration.)

Avelumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection concentrate, for IV infusion only

20 mg/mL (200 mg)

Bavencio

EMD Serono, (comarketed with Pfizer)

AHFS DI Essentials. © Copyright 2018, Selected Revisions February 5, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. EMD Serono, Inc. Bavencio (avelumab) injection for intravenous infusion prescribing information. Rockland, MA; 2017 Jun.

2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761049Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf

3. Kaufman HL, Russell J, Hamid O et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016; 17:1374-1385. http://www.ncbi.nlm.nih.gov/pubmed/27592805?dopt=AbstractPlus

4. EMD Serono, Inc. and Pfizer, Inc. Bavencio Product information sheet. From EMD Serono, Inc. and Pfizer, Inc. for Healthcare Professionals website. Accessed 2017 Jun 23. https://www.bavencio.com/en_US/document/Bavencio%20Product%20Info%20Sheet.pdf

5. Heery CR, O'Sullivan-Coyne G, Madan RA et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017; 18:587-598. http://www.ncbi.nlm.nih.gov/pubmed/28373007?dopt=AbstractPlus

6. Robert C, Ribas A, Wolchok JD et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384:1109-17. http://www.ncbi.nlm.nih.gov/pubmed/25034862?dopt=AbstractPlus

7. Hamid O, Robert C, Daud A et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013; 369:134-44. http://www.ncbi.nlm.nih.gov/pubmed/23724846?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4126516&blobtype=pdf

8. Poole RM. Pembrolizumab: first global approval. Drugs. 2014; 74:1973-81. http://www.ncbi.nlm.nih.gov/pubmed/25331768?dopt=AbstractPlus

9. Gentzler R, Hall R, Kunk PR et al. Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors. Immunotherapy. 2016; 8:583-600. http://www.ncbi.nlm.nih.gov/pubmed/27140411?dopt=AbstractPlus

10. Markham A. Atezolizumab: First Global Approval. Drugs. 2016; 76:1227-32. http://www.ncbi.nlm.nih.gov/pubmed/27412122?dopt=AbstractPlus

11. Apolo AB, Infante JR, Balmanoukian A et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol. 2017; :JCO2016716795. http://www.ncbi.nlm.nih.gov/pubmed/28375787?dopt=AbstractPlus

12. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2017 Jun 23. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

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