Bavencio

If Bavencio is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention. 

Avelumab is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Avelumab is used to treat a type of skin cancer called Merkel cell carcinoma that has spread to other parts of the body. This medicine is for use in adults and children who are at least 12 years old.

Avelumab is also used to treat a certain type of cancer of the bladder or urinary tract that has spread or cannot be removed with surgery. Avelumab is given for this condition after other cancer medicines such as cisplatin or carboplatin have been tried without success.

Avelumab was approved by the US Food and Drug Administration (FDA) on an "accelerated" basis. In clinical studies, tumors responded to this medicine. However, further studies are needed.

Avelumab may also be used for purposes not listed in this medication guide.

Other drugs may interact with avelumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

General

Avelumab is available in the following dosage form(s) and strength(s):

Injection: 200 mg/10 mL (20 mg/mL) solution in single-dose vial.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

• Administer 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks.1

• Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed.1

Contraindications

None.1

Warnings/Precautions

Immune-mediated Pneumonitis

Avelumab can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis and evaluate patients with suspected pneumonitis with radiographic imaging. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper) for Grade 2 or greater pneumonitis. Withhold avelumab for moderate (Grade 2) pneumonitis, and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis.1

Pneumonitis occurred in 1.2% (21/1738) of patients receiving avelumab including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3 pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of avelumab in 0.3% (6/1738) of patients. Among the 21 patients with immune-mediated pneumonitis, the median time to onset was 2.5 months (range: 3 days to 11 months) and the median duration of pneumonitis was 7 weeks (range: 4 days to 4+ months). All 21 patients were treated with systemic corticosteroids; 17 (81%) of the 21 patients received high-dose corticosteroids for a median of 8 days (range: 1 day to 2.3 months). Resolution of pneumonitis occurred in 12 (57%) of the 21 patients at the time of data cut-off.1

Immune-mediated Hepatitis

Avelumab can cause immune-mediated hepatitis including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper) for Grade 2 or greater hepatitis. Withhold avelumab for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3), or life-threatening (Grade 4) immune-mediated hepatitis.1

Immune-mediated hepatitis occurred in 0.9% (16/1738) of patients receiving avelumab including two (0.1%) patients with Grade 5 and 11 (0.6 %) patients with Grade 3 immune-mediated hepatitis. Immune-mediated hepatitis led to permanent discontinuation of avelumab in 0.5% (9/1738) of patients. Among the 16 patients with immune-mediated hepatitis, the median time to onset was 3.2 months (range: 1 week to 15 months), and the median duration of hepatitis was 2.5 months (range: 1 day to 7.4+ months). All 16 patients were treated with corticosteroids; 15 (94%) of the 16 patients received high-dose corticosteroids for a median of 14 days (range: 1 day to 2.5 months). Resolution of hepatitis occurred in nine (56%) of the 16 patients at the time of data cut-off.1

Immune-mediated Colitis

Avelumab can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) for Grade 2 or greater colitis. Withhold avelumab for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue avelumab for life-threatening (Grade 4) or for recurrent (Grade 3) colitis upon re-initiation of avelumab.1

Immune-mediated colitis occurred in 1.5% (26/1738) of patients receiving avelumab including seven (0.4%) patients with Grade 3 colitis. Immune-mediated colitis led to permanent discontinuation of avelumab in 0.5% (9/1738) of patients. Among the 26 patients with immune-mediated colitis, the median time to onset was 2.1 months (range: 2 days to 11 months) and the median duration of colitis was 6 weeks (range: 1 day to 14+ months). All 26 patients were treated with corticosteroids; 15 (58%) of the 26 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months). Resolution of colitis occurred in 18 (70%) of the patients at the time of data cut-off.1

Immune-mediated Endocrinopathies

Avelumab can cause immune-mediated endocrinopathies.1

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment. Administer corticosteroids as appropriate for adrenal insufficiency. Withhold avelumab for severe (Grade 3) or life threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency occurred in 0.5% (8/1738) of patients receiving avelumab including one patient (0.1%) with Grade 3 adrenal insufficiency. Immune-mediated adrenal insufficiency led to permanent discontinuation of avelumab in 0.1% (2/1738) of patients. Among the 8 patients with immune-mediated adrenal insufficiency, the median time to onset was 2.5 months (range: 1 day to 8 months). All eight patients were treated with corticosteroids; four (50%) of the eight patients received high-dose corticosteroids for a median of 1 day (range: 1 day to 24 days).1

Avelumab can cause immune-mediated thyroid disorders. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone-replacement therapy. Initiate medical management for control of hyperthyroidism. Withhold avelumab for severe (Grade 3) or life threatening (Grade 4) thyroid disorders. Immune-mediated thyroid disorders occurred in 6% (98/1738) of patients receiving avelumab including 3 (0.2%) Grade 3 immune-mediated thyroid disorders. Immune-mediated thyroid disorders led to discontinuation of avelumab in 0.1% (2/1738) of patients. Hypothyroidism occurred in 90 (5%) patients, hyperthyroidism in seven (0.4%), and thyroiditis in four (0.2%) patients treated with avelumab. Among the 98 patients with immune-mediated thyroid disorders, the median time to onset was 2.8 months (range: 2 weeks to 13 months) and the median duration was not estimable (range: 6 days to more than 26 months). Immune-mediated thyroid disorders resolved in seven (7%) of the 98 patients.1

Avelumab can cause type 1 diabetes mellitus, including diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold avelumab and administer anti-hyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia. Resume treatment with avelumab when metabolic control is achieved on insulin replacement or anti-hyperglycemics. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients including two cases of Grade 3 hyperglycemia that led to permanent discontinuation of avelumab.1

Immune-mediated Nephritis and Renal Dysfunction

Avelumab can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) for Grade 2 or greater nephritis. Withhold avelumab for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to ≤ Grade 1. Permanently discontinue avelumab for life-threatening (Grade 4) nephritis.1

Immune-mediated nephritis occurred in 0.1% (1/1738) of patients receiving avelumab; avelumab was permanently discontinued in this patient.1

Other Immune-mediated Adverse Reactions

Avelumab can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. Most immune-mediated reactions initially manifest during avelumab treatment; however, immune-mediated adverse reactions can occur after discontinuation of avelumab.1

For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending upon the severity of the adverse reaction, withhold or permanently discontinue avelumab, administer high dose corticosteroids, and if appropriate, initiate hormone replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper. Resume avelumab when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue avelumab for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. 1

The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% of 1738 patients treated with avelumab for each of the following adverse reactions: immune-mediated myocarditis including fatal cases, immune-mediated myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response. The following clinically significant, immune-mediated adverse reactions have been reported with other products in this class: bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis.1

Infusion-related Reactions

Avelumab can cause severe or life-threatening infusion-related reactions. Premedicate with antihistamine and acetaminophen prior to the first 4 infusions. Monitor patients for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue avelumab for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions.1

Infusion-related reactions occurred in 25% (439/1738) of patients treated with avelumab including three (0.2%) Grade 4 and nine (0.5%) Grade 3 infusion-related reactions. Ninety-three percent (1615/1738) of patients received premedication with antihistamine and acetaminophen. Eleven (92%) of the 12 patients with Grade ≥ 3 reactions were treated with intravenous corticosteroids.1

Embryo-fetal Toxicity

Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking avelumab, inform the patient of the potential risk to a 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.1

Specific Populations

Based on its mechanism of action, avelumab can cause fetal harm when administered to a pregnant woman. There are no available data on the use of avelumab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Human IgG1 immunoglobulins (IgG1) are known to cross the placenta. Therefore, avelumab has the potential to be transmitted from the mother to the developing fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal reproduction studies have not been conducted with avelumab to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering avelumab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to avelumab may increase the risk of developing immune-related disorders or altering the normal immune response.1

There is no information regarding the presence of avelumab in human milk, the effects on the breastfed infant, or the effects on milk production. Since many drugs including antibodies are excreted in human milk, advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of avelumab due to the potential for serious adverse reactions in breastfed infants.1

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

The safety and effectiveness of avelumab have been established in pediatric patients age 12 years and older. Use of avelumab in this age group is supported by evidence from adequate and well-controlled studies of avelumab in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady state exposure of avelumab, that drug exposure is generally similar between adults and pediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients. The recommended dose in pediatric patients 12 years of age or greater is the same as that in adults.1

Safety and effectiveness of avelumab have not been established in pediatric patients less than 12 years of age.1

Of the 88 patients with metastatic MCC treated with avelumab, 75% were 65 years or over. However, clinical studies of avelumab in metastatic MCC had fewer than 100 patients aged 65 and over, therefore, a determination cannot be made as to whether geriatric patients respond differently than younger patients.1

Common Adverse Effects

Most common adverse reactions (reported in ≥ 20% of patients) were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.1

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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak.
• Muscle or joint pain.
• Bone pain.
• Loose stools (diarrhea).
• Hard stools (constipation).
• Upset stomach or throwing up.
• Belly pain.
• Not hungry.
• Weight loss.
• Headache.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Premedication

Premedicate patients with an antihistamine and with acetaminophen prior to the first 4 infusions of Bavencio. Premedication should be administered for subsequent Bavencio doses based upon clinical judgment and presence/severity of prior infusion reactions [see Dosage and Administration (2.3) and Warnings and Precautions (5.7)].

Recommended Dosage

The recommended dose of Bavencio is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Dose Modifications

Recommended dose modifications of Bavencio for adverse reactions are provided in Table 1. Detailed information regarding clinical and laboratory monitoring guidelines for early detection of adverse reactions of Bavencio and recommended management (immunosuppressant treatment guidelines) are described in Warnings and Precautions (5).

Preparation and Administration

Preparation

• Visually inspect vial for particulate matter and discoloration. Bavencio is a clear, colorless to slightly yellow solution. Discard vial if the solution is cloudy, discolored, or contains particulate matter.
• Withdraw the required volume of Bavencio from the vial(s) and inject it into a 250 mL infusion bag containing either 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection.
• Gently invert the bag to mix the diluted solution and avoid foaming or excessive shearing.
• Inspect the solution to ensure it is clear, colorless, and free of visible particles.
• Discard any partially used or empty vials.

Storage of diluted Bavencio solution

Protect from light.

Store diluted Bavencio solution:

• At room temperature up to 77°F (25°C) for no more than 4 hours from the time of dilution.

Or

• Under refrigeration at 36°F to 46°F (2°C to 8°C) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Do not freeze or shake diluted solution.

Administration

• Administer the diluted solution over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micron).
• Do not co-administer other drugs through the same intravenous line.

None.

No information on Bavencio overdosage is available.

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Other drugs may interact with avelumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Applies to avelumab: intravenous solution

Cardiovascular

Very common (10% or more): Hypotension (25%), hypertension (13%)
Uncommon (0.1% to 1%): Myocarditis[Ref]

Dermatologic

Very common (10% or more): Urticaria (25%), rash (e.g., maculopapular, erythema, dermatitis bullous) (22%), pruritus (10%)
Uncommon (0.1% to 1%): Psoriasis, arthritis, exfoliative dermatitis, pemphigoid, Stevens Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), histiocytic necrotizing lymphadenitis, vasculitis, hypophysitis[Ref]

Endocrine

Common (1% to 10%): Immune-mediated thyroid disorders (hypothyroidism/hyperthyroidism)
Uncommon (0.1% to 1%): Adrenal insufficiency, hypopituitarism, hypophysitis[Ref]

Gastrointestinal

Very common (10% or more): Abdominal pain (25%), diarrhea (23%), nausea (22%), constipation (17%)
Common (1% to 10%): Immune-mediated colitis
Uncommon (0.1% to 1%): Pancreatitis[Ref]

Hematologic

Very common (10% or more): Lymphopenia (49%), anemia (35%), thrombocytopenia (27%)
Common (1% to 10%): Neutropenia
Rare (0.01% to 0.1%): Hemolytic anemia[Ref]

Hepatic

Very common (10% or more): Increased aspartate aminotransferase (AST) (34%), increased alanine aminotransferase (ALT) (20%)
Common (1% to 10%): Increased bilirubin
Uncommon (0.1% to 1%): Immune-mediated hepatitis[Ref]

Immunologic

Common (1% to 10%): Immunogenicity[Ref]

Local

Very common (10% or more): Anorexia (20%), weight loss (15%), increased lipase (14%)
Common (1% to 10%): Increased amylase[Ref]

Metabolic

Very common (10% or more): Anorexia (20%), weight loss (15%), increased lipase (14%)
Common (1% to 10%): Increased amylase[Ref]

Musculoskeletal

Very common (10% or more): Musculoskeletal pain (32%), back pain (25%), arthralgia (16%)
Common (1% to 10%):
Uncommon (0.1% to 1%): Myositis, rhabdomyolysis, myasthenia gravis[Ref]

Nervous system

Very common (10% or more): Dizziness (14%), headache (10%)
Uncommon (0.1% to 1%): Guillain-Barre syndrome, demyelination, encephalitis[Ref]

Respiratory

Very common (10% or more): Couth (18%), dyspnea (11%)
Common (1% to 10%): Immune-mediated pneumonitis, wheezing[Ref]

Renal

Rare (less than 0.1%): Immune-mediated nephritis[Ref]

Other

Very common (10% or more): Fatigue (50%), pyrexia (25%), chills (25%), flushing (25%), peripheral edema (20%)[Ref]

Ocular

Uncommon (0.1% to 1%): Uveitis, iritis[Ref]

Some side effects of Bavencio may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.