Avelumab

Name: Avelumab

Pregnancy

Pregnancy

Based on its mechanism of action, 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 this drug, advise the patient of the potential risk to a fetus

Contraception

  • Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose

Lactation

Unknown if distributed in human breast milk

Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose owing to the potential for serious adverse reactions in breastfed infants

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Pharmacology

Mechanism of Action

Anti-PD-L1 IgG1 monoclonal antibody

PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the antitumor immune response in the tumor microenvironment

Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen-presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production

Avelumab binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1; this interaction releases the inhibitory effects of PD-L1 on the immune response, resulting in the restoration of immune responses, including antitumor immune responses

Distribution

Vd: 4.72 L

Elimination

Half-life: 6.1 days

Primary elimination mechanism is proteolytic degradation

Total systemic clearance: 0.59 L/day

What is avelumab?

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.

What should I avoid while receiving avelumab?

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

Avelumab side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some side effects may occur during the injection. Tell your caregiver right away if you feel light-headed, itchy, feverish, chilled, or have stomach or back pain, trouble breathing, or flushing (warmth, redness, or tingly feeling).

Avelumab works by causing your immune system to attack tumor cells. Avelumab may cause your immune system to attack healthy organs and tissues in your body. This could lead to serious or life-threatening side effects on your lungs, liver, pancreas, kidneys, intestines, thyroid, or adrenal glands.

Call your doctor at once if you have:

  • sudden chest pain or discomfort, new or worsening cough, feeling short of breath;

  • severe stomach pain, diarrhea, bloody or tarry stools;

  • blistering or peeling skin rash;

  • pounding heartbeats or fluttering in your chest;

  • fever, flu-like symptoms;

  • joint pain, severe muscle pain or weakness;

  • vision changes;

  • liver problems--loss of appetite, upper stomach pain, tiredness, easy bruising or bleeding, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

  • kidney problems--little or no urination, red or pink urine, swelling in your feet or ankles; or

  • signs of a hormonal disorder--feeling light-headed or very tired, rapid heartbeats, mood or behavior changes, hoarse or deepened voice, increased hunger or thirst, increased urination, constipation, vomiting, hair loss, sweating, feeling cold, weight gain, or weight loss.

Common side effects may include:

  • nausea, diarrhea, loss of appetite;

  • feeling tired;

  • bone pain;

  • muscle pain;

  • rash; or

  • swelling in your hands or feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Cautions for Avelumab

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

Pregnancy

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

Lactation

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

Females And Males Of Reproductive Potential

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

Pediatric Use

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

Geriatric Use

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

Actions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about avelumab, please talk with the doctor, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about avelumab. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using avelumab.

Review Date: October 4, 2017

Contraindications

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

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.

Usual Pediatric Dose for Merkel Cell Carcinoma

12 years and older:
10 mg/kg IV over 60 minutes every 2 weeks

Duration of therapy: Until disease progression or unacceptable toxicity

Comments:
-Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions; premedication should be administered for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions.

Uses:
-For metastatic Merkel cell carcinoma (MCC)
-For the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) 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

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