U.S. FDA APPROVED  DRUGS DURING 2017

 

Sr.No-  8

  

Name of the  Drug-         Bavencio

 

Active Ingredient-           Avelumab                                                                                                                                                                                                               Pharmacological Classification- 

 

                       To treat  Merkel cell carcinoma                    

                                                                                                                           

Date of Approval-          03-23-2017

 

 (Ref- FDA approved List 2017                                                                                                                                                                                                                        HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use 

BAVENCIO safely and effectively. 

See full prescribing information for BAVENCIO.

 

BAVENCIO® (avelumab) injection, for intravenous use

 Initial U.S. Approval: 2017

 

                                                                                                                                               INDICATIONS AND USAGE

 

BAVENCIO is a programmed death ligand-1 (PD-L1) blocking antibody 

indicated for the treatment of adults and pediatric patients 12 years 

and older with metastatic Merkel cell carcinoma (MCC)

 

 This indication is approved under accelerated approval.

Continued approval for this indication may be contingent upon 

verification and description of clinical benefit in confirmatory trials.

 

                           

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

 

ADVERSE REACTIONS

 

Most common adverse reactions (reported in . 20% of patients) were -

fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction,

 rash, decreased appetite, and peripheral edema. 

CONTRAINDICATIONS

None.

 

WARNINGS AND PRECAUTIONS-

Immune-mediated pneumonitis: 

Withhold for moderate pneumonitis; permanently discontinue

for severe, life-threatening or recurrent moderate pneumonitis. 

 

Immune-mediated hepatitis: 

Monitor for changes in liver function. Withhold for moderate hepatitis;

 permanently discontinue for severe or life-threatening hepatitis. 

 

Immune-mediated colitis:

 Withhold for moderate or severe colitis; permanently discontinue 

for life-threatening or recurrent severe colitis. 

 

Immune-mediated endocrinopathies: 

Withhold for severe or life-threatening endocrinopathies 

 

Immune-mediated nephritis and renal dysfunction: 

Withhold for moderate or severe nephritis and renal dysfunction; 

permanently discontinue for life-threatening nephritis or renal dysfunction. 

 

Infusion-related reactions:

Interrupt or slow the rate of infusion for mild or moderate

infusion-related reactions. 

Stop the infusion and permanently discontinue BAVENCIO 

for severe or life-threatening infusion-related reactions. 

 

Embryo-fetal toxicity:

 BAVENCIO can cause fetal harm. Advise of potential risk to a fetus

 and use of effective contraception.

 

 

 

INDICATIONS AND USAGE

 

BAVENCIO is a programmed death ligand-1 (PD-L1) blocking antibody 

indicated for the treatment of adults and pediatric patients 12 years 

and older with metastatic Merkel cell carcinoma (MCC)

 

 This indication is approved under accelerated approval.

Continued approval for this indication may be contingent upon 

verification and description of clinical benefit in confirmatory trials.

 

DOSAGE AND ADMINISTRATION

 

Administer 10 mg/kg as an intravenous infusion over 60 minutes 

every 2 weeks. 

 

Premedicate with acetaminophen and an antihistamine for the first

 4 infusions and subsequently as needed.

 

DOSAGE FORMS AND STRENGTHS

Injection:

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

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

 

Immune-Mediated Adverse Reactions

Inform patients of the risk of  immune-mediated adverse reactions requiring corticosteroids or hormone replacement therapy, including, but not limited to:

 

Pneumonitis: 

Advise patients to contact their healthcare provider immediately for new 

or worsening cough, chest pain, or shortness of breath .

 

Hepatitis:

Advise patients to contact their healthcare provider immediately for jaundice, 

severe nausea or vomiting, pain on the right side of abdomen, lethargy, 

or easy bruising or bleeding .

 

Colitis: 

Advise patients to contact their healthcare provider immediately

 for diarrhea or severe abdominal pain 

 

Endocrinopathies: 

Advise patients to contact their healthcare provider immediately for signs 

or symptoms of adrenal insufficiency, hypothyroidism, hyperthyroidism, 

and diabetes mellitus. 

 

Nephritis and Renal Dysfunction: 

Advise patients to contact their healthcare provider immediately 

for signs or symptoms of nephritis including decreased urine output, 

blood in urine, swelling in ankles, loss of appetite, and any other 

symptoms of renal dysfunction.

 

Infusion-related reactions-

Advise patients to contact their healthcare  provider immediately

for signs or symptoms of potential infusion-related  reactions .

 

Embryo-Fetal Toxicity

 Advise females of reproductive potential that BAVENCIO can cause fetal harm.

 Instruct females of reproductive potential to use highly effective contraception 

during and for at least one month after the last dose of BAVENCIO 

 

Lactation

 Advise nursing mothers not to breastfeed while taking BAVENCIO and for 

at least one month after the final dose.

 

Manufacturer: Marketed by: EMD Serono, Inc. EMD Serono, Inc. 

and Pfizer Inc., NY, NY 10017 Rockland, MA 02370

U.S.A.

US License No: 1773 BAVENCIO is a trademark of Merck KGaA, 

Darmstadt, Germany Product of Switzerland

Page

 CLINICAL PHARMACOLOGY

 

1. Mechanism of Action

 PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells

 and can contribute to the inhibition of the anti-tumor 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 anti-tumor immune responses. 

 

Avelumab has also been shown to induce antibody-dependent cell-mediated

 cytotoxicity (ADCC) in vitro. In syngeneic mouse tumor models, 

blocking PD-L1 activity resulted in decreased tumor growth.

 

2 Pharmacokinetics

The pharmacokinetics of avelumab was studied in 1629 patients who received 

doses ranging from 1 to 20 mg/kg every 2 weeks. The data showed that the

 exposure of avelumab increased dose-proportionally in the dose range 

of 10 to 20 mg/kg every 2 weeks.

 

 Steady-state concentrations of avelumab were reached after approximately

 4 to 6 weeks (2 to 3 cycles) of repeated dosing, and the systemic accumulation

 was approximately 1.25-fold.

 

Distribution 

The geometric mean volume of distribution at steady state

 for a subject receiving 10 mg/kg was 4.72 L.

 

Elimination 

The primary elimination mechanism of avelumab is proteolytic degradation.

 

 Based on population pharmacokinetic analyses in patients with solid tumors,

 the total systemic clearance was 0.59 L/day and the terminal half-life 

was 6.1 days in patients receiving 10 mg/kg. In a post hoc analysis,

 avelumab clearance was found to decrease over time in patients with MCC,

 with a mean maximal reduction (% coefficient of variation [CV%]) from

 baseline value of approximately 41.7% (40.0%).

 

Specific populations Body weight was positively correlated with total 

systemic clearance in population pharmacokinetic analyses. 

 

No clinically meaningful differences in pharmacokinetics were observed

 in the clearance of avelumab based on age; sex; race; PD-L1 status; 

tumor burden; mild [calculated creatinine clearance (CLcr) 60 to 

89 mL/min, n=623 as estimated by the Cockcroft-Gault formula],

 moderate [CLcr 30 to 59 mL/min, n=320] or severe [CLcr 15 to 29 ml/min,

 n=4] renal impairment; and mild [bilirubin less than or equal to ULN 

and AST greater than ULN or bilirubin between 1 and 1.5 times ULN, n=217

or moderate [bilirubin between 1.5 and 3 times ULN; n=4] hepatic impairment. 

 

There are limited data from patients with severe hepatic impairment

[bilirubin greater than 3 times ULN, n=1], and the effect of severe hepatic

 impairment on the pharmacokinetics of avelumab is unknown.

 

 USE IN SPECIFIC POPULATIONS

 

1. Pregnancy

Risk Summary Based on its mechanism of action, 

BAVENCIO can cause fetal harm when administered to a pregnant woman. 

There are no available data on the use of BAVENCIO 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, BAVENCIO 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.

 

2. Lactation

Risk Summary 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 BAVENCIO due to the potential for serious

 adverse reactions in breastfed infants.

 

3. Females and Males of Reproductive Potential

Contraception Based on its mechanism of action, BAVENCIO can cause 

fetal harm when administered to a pregnant woman 

 

 Advise females of reproductive potential to use effective contraception 

during treatment with BAVENCIO and for at least 1 month after the 

last dose of BAVENCIO.

 

4. Pediatric Use

The safety and effectiveness of BAVENCIO have been established in pediatric

 patients age 12 years and older. 

 

Use of BAVENCIO in this age group  is supported by evidence from adequate 

and well-controlled studies of BAVENCIO 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 , Safety and effectiveness of BAVENCIO have not been

 established in pediatric patients less than 12 years of age.

 

5. Geriatric Use

Of the 88 patients with metastatic MCC treated with BAVENCIO, 75% were 65 years

 or over. However, clinical studies of BAVENCIO 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.

 

 OVERDOSAGE

No information on BAVENCIO overdosage is available.