U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  31

ADVERSE REACTIONS

• The most common adverse reactions (=20%) are keratopathy (corneal epithelium change on eye exam), decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue. 

• The most common grade 3 or 4 laboratory abnormalities (=5%) are platelets decreased, lymphocytes decreased, hemoglobin decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase increased. 

 CONTRAINDICATIONS-                                                                                                  ­ None.

 WARNINGS AND PRECAUTIONS

­ • Thrombocytopenia:                                                                                                    Perform complete blood counts at baseline and during treatment as clinically indicated. Consider withholding and/or reducing the dose based on severity. 

• Infusion-Related Reactions:                                                                             Monitor patients for infusion-related reactions. Interrupt and then reduce the rate or permanently discontinue based on the severity. 

• Embryo-Fetal Toxicity:                                                                                            Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. 

 PATIENT COUNSELING INFORMATION

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

Ocular Toxicity                                                                                                               • Advise patients that ocular toxicity may occur during treatment with BLENREP 

• Advise patients to administer preservative-free lubricant eye drops as recommended during treatment and to avoid wearing contact lenses during treatment unless directed by a healthcare professional.

• Advise patients to use caution when driving or operating machinery as BLENREP may adversely affect their vision.BLENREP REMS BLENREP is available only through a restricted program called BLENREP REMS 

Inform the patient of the following notable requirements:                                                      • Patients must complete the enrollment form with their provider.                                      • Patients must comply with ongoing monitoring for eye exams 

Thrombocytopenia                                                                                                        • Advise patients to inform their healthcare provider if they develop signs or symptoms of bleeding 

Infusion-Related Reactions                                                                                           • Advise patients to immediately report any signs and symptoms of infusion-related reactions to their healthcare provider 

Embryo-Fetal Toxicity                                                                                                    • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy 

• Advise women of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose.

• Advise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for 6 months after the last dose.

Lactation                                                                                                                        • Advise women not to breastfeed during treatment with BLENREP and for 3 months after the last dose.

Infertility                                                                                                                          • Advise males and females of reproductive potential that BLENREP may impair fertility 

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 CLINICAL PHARMACOLOGY

1. Mechanism of Action -                                                                                           Belantamab mafodotin-blmf is an antibody-drug conjugate (ADC).

The antibody component is an afucosylated IgG1 directed against BCMA, a protein expressed on normal B lymphocytes and multiple myeloma cells.

The small molecule component is MMAF, a microtubule inhibitor. Upon binding to BCMA, belantamab mafodotin-blmf is internalized followed by release of MMAF via proteolytic cleavage. The released MMAF intracellularly disrupts the microtubule network, leading to cell cycle arrest and apoptosis.

Belantamab mafodotin-blmf had antitumor activity in multiple myeloma cells and mediated killing of tumor cells through MMAF-induced apoptosis, as well as by tumor cell lysis through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

2. Pharmacodynamics Exposure-                                                                   Response Relationships Higher belantamab mafodotin-blmf exposure was associated with higher incidence of some adverse reactions (e.g., Grade =2 corneal toxicity).

No exposure-response relationship for efficacy was observed at doses of 2.5 mg/kg or 3.4 mg/kg (1.4 times the recommended dose) after accounting for the effect of baseline disease-related characteristics, such as soluble BCMA, IgG, and ß2-microglobulin.

Cardiac Electrophysiology-                                                                                 Belantamab mafodotin-blmf had no large QTc prolongation (>10 ms) at the recommended dosage of 2.5 mg/kg once every 3 weeks.

3. Pharmacokinetics-                                                                                      Belantamab mafodotin-blmf exhibited dose-proportional pharmacokinetics, with a gradual decrease in clearance over time; the time to reach steady state was ~70 days.

After a planned infusion duration of 0.5 hours, maximum belantamab mafodotin-blmf plasma concentrations occurred at or shortly after the end of the infusion. Accumulation of belantamab mafodotin-blmf was ~70% with a dosing regimen of every 3 weeks. 

Distribution                                                                                                                   The mean steady-state volume of distribution of belantamab mafodotin-blmf was 11 L (15%).

Elimination-                                                                                                                Total plasma clearance (mean [CV%]) of belantamab mafodotin-blmf was approximately 22% lower at steady state (0.7 L/day [50%]) than after the first dose (0.9 L/day [42%]). The terminal phase half-life of belantamab mafodotin-blmf was 12 days after the first dose and 14 days at steady state.

Metabolism:                                                                                                               The monoclonal antibody portion of belantamab mafodotin-blmf is expected to be metabolized into small peptides and individual amino acids by catabolic pathways. In vitro, cysmcMMAF is mainly hydrolyzed and dehydrated to a cyclized isomeric form of cys-mcMMAF.

Specific Populations-                                                                                                 No clinically significant differences in the pharmacokinetics of belantamab mafodotin-blmf were observed based on age (34 to 89 years), sex, race (White vs. Black), body weight (42 to 130 kg), mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73m2 ), or mild hepatic impairment (total bilirubin =ULN and AST >ULN or total bilirubin 1 to =1.5 x ULN and any AST).

The effects of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2 ) or ESRD with eGFR <15 mL/min/1.73 m2 not on dialysis or requiring dialysis, or moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and any AST) on the pharmacokinetics of belantamab mafodotin-blmf are unknown.

Drug Interaction Studies-                                                                                             In Vitro Studies: Transporter Systems: Cys-mcMMAF is a substrate of organic anion transporting polypeptide (OATP)1B1 and OATP1B3, multidrug resistance-associated protein (MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and a possible substrate of Pglycoprotein (P-gp).

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                          Based on its mechanism of action, BLENREP can cause fetal harm when administered to a pregnant woman, because it contains a genotoxic compound (the microtubule inhibitor, MMAF) and it targets actively dividing cells 

Human immunoglobulin G (IgG) is known to cross the placenta; therefore, belantamab mafodotin-blmf has the potential to be transmitted from the mother to the developing fetus.

There are no available data on the use of BLENREP in pregnant women to evaluate for drugassociated risk. No animal reproduction studies were conducted with BLENREP. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcome.

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 data on the presence of belantamab mafodotin-blmf in human milk or the effects on the breastfed child or milk production.

Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with BLENREP and for 3 months after the last dose. 12 Reference ID: 4652412

3.Females and Males of Reproductive Potential-                                                     BLENREP can cause fetal harm when administered to pregnant women 

Pregnancy Testing-                                                                                                  Pregnancy testing is recommended for females of reproductive potential prior to initiating BLENREP.

Contraception -                                                                                                        Females:                                                                                                                Advise women of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Males:                                                                                                                       Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for 6 months after the last dose 

Infertility-                                                                                                                 Based on findings in animal studies, BLENREP may impair fertility in females and males. The effects were not reversible in male rats, but were reversible in female rats [see Nonclinical Toxicology (13.1)].

4 Pediatric Use -                                                                                                        The safety and effectiveness of BLENREP in pediatric patients have not been established.

5. Geriatric Use -                                                                                                             Of the 218 patients who received BLENREP in DREAMM-2, 43% were aged 65 to less than 75 years and 17% were aged 75 years and older.

Clinical studies of BLENREP did not include sufficient numbers of patients aged 65 and older to determine whether the effectiveness differs compared with that of younger patients.

Keratopathy occurred in 80% of patients aged less than 65 years and 73% of patients aged 65 years and older. Among the patients who received BLENREP at the 2.5-mg/kg dose in DREAMM-2 (n = 95), keratopathy occurred in 67% of patients aged less than 65 years and 73% of patients aged 65 years and older.

Clinical studies did not include sufficient numbers of patients 75 years and older to determine whether they respond differently compared with younger patients.

6. Renal Impairment-                                                                                                   No dose adjustment is recommended for patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min/1.73m2 as estimated by the Modification of Diet in Renal Disease [MDRD] equation) 

The recommended dosage has not been established in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2 ) or end-stage renal disease (ESRD) with eGFR <15 mL/min/1.73 m2 not on dialysis or requiring dialysis [see Clinical Pharmacology (12.3)].

7 Hepatic Impairment-                                                                                                 No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin =upper limit of normal [ULN] and aspartate aminotransferase (AST) >ULN or total bilirubin 1 to =1.5 × ULN and any AST).

The recommended dosage of BLENREP has not been established in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST)