ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:oOcular toxicity [see Warnings and Precautions (5.1)].oThrombocytopenia [see Warnings and Precautions (5.3)].oInfusion-related reactions [see Warnings and Precautions (5.4)].. oOcular toxicity [see Warnings and Precautions (5.1)].. oThrombocytopenia [see Warnings and Precautions (5.3)].. oInfusion-related reactions [see Warnings and Precautions (5.4)].. oThe 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. (6.1)oThe most common grade or laboratory abnormalities (>=5%) are platelets decreased, lymphocytes decreased, hemoglobin decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase increased. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oThe 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. (6.1). oThe most common grade or laboratory abnormalities (>=5%) are platelets decreased, lymphocytes decreased, hemoglobin decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase increased. (6.1). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in Warnings and Precautions reflects exposure to BLENREP at dosage of 2.5 mg/kg or 3.4 mg/kg (1.4 times the recommended dose) administered intravenously once every weeks in 218 patients in DREAMM-2. Of these patients, 194 received liquid formulation (not the approved dosage form) rather than the lyophilized powder. Among the 218 patients, 24% were exposed for months or longer.Relapsed or Refractory Multiple MyelomaThe safety of BLENREP as single agent was evaluated in DREAMM-2 [see Clinical Studies (14.1)]. Patients received BLENREP at the recommended dosage of 2.5 mg/kg administered intravenously once every weeks (n 95). Among these patients, 22% were exposed for months or longer.Serious adverse reactions occurred in 40% of patients who received BLENREP. Serious adverse reactions in >3% of patients included pneumonia (7%), pyrexia (6%), renal impairment (4.2%), sepsis (4.2%), hypercalcemia (4.2%), and infusion-related reactions (3.2%). Fatal adverse reactions occurred in 3.2% of patients, including sepsis (1%), cardiac arrest (1%), and lung infection (1%).Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received BLENREP; keratopathy (2.1%) was the most frequent adverse reaction resulting in permanent discontinuation.Dosage interruptions due to an adverse reaction occurred in 54% of patients who received BLENREP. Adverse reactions which required dosage interruption in >3% of patients included keratopathy (47%), blurred vision (5%), dry eye (3.2%), and pneumonia (3.2%).Dose reductions due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dose reduction in >3% of patients included keratopathy (23%) and thrombocytopenia (5%).The most common adverse reactions (>=20%) were keratopathy, decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue. The most common Grade or (>=5%) laboratory abnormalities were lymphocytes decreased, platelets decreased, hemoglobin decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase increased.Table summarizes the adverse reactions in DREAMM-2 for patients who received the recommended dosage of 2.5 mg/kg once every weeks.Table 3. Adverse Reactions (>=10%) in Patients Who Received BLENREP in DREAMM-2a Keratopathy was based on slit lamp eye examination, characterized as corneal epithelium changes with or without symptoms. Visual acuity changes were determined upon eye examination. Blurred vision included diplopia, vision blurred, visual acuity reduced, and visual impairment. Dry eyes included dry eye, ocular discomfort, and eye pruritus. Fatigue included fatigue and asthenia. Infusion-related reactions included infusion-related reaction, pyrexia, chills, diarrhea, nausea, asthenia, hypertension, lethargy, tachycardia. Upper respiratory tract infection included upper respiratory tract infection, nasopharyngitis, rhinovirus infections, and sinusitis.Adverse ReactionsBLENREPN 95All Grades(%)Grade 3-4(%)Eye disordersKeratopathya 7144Decreased visual acuityb 5328Blurred visionc 224Dry eyesd 141Gastrointestinal disordersNausea240Constipation130Diarrhea131General disorders and administration site conditionsPyrexia223Fatiguee 202Procedural complicationsInfusion-related reactionsf 213Musculoskeletal and connective tissue disordersArthralgia120Back pain112Metabolic and nutritional disordersDecreased appetite120InfectionsUpper respiratory tract infectiong 110Clinically relevant adverse reactions in <10% of patients included:Eye Disorders: Photophobia, eye irritation, infective keratitis, ulcerative keratitis.Gastrointestinal Disorders: Vomiting.Infections: Pneumonia.Investigations: Albuminuria.Table summarizes the laboratory abnormalities in DREAMM-2.Table 4. Laboratory Abnormalities (>=20%) Worsening from Baseline in Patients Who Received BLENREP in DREAMM-2Laboratory AbnormalityBLENREPN 95All Grades(%)Grades 3-4(%)HematologyPlatelets decreased6221Lymphocytes decreased4922Hemoglobin decreased3218Neutrophils decreased289ChemistryAspartate aminotransferase increased572Albumin decreased434Glucose increased383Creatinine increased285Alkaline phosphatase increased261Gamma-glutamyl transferase increased255Creatinine phosphokinase increased221Sodium decreased212Potassium decreased202. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.The immunogenicity of BLENREP was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-belantamab mafodotin antibodies. In clinical studies of BLENREP, 2/274 patients (<1%) tested positive for anti-belantamab mafodotin antibodies after treatment. One of the patients tested positive for neutralizing anti-belantamab mafodotin antibodies following weeks on therapy. Due to the limited number of patients with antibodies against belantamab mafodotin-blmf, no conclusions can be drawn concerning potential effect of immunogenicity on pharmacokinetics, efficacy, or safety.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Increased mitoses of corneal epithelial cells with bilateral single-cell necrosis were observed following intravenous administration of belantamab mafodotin-blmf in rats and rabbits.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. BLENREP (belantamab mafodotin-blmf) for injection is sterile, preservative-free, white to yellow lyophilized powder for reconstitution and further dilution prior to intravenous use.BLENREP is supplied in carton containing one 100-mg single-dose vial with rubber stopper (not made with natural rubber latex) and aluminum overseal with removable cap (NDC 0173-0896-01).Store vials refrigerated at 36oF to 46oF (2oC to 8oC).BLENREP is hazardous drug. Follow applicable special handling and disposal procedures.1.

BOXED WARNING SECTION.

WARNING: OCULAR TOXICITY BLENREP caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms, such as blurred vision and dry eyes [see Warnings and Precautions (5.1)].Conduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms. Withhold BLENREP until improvement and resume, or permanently discontinue, based on severity [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].Because of the risk of ocular toxicity, BLENREP is available only through restricted program under Risk Evaluation and Mitigation Strategy (REMS) called the BLENREP REMS [see Warnings and Precautions (5.2)].. WARNING: OCULAR TOXICITY See full prescribing information for complete boxed warning.oBLENREP caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms, such as blurred vision and dry eyes. (5.1)oConduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms. Withhold BLENREP until improvement and resume, or permanently discontinue, based on severity. (2.3, 5.1)oBLENREP is available only through restricted program, called the BLENREP REMS. (5.2). oBLENREP caused changes in the corneal epithelium resulting in changes in vision, including severe vision loss and corneal ulcer, and symptoms, such as blurred vision and dry eyes. (5.1). oConduct ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms. Withhold BLENREP until improvement and resume, or permanently discontinue, based on severity. (2.3, 5.1). oBLENREP is available only through restricted program, called the BLENREP REMS. (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with belantamab mafodotin-blmf.Belantamab mafodotin-blmf was genotoxic in an in vitro micronucleus assay in human lymphocytes through an aneugenic mechanism. These results are consistent with the pharmacological effect of MMAF binding to tubulin causing microtubule depolymerization resulting in spindle disorganization during cell division. Cys-mcMMAF was not mutagenic in the bacterial reverse mutation assay (Ames test), the L5178Y mouse lymphoma forward mutation assay, or the in vivo rat bone marrow micronucleus assay.Fertility studies have not been conducted with belantamab mafodotin-blmf. Results of repeat-dose toxicity studies with intravenous administration of belantamab mafodotin-blmf in rats indicate the potential for impaired male and female reproductive function and fertility. In rats, weekly dosing for weeks at doses >=10 mg/kg (approximately times the exposure at the maximum recommended human dose [MRHD] of 2.5 mg/kg based on the AUC of belantamab mafodotin-blmf) resulted in degeneration and atrophy of seminiferous tubules in the testes and luteinized nonovulatory follicles in the ovaries. Findings in females were reversible; findings in the testes were not reversible at the end of the 12-week recovery period with weekly dosing or when given every weeks for 13 weeks at doses >=10 mg/kg. In male monkeys, the highest dose tested of 10 mg/kg (approximately times the exposure at the MRHD based on AUC of belantamab mafodotin-blmf) given weekly for 13 weeks resulted in seminiferous tubules degeneration in the testes that was fully reversed following the 12-week recovery period.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Belantamab mafodotin-blmf is an antibody-drug conjugate (ADC). The antibody component is an afucosylated IgG1 directed against BCMA, protein expressed on normal lymphocytes and multiple myeloma cells. The small molecule component is MMAF, 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).. 12.2 Pharmacodynamics. Exposure-Response RelationshipsHigher 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 ElectrophysiologyBelantamab mafodotin-blmf had no large QTc prolongation (>10 ms) at the recommended dosage of 2.5 mg/kg once every weeks.. 12.3 Pharmacokinetics. Belantamab mafodotin-blmf exhibited dose-proportional pharmacokinetics, with gradual decrease in clearance over time; the time to reach steady state was ~70 days. After 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 dosing regimen of every weeks.The pharmacokinetics of belantamab mafodotin-blmf after dose of 2.5 mg/kg in Cycle are shown in Table 5.Table 5. Belantamab Mafodotin-blmf Pharmacokinetics at Cycle in Patients Who Received Dose of 2.5 mg/kgAUC Area under curve over the dosing interval; Cmax Maximum observed plasma concentration; tmax Time of Cmax; Ctrough Observed plasma concentration prior to next dose.Data presented as geometric mean (%CV), except tmax, which is presented as median (minimum, maximum).ParameterBelantamab Mafodotin-blmfnValueAUC (mcg.h/mL)304,666 (46)Cmax (mcg/mL)3242 (26)tmax (h)320.78 (0.4, 2.5)Ctrough (mcg/mL)692.4 (52)DistributionThe mean steady-state volume of distribution of belantamab mafodotin-blmf was 11 (15%).EliminationTotal 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, cys-mcMMAF is mainly hydrolyzed and dehydrated to cyclized isomeric form of cys-mcMMAF.Specific PopulationsNo 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 to <=1.5 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 ULN and any AST) on the pharmacokinetics of belantamab mafodotin-blmf are unknown.Drug Interaction StudiesIn Vitro Studies: Transporter Systems: Cys-mcMMAF is substrate of organic anion transporting polypeptide (OATP)1B1 and OATP1B3, multidrug resistance-associated protein (MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and possible substrate of P-glycoprotein (P-gp).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Relapsed or Refractory Multiple Myeloma. The efficacy of BLENREP was evaluated in DREAMM-2, an open-label, multicenter study (NCT 03525678). Eligible patients had relapsed or refractory multiple myeloma, had previously received or more prior therapies, including an anti-CD38 monoclonal antibody, and were refractory to an immunomodulatory agent and proteasome inhibitor. Patients had measurable disease by International Myeloma Working Group (IMWG) criteria. Patients with corneal epithelial disease, except mild punctate keratopathy, at baseline were excluded from the study. Patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73m2) at baseline were also eligible for the study. Patients received either BLENREP 2.5 mg/kg or 3.4 mg/kg intravenously once every weeks until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate as evaluated by an Independent Review Committee (IRC) based on the IMWG Uniform Response Criteria for Multiple Myeloma. Only the results of the recommended dosage of 2.5 mg/kg are described below.A total of 97 patients received BLENREP at dose of 2.5 mg/kg administered intravenously once every weeks. The median age was 65 years (range: 39 to 85 years), 53% were male, 74% were White, and 16% were Black. Most patients (77%) were International Staging System (ISS) Stage II or III, 87% had received prior autologous stem cell transplantation (ASCT), and 16% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. High-risk cytogenetic factors (presence of t[4;14], t[14;16] and 17p13del) were present in 27% of patients. The median number of prior lines of therapy was (range: to 21).Efficacy results are summarized in Table 6. The median time to first response was 1.4 months (95% CI: 1.0, 1.6). Seventy-three percent of responders had duration of response >=6 months.Table 6. Efficacy in DREAMM-2a NR Not reached.BLENREPN 97Overall response rate (ORR), (%)(97.5% CI)30 (31%)(21%, 43%) Stringent complete response (sCR), (%)2 (2%) Complete response (CR), (%)1 (1%) Very good partial response (VGPR), (%)15 (15%) Partial response (PR), (%)12 (12%)Median duration of response in monthsa (range)NR [NR to NR].

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Belantamab mafodotin-blmf is B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate. Belantamab mafodotin-blmf is an antibody conjugate composed of components: 1) afucosylated, humanized immunoglobulin G1 monoclonal antibody covalently linked to 2) the microtubule inhibitor MMAF via 3) protease-resistant maleimidocaproyl linker.The antibody is produced in mammalian cell line (Chinese Hamster Ovary) using recombinant DNA technology and the microtubule inhibitor and linker are produced by chemical synthesis. Approximately molecules of mafodotin are attached to each antibody molecule. The molecular weight of belantamab mafodotin-blmf is approximately 152 kDa. Belantamab mafodotin-blmf has the following structure:BLENREP (belantamab mafodotin-blmf) for injection is sterile, preservative-free, white to yellow, lyophilized powder in single-dose vial for reconstitution and further dilution prior to intravenous use. BLENREP is supplied as 100 mg per vial and requires reconstitution with mL of Sterile Water for Injection, USP, to obtain concentration of 50 mg/mL. Each mL of reconstituted solution contains belantamab mafodotin-blmf (50 mg) and the inactive ingredients, citric acid (0.42 mg), disodium edetate dihydrate (0.019 mg), polysorbate 80 (0.2 mg), trehalose dihydrate (75.6 mg), and trisodium citrate dihydrate (6.7 mg). The pH of the reconstituted solution is 6.2.. Belantamab mafodotin-blmf chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oThe recommended dosage is 2.5 mg/kg as an intravenous infusion over approximately 30 minutes once every weeks. (2.2)oSee Full Prescribing Information for instructions on preparation and administration. (2.4). oThe recommended dosage is 2.5 mg/kg as an intravenous infusion over approximately 30 minutes once every weeks. (2.2). oSee Full Prescribing Information for instructions on preparation and administration. (2.4). 2.1 Important Safety Information. Perform an ophthalmic exam prior to initiation of BLENREP and during treatment [see Warnings and Precautions (5.1)].Advise patients to use preservative-free lubricant eye drops and avoid contact lenses unless directed by an ophthalmologist [see Warnings and Precautions (5.1)].. 2.2 Recommended Dosage. The recommended dosage of BLENREP is 2.5 mg/kg of actual body weight given as an intravenous infusion over approximately 30 minutes once every weeks until disease progression or unacceptable toxicity.. 2.3 Dosage Modifications for Adverse Reactions. The recommended dose reduction for adverse reactions is:oBLENREP 1.9 mg/kg intravenously once every weeks.Discontinue BLENREP in patients who are unable to tolerate dose of 1.9 mg/kg (see Tables and 2).Corneal Adverse ReactionsThe recommended dosage modifications for corneal adverse reactions, based on both corneal examination findings and changes in best-corrected visual acuity (BCVA), are provided in Table [see Warnings and Precautions (5.1)]. Determine the recommended dosage modification of BLENREP based on the worst finding in the worst affected eye. Worst finding should be based on either corneal examination finding or change in visual acuity per the Keratopathy and Visual Acuity (KVA) scale.Table 1. Dosage Modifications for Corneal Adverse Reactions per the KVA Scalea Mild superficial keratopathy (documented worsening from baseline), with or without symptoms. Changes in visual acuity due to treatment-related corneal findings. Moderate superficial keratopathy with or without patchy microcyst-like deposits, sub-epithelial haze (peripheral), or new peripheral stromal opacity. Severe superficial keratopathy with or without diffuse microcyst-like deposits, sub-epithelial haze (central), or new central stromal opacity. Corneal epithelial defect such as corneal ulcers.Corneal Adverse ReactionRecommendedDosage ModificationsGrade 1Corneal examination finding(s): Mild superficial keratopathya Change in BCVAb: Decline from baseline of line on Snellen Visual AcuityContinue treatment at current dose.Grade 2Corneal examination finding(s): Moderate superficial keratopathyc Change in BCVAb: Decline from baseline of or lines on Snellen Visual Acuity and not worse than 20/200Withhold BLENREP until improvement in both corneal examination findings and change in BCVA to Grade or better and resume at same dose.Grade 3Corneal examination finding(s): Severe superficial keratopathyd Change in BCVAb: Decline from baseline by more than lines on Snellen Visual Acuity and not worse than 20/200Withhold BLENREP until improvement in both corneal examination findings and change in BCVA to Grade or better and resume at reduced dose.Grade 4Corneal examination finding(s): Corneal epithelial defecte Change in BCVAb: Snellen Visual Acuity worse than 20/200Consider permanent discontinuation of BLENREP. If continuing treatment, withhold BLENREP until improvement in both corneal examination findings and change in BCVA to Grade or better and resume at reduced dose.Other Adverse ReactionsThe recommended dosage modifications for other adverse reactions are provided in Table 2.Table 2. Dosage Modifications for Other Adverse ReactionsAdverse ReactionSeverityRecommended Dosage ModificationsThrombocytopenia[see Warnings and Precautions (5.3)]Platelet count 25,000 to less than 50,000/mcLConsider withholding BLENREP and/or reducing the dose of BLENREP.Platelet count less than 25,000/mcLWithhold BLENREP until platelet count improves to Grade or better. Consider resuming at reduced dose.Infusion-related reactions[see Warnings and Precautions (5.4)]Grade (moderate) or Grade (severe)Interrupt infusion and provide supportive care. Once symptoms resolve, resume at lower infusion rate; reduce the infusion rate by at least 50%.Grade (life-threatening)Permanently discontinue BLENREP and provide emergency care.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3Withhold BLENREP until improvement to Grade or better. Consider resuming at reduced dose.Grade 4Consider permanent discontinuation of BLENREP. If continuing treatment, withhold BLENREP until improvement to Grade or better and resume at reduced dose.. oBLENREP 1.9 mg/kg intravenously once every weeks.. 2.4 Preparation and Administration. BLENREP is hazardous drug. Follow applicable special handling and disposal procedures.1 Calculate the dose (mg), total volume (mL) of solution required, and the number of vials of BLENREP needed based on the patients actual body weight. More than vial may be needed for full dose. Do not round down for partial vials.ReconstitutionoRemove the vial(s) of BLENREP from the refrigerator and allow to stand for approximately 10 minutes to reach room temperature (68F to 77F [20C to 25C]).oReconstitute each 100-mg vial of BLENREP with mL of Sterile Water for Injection, USP, to obtain final concentration of 50 mg/mL. Gently swirl the vial to aid dissolution. Do not shake.oIf the reconstituted solution is not used immediately, store refrigerated at 36oF to 46oF (2oC to 8oC) or at room temperature (68F to 77F [20C to 25C]) for up to hours in the original container. Discard if not diluted within hours. Do not freeze.oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to opalescent, colorless to yellow to brown liquid. Discard if extraneous particulate matter is observed.DilutionoWithdraw the calculated volume of BLENREP from the appropriate number of vials and dilute in 250-mL infusion bag of 0.9% Sodium Chloride Injection, USP, to final concentration of 0.2 mg/mL to mg/mL. The infusion bags must be made of polyvinylchloride (PVC) or polyolefin (PO).oMix the diluted solution by gentle inversion. Do not shake.oDiscard any unused reconstituted solution of BLENREP left in the vial(s).oIf the diluted infusion solution is not used immediately, store refrigerated at 36oF to 46oF (2oC to 8oC) for up to 24 hours. Do not freeze. Once removed from refrigeration, administer the diluted infusion solution of BLENREP within hours (including infusion time).oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted infusion solution should be clear and colorless. Discard if particulate matter is observed.AdministrationoIf refrigerated, allow the diluted infusion solution to equilibrate to room temperature (68oF to 77oF [20oC to 25oC]) prior to administration. Diluted infusion solution may be kept at room temperature for no more than hours (including infusion time).oAdminister by intravenous infusion over approximately 30 minutes using an infusion set made of polyvinyl chloride (PVC) or polyolefin (PO).oFiltration of the diluted solution is not required; however, if the diluted solution is filtered, use polyethersulfone (PES)-based filter (0.2 micron).Do not mix or administer BLENREP as an infusion with other products. The product does not contain preservative.. oRemove the vial(s) of BLENREP from the refrigerator and allow to stand for approximately 10 minutes to reach room temperature (68F to 77F [20C to 25C]).. oReconstitute each 100-mg vial of BLENREP with mL of Sterile Water for Injection, USP, to obtain final concentration of 50 mg/mL. Gently swirl the vial to aid dissolution. Do not shake.. oIf the reconstituted solution is not used immediately, store refrigerated at 36oF to 46oF (2oC to 8oC) or at room temperature (68F to 77F [20C to 25C]) for up to hours in the original container. Discard if not diluted within hours. Do not freeze.. oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear to opalescent, colorless to yellow to brown liquid. Discard if extraneous particulate matter is observed.. oWithdraw the calculated volume of BLENREP from the appropriate number of vials and dilute in 250-mL infusion bag of 0.9% Sodium Chloride Injection, USP, to final concentration of 0.2 mg/mL to mg/mL. The infusion bags must be made of polyvinylchloride (PVC) or polyolefin (PO).. oMix the diluted solution by gentle inversion. Do not shake.. oDiscard any unused reconstituted solution of BLENREP left in the vial(s).. oIf the diluted infusion solution is not used immediately, store refrigerated at 36oF to 46oF (2oC to 8oC) for up to 24 hours. Do not freeze. Once removed from refrigeration, administer the diluted infusion solution of BLENREP within hours (including infusion time).. oParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The diluted infusion solution should be clear and colorless. Discard if particulate matter is observed.. oIf refrigerated, allow the diluted infusion solution to equilibrate to room temperature (68oF to 77oF [20oC to 25oC]) prior to administration. Diluted infusion solution may be kept at room temperature for no more than hours (including infusion time).. oAdminister by intravenous infusion over approximately 30 minutes using an infusion set made of polyvinyl chloride (PVC) or polyolefin (PO).. oFiltration of the diluted solution is not required; however, if the diluted solution is filtered, use polyethersulfone (PES)-based filter (0.2 micron).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For injection: 100 mg of belantamab mafodotin-blmf as white to yellow lyophilized powder in single-dose vial for reconstitution and further dilution.. For injection: 100 mg as lyophilized powder in single-dose vial for reconstitution and further dilution. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential BLENREP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating BLENREP.ContraceptionFemales: Advise women of reproductive potential to use effective contraception during treatment and for 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 months after the last dose [see Nonclinical Toxicology (13.1)].InfertilityBased 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)].

GERIATRIC USE SECTION.

8.5 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. BLENREP is indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least prior therapies, including an anti-CD38 monoclonal antibody, proteasome inhibitor, and an immunomodulatory agent.This indication is approved under accelerated approval based on response rate [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).. BLENREP is B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least prior therapies including an anti-CD38 monoclonal antibody, proteasome inhibitor, and an immunomodulatory agent.This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Ocular ToxicityoAdvise patients that ocular toxicity may occur during treatment with BLENREP [see Warnings and Precautions (5.1)].oAdvise patients to administer preservative-free lubricant eye drops as recommended during treatment and to avoid wearing contact lenses during treatment unless directed by healthcare professional [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].oAdvise patients to use caution when driving or operating machinery as BLENREP may adversely affect their vision [see Warnings and Precautions (5.1)].BLENREP REMSBLENREP is available only through restricted program called BLENREP REMS [see Warnings and Precautions (5.2)]. Inform the patient of the following notable requirements:oPatients must complete the enrollment form with their provider.oPatients must comply with ongoing monitoring for eye exams [see Warnings and Precautions (5.1)].ThrombocytopeniaoAdvise patients to inform their healthcare provider if they develop signs or symptoms of bleeding [see Warnings and Precautions (5.3)].Infusion-Related ReactionsoAdvise patients to immediately report any signs and symptoms of infusion-related reactions to their healthcare provider [see Warnings and Precautions (5.4)].Embryo-Fetal ToxicityoAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].oAdvise women of reproductive potential to use highly effective contraception during treatment and for months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.3)].oAdvise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].LactationoAdvise women not to breastfeed during treatment with BLENREP and for months after the last dose [see Use in Specific Populations (8.2)].InfertilityoAdvise males and females of reproductive potential that BLENREP may impair fertility [see Use in Specific Populations (8.3)].Trademarks are owned by or licensed to the GSK group of companies.Manufactured by:GlaxoSmithKline Intellectual Property Development Ltd. EnglandBrentford, Middlesex, UK TW8 9GSU.S. License No. 2148including by use of Potelligent technology licensed from BioWa, Inc.For:GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2020 GSK group of companies or its licensor.BRP:1PI. oAdvise patients that ocular toxicity may occur during treatment with BLENREP [see Warnings and Precautions (5.1)].. oAdvise patients to administer preservative-free lubricant eye drops as recommended during treatment and to avoid wearing contact lenses during treatment unless directed by healthcare professional [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].. oAdvise patients to use caution when driving or operating machinery as BLENREP may adversely affect their vision [see Warnings and Precautions (5.1)].. oPatients must complete the enrollment form with their provider.. oPatients must comply with ongoing monitoring for eye exams [see Warnings and Precautions (5.1)].. oAdvise patients to inform their healthcare provider if they develop signs or symptoms of bleeding [see Warnings and Precautions (5.3)].. oAdvise patients to immediately report any signs and symptoms of infusion-related reactions to their healthcare provider [see Warnings and Precautions (5.4)].. oAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].. oAdvise women of reproductive potential to use highly effective contraception during treatment and for months after the last dose [see Warnings and Precautions (5.5), Use in Specific Populations (8.3)].. oAdvise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].. oAdvise women not to breastfeed during treatment with BLENREP and for months after the last dose [see Use in Specific Populations (8.2)].. oAdvise males and females of reproductive potential that BLENREP may impair fertility [see Use in Specific Populations (8.3)].

LACTATION SECTION.

8.2 Lactation Risk SummaryThere 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 months after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Belantamab mafodotin-blmf is an antibody-drug conjugate (ADC). The antibody component is an afucosylated IgG1 directed against BCMA, protein expressed on normal lymphocytes and multiple myeloma cells. The small molecule component is MMAF, 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).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with belantamab mafodotin-blmf.Belantamab mafodotin-blmf was genotoxic in an in vitro micronucleus assay in human lymphocytes through an aneugenic mechanism. These results are consistent with the pharmacological effect of MMAF binding to tubulin causing microtubule depolymerization resulting in spindle disorganization during cell division. Cys-mcMMAF was not mutagenic in the bacterial reverse mutation assay (Ames test), the L5178Y mouse lymphoma forward mutation assay, or the in vivo rat bone marrow micronucleus assay.Fertility studies have not been conducted with belantamab mafodotin-blmf. Results of repeat-dose toxicity studies with intravenous administration of belantamab mafodotin-blmf in rats indicate the potential for impaired male and female reproductive function and fertility. In rats, weekly dosing for weeks at doses >=10 mg/kg (approximately times the exposure at the maximum recommended human dose [MRHD] of 2.5 mg/kg based on the AUC of belantamab mafodotin-blmf) resulted in degeneration and atrophy of seminiferous tubules in the testes and luteinized nonovulatory follicles in the ovaries. Findings in females were reversible; findings in the testes were not reversible at the end of the 12-week recovery period with weekly dosing or when given every weeks for 13 weeks at doses >=10 mg/kg. In male monkeys, the highest dose tested of 10 mg/kg (approximately times the exposure at the MRHD based on AUC of belantamab mafodotin-blmf) given weekly for 13 weeks resulted in seminiferous tubules degeneration in the testes that was fully reversed following the 12-week recovery period.. 13.2 Animal Toxicology and/or Pharmacology. Increased mitoses of corneal epithelial cells with bilateral single-cell necrosis were observed following intravenous administration of belantamab mafodotin-blmf in rats and rabbits.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELNDC 0173-0896-01BLENREP(belantamab mafodotin-blmf)for injection100 mg/vialCAUTION: Hazardous Agent.For intravenous infusion after reconstitution and dilution.Single-dose vial.Discard unused portion.No preservative.No U.S. standard of potency.Dispense the enclosed Medication Guide to each patient.(C)2020 GSK group of companies or its licensor.Rev. 8/2062000000041460. Blenrep carton.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure-Response RelationshipsHigher 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 ElectrophysiologyBelantamab mafodotin-blmf had no large QTc prolongation (>10 ms) at the recommended dosage of 2.5 mg/kg once every weeks.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Belantamab mafodotin-blmf exhibited dose-proportional pharmacokinetics, with gradual decrease in clearance over time; the time to reach steady state was ~70 days. After 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 dosing regimen of every weeks.The pharmacokinetics of belantamab mafodotin-blmf after dose of 2.5 mg/kg in Cycle are shown in Table 5.Table 5. Belantamab Mafodotin-blmf Pharmacokinetics at Cycle in Patients Who Received Dose of 2.5 mg/kgAUC Area under curve over the dosing interval; Cmax Maximum observed plasma concentration; tmax Time of Cmax; Ctrough Observed plasma concentration prior to next dose.Data presented as geometric mean (%CV), except tmax, which is presented as median (minimum, maximum).ParameterBelantamab Mafodotin-blmfnValueAUC (mcg.h/mL)304,666 (46)Cmax (mcg/mL)3242 (26)tmax (h)320.78 (0.4, 2.5)Ctrough (mcg/mL)692.4 (52)DistributionThe mean steady-state volume of distribution of belantamab mafodotin-blmf was 11 (15%).EliminationTotal 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, cys-mcMMAF is mainly hydrolyzed and dehydrated to cyclized isomeric form of cys-mcMMAF.Specific PopulationsNo 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 to <=1.5 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 ULN and any AST) on the pharmacokinetics of belantamab mafodotin-blmf are unknown.Drug Interaction StudiesIn Vitro Studies: Transporter Systems: Cys-mcMMAF is substrate of organic anion transporting polypeptide (OATP)1B1 and OATP1B3, multidrug resistance-associated protein (MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and possible substrate of P-glycoprotein (P-gp).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action, BLENREP can cause fetal harm when administered to pregnant woman, because it contains genotoxic compound (the microtubule inhibitor, MMAF) and it targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Human immunoglobulin (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 drug-associated risk. No animal reproduction studies were conducted with BLENREP. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.DataAnimal Data: Animal reproductive or developmental toxicity studies were not conducted with belantamab mafodotin-blmf. The cytotoxic component of BLENREP, MMAF, disrupts microtubule function, is genotoxic, and can be toxic to rapidly dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.

REFERENCES SECTION.

15 REFERENCES. 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.. 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE BLENREP (BLEN-REP) (belantamab mafodotin-blmf) for injection, for intravenous useWhat is the most important information should know about BLENREPBefore you receive BLENREP, you must read and agree to all of the instructions in the BLENREP REMS. Before prescribing BLENREP, your healthcare provider will explain the BLENREP REMS to you and have you sign the Patient Enrollment Form.BLENREP can cause serious side effects, including:Eye problems. Eye problems are common with BLENREP. BLENREP can cause changes to the surface of your eye that can lead to dry eyes, blurred vision, worsening vision, severe vision loss, and corneal ulcer. Tell your healthcare provider if you have any vision changes or eye problems during treatment with BLENREP.oYour healthcare provider will send you to an eye specialist to check your eyes before you start treatment with BLENREP, prior to each dose of BLENREP, and for worsening symptoms of eye problems.oEven if your vision seems fine, it is important that you get your eyes checked during treatment with BLENREP because some changes can happen without symptoms and may only be seen on an eye exam.oYou should use preservative-free lubricant eye drops at least times per day during treatment with BLENREP as instructed by your healthcare provider.oYou should use caution when driving or operating machinery as BLENREP may affect your vision.oAvoid wearing contact lenses during treatment with BLENREP unless directed by your eye specialist.See What are the possible side effects of BLENREP for more information about serious side effects.What is BLENREPBLENREP is prescription medicine used to treat adults with multiple myeloma who:ohave received at least prior medicines to treat multiple myeloma, andotheir cancer has come back or did not respond to prior treatment.It is not known if BLENREP is safe and effective in children.Before receiving BLENREP, tell your healthcare provider about all of your medical conditions, including if you:ohave history of vision or eye problems.ohave bleeding problems or history of bleeding problems.oare pregnant or plan to become pregnant. BLENREP can harm your unborn baby.Females who are able to become pregnant:oYour healthcare provider may do pregnancy test before you start treatment with BLENREP.oYou should use effective birth control during treatment with BLENREP and for months after the last dose. Talk to your healthcare provider about birth control methods you can use during this time.oTell your healthcare provider if you become pregnant or think you may be pregnant during treatment with BLENREP. Males with female partners who are able to become pregnant should use effective birth control during treatment with BLENREP and for months after the last dose.oare breastfeeding or plan to breastfeed. It is not known if BLENREP passes into your breast milk. Do not breastfeed during treatment with BLENREP and for months after the last dose.oBLENREP may affect fertility in males and females. Talk to your healthcare provider if this is concern for you.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive BLENREPoBLENREP will be given to you by your healthcare provider by intravenous infusion into your vein over approximately 30 minutes.oBLENREP is usually given every weeks.oYour healthcare provider will decide how many treatments you need.oYour healthcare provider may decrease your dose, temporarily stop or completely stop treatment with BLENREP if you have serious side effects.oIf you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What are the possible side effects of BLENREPBLENREP can cause serious side effects, including:oSee Eye Problems in What is the most important information should know about BLENREPoDecrease in platelets (thrombocytopenia) is common with BLENREP, and can also be serious. Platelets are type of blood cell that help your blood to clot. Your healthcare provider will check your blood cell counts before you start treatment with BLENREP and during treatment. Tell your healthcare provider if you have bleeding or bruising during treatment with BLENREP.oInfusion reactions are common with BLENREP, and can also be serious. Tell your healthcare provider or nurse right away if you get any of the following signs or symptoms of an infusion reaction while receiving BLENREP:ochills or shakingoredness of your face (flushing)oitching or rashoshortness of breath, cough, or wheezingoswelling of your lips, tongue, throat, or faceodizzinessofeel like passing outotirednessofeverofeel like your heart is racing (palpitations)oThe most common side effects of BLENREP include vision or eye changes such as findings on eye exam (keratopathy), decreased vision or blurred vision, nausea, low blood cell counts, fever, infusion-related reactions, tiredness, and changes in kidney or liver function blood tests.These are not all the possible side effects of BLENREP.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of BLENREP.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about BLENREP that is written for health professionals.What are the ingredients in BLENREPActive Ingredient: belantamab mafodotin-blmfInactive Ingredients: citric acid, disodium edetate dihydrate, polysorbate 80, trehalose dihydrate, trisodium citrate dihydrate. Manufactured by: GlaxoSmithKline Intellectual Property Development Ltd., England Brentford, Middlesex, UK TW8 9GS U.S. License No. 2148 including by use of Potelligent technology licensed from BioWa, Inc.For:GlaxoSmithKline, Research Triangle Park, NC 27709(C)2020 GSK group of companies or its licensor.BRP:1MGFor more information, call GlaxoSmithKline (GSK) at 1-888-825-5249.Trademarks are owned by or licensed to the GSK group of companies.This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 08/2020. MEDICATION GUIDE. BLENREP (BLEN-REP). (belantamab mafodotin-blmf). for injection, for intravenous use. oYour healthcare provider will send you to an eye specialist to check your eyes before you start treatment with BLENREP, prior to each dose of BLENREP, and for worsening symptoms of eye problems.. oEven if your vision seems fine, it is important that you get your eyes checked during treatment with BLENREP because some changes can happen without symptoms and may only be seen on an eye exam.. oYou should use preservative-free lubricant eye drops at least times per day during treatment with BLENREP as instructed by your healthcare provider.. oYou should use caution when driving or operating machinery as BLENREP may affect your vision.. oAvoid wearing contact lenses during treatment with BLENREP unless directed by your eye specialist.. ohave received at least prior medicines to treat multiple myeloma, and. otheir cancer has come back or did not respond to prior treatment.. ohave history of vision or eye problems.. ohave bleeding problems or history of bleeding problems.. oare pregnant or plan to become pregnant. BLENREP can harm your unborn baby.Females who are able to become pregnant:oYour healthcare provider may do pregnancy test before you start treatment with BLENREP.oYou should use effective birth control during treatment with BLENREP and for months after the last dose. Talk to your healthcare provider about birth control methods you can use during this time.oTell your healthcare provider if you become pregnant or think you may be pregnant during treatment with BLENREP.. oYour healthcare provider may do pregnancy test before you start treatment with BLENREP.. oYou should use effective birth control during treatment with BLENREP and for months after the last dose. Talk to your healthcare provider about birth control methods you can use during this time.. oTell your healthcare provider if you become pregnant or think you may be pregnant during treatment with BLENREP.. Males with female partners who are able to become pregnant should use effective birth control during treatment with BLENREP and for months after the last dose.. oare breastfeeding or plan to breastfeed. It is not known if BLENREP passes into your breast milk. Do not breastfeed during treatment with BLENREP and for months after the last dose.. oBLENREP may affect fertility in males and females. Talk to your healthcare provider if this is concern for you.. oBLENREP will be given to you by your healthcare provider by intravenous infusion into your vein over approximately 30 minutes.. oBLENREP is usually given every weeks.. oYour healthcare provider will decide how many treatments you need.. oYour healthcare provider may decrease your dose, temporarily stop or completely stop treatment with BLENREP if you have serious side effects.. oIf you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.. oSee Eye Problems in What is the most important information should know about BLENREP. oDecrease in platelets (thrombocytopenia) is common with BLENREP, and can also be serious. Platelets are type of blood cell that help your blood to clot. Your healthcare provider will check your blood cell counts before you start treatment with BLENREP and during treatment. Tell your healthcare provider if you have bleeding or bruising during treatment with BLENREP.. oInfusion reactions are common with BLENREP, and can also be serious. Tell your healthcare provider or nurse right away if you get any of the following signs or symptoms of an infusion reaction while receiving BLENREP:. ochills or shaking. oredness of your face (flushing). oitching or rash. oshortness of breath, cough, or wheezing. oswelling of your lips, tongue, throat, or face. odizziness. ofeel like passing out. otiredness. ofever. ofeel like your heart is racing (palpitations). oThe most common side effects of BLENREP include vision or eye changes such as findings on eye exam (keratopathy), decreased vision or blurred vision, nausea, low blood cell counts, fever, infusion-related reactions, tiredness, and changes in kidney or liver function blood tests.. Manufactured by:. GlaxoSmithKline Intellectual Property Development Ltd., England. Brentford, Middlesex, UK TW8 9GS. U.S. License No. 2148. including by use of Potelligent technology licensed from BioWa, Inc.

SPL UNCLASSIFIED SECTION.

2.1 Important Safety Information. Perform an ophthalmic exam prior to initiation of BLENREP and during treatment [see Warnings and Precautions (5.1)].Advise patients to use preservative-free lubricant eye drops and avoid contact lenses unless directed by an ophthalmologist [see Warnings and Precautions (5.1)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, BLENREP can cause fetal harm when administered to pregnant woman, because it contains genotoxic compound (the microtubule inhibitor, MMAF) and it targets actively dividing cells [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. Human immunoglobulin (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 drug-associated risk. No animal reproduction studies were conducted with BLENREP. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.DataAnimal Data: Animal reproductive or developmental toxicity studies were not conducted with belantamab mafodotin-blmf. The cytotoxic component of BLENREP, MMAF, disrupts microtubule function, is genotoxic, and can be toxic to rapidly dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.. 8.2 Lactation Risk SummaryThere 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 months after the last dose.. 8.3 Females and Males of Reproductive Potential BLENREP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to initiating BLENREP.ContraceptionFemales: Advise women of reproductive potential to use effective contraception during treatment and for 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 months after the last dose [see Nonclinical Toxicology (13.1)].InfertilityBased 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)].. 8.4 Pediatric Use. The safety and effectiveness of BLENREP in pediatric patients have not been established.. 8.5 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.. 8.6 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) [see Clinical Pharmacology (12.3)].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)].. 8.7 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 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) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oThrombocytopenia: Perform complete blood counts at baseline and during treatment as clinically indicated. Consider withholding and/or reducing the dose based on severity. (2.3, 5.3)oInfusion-Related Reactions: Monitor patients for infusion-related reactions. Interrupt and then reduce the rate or permanently discontinue based on the severity. (2.3, 5.4)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.5, 8.1, 8.3). oThrombocytopenia: Perform complete blood counts at baseline and during treatment as clinically indicated. Consider withholding and/or reducing the dose based on severity. (2.3, 5.3). oInfusion-Related Reactions: Monitor patients for infusion-related reactions. Interrupt and then reduce the rate or permanently discontinue based on the severity. (2.3, 5.4). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.5, 8.1, 8.3). 5.1 Ocular Toxicity. Ocular adverse reactions occurred in 77% of the 218 patients in the pooled safety population. Ocular adverse reactions included keratopathy (76%), changes in visual acuity (55%), blurred vision (27%), and dry eye (19%) [see Adverse Reactions (6.1)]. Among patients with keratopathy (n 165), 49% had ocular symptoms, 65% had clinically relevant visual acuity changes (decline of or more lines on Snellen Visual Acuity in any eye), and 34% had both ocular symptoms and visual acuity changes.KeratopathyKeratopathy was reported as Grade in 7% of patients, Grade in 22%, Grade in 45%, and Grade in 0.5% per the KVA scale. Cases of corneal ulcer (ulcerative and infective keratitis) have been reported. Most keratopathy events developed within the first treatment cycles (cumulative incidence of 65% by Cycle 2). Of the patients with Grade to keratopathy (n 149), 39% of patients recovered to Grade or lower after median follow-up of 6.2 months. Of the 61% who had ongoing keratopathy, 28% were still on treatment, 9% were in follow-up, and in 24% the follow-up ended due to death, study withdrawal, or lost to follow up. For patients in whom events resolved, the median time to resolution was months (range: 11 days to 8.3 months).Visual Acuity ChangesA clinically significant decrease in visual acuity of worse than 20/40 in the better-seeing eye was observed in 19% of the 218 patients and of 20/200 or worse in the better-seeing eye in 1.4%. Of the patients with decreased visual acuity of worse than 20/40, 88% resolved and the median time to resolution was 22 days (range: days to 4.2 months). Of the patients with decreased visual acuity of 20/200 or worse, all resolved and the median duration was 22 days (range: 15 to 22 days).Monitoring and Patient InstructionConduct ophthalmic examinations (visual acuity and slit lamp) at baseline, prior to each dose, and promptly for worsening symptoms. Perform baseline examinations within weeks prior to the first dose. Perform each follow-up examination at least week after the previous dose and within weeks prior to the next dose. Withhold BLENREP until improvement and resume at same or reduced dose, or consider permanently discontinuing based on severity [see Dosage and Administration (2.3)].Advise patients to use preservative-free lubricant eye drops at least times day starting with the first infusion and continuing until end of treatment. Avoid use of contact lenses unless directed by an ophthalmologist [see Dosage and Administration (2.1)].Changes in visual acuity may be associated with difficulty for driving and reading. Advise patients to use caution when driving or operating machinery.BLENREP is only available through restricted program under REMS [see Warnings and Precautions (5.2)].. 5.2 BLENREP REMS. BLENREP is available only through restricted program under REMS called the BLENREP REMS because of the risks of ocular toxicity [see Warnings and Precautions (5.1)].Notable requirements of the BLENREP REMS include the following:oPrescribers must be certified with the program by enrolling and completing training in the BLENREP REMS.oPrescribers must counsel patients receiving BLENREP about the risk of ocular toxicity and the need for ophthalmic examinations prior to each dose.oPatients must be enrolled in the BLENREP REMS and comply with monitoring.oHealthcare facilities must be certified with the program and verify that patients are authorized to receive BLENREP.oWholesalers and distributers must only distribute BLENREP to certified healthcare facilities.Further information is available, at www.BLENREPREMS.com and 1-855-209-9188.. oPrescribers must be certified with the program by enrolling and completing training in the BLENREP REMS.. oPrescribers must counsel patients receiving BLENREP about the risk of ocular toxicity and the need for ophthalmic examinations prior to each dose.. oPatients must be enrolled in the BLENREP REMS and comply with monitoring.. oHealthcare facilities must be certified with the program and verify that patients are authorized to receive BLENREP.. oWholesalers and distributers must only distribute BLENREP to certified healthcare facilities.. 5.3 Thrombocytopenia. Thrombocytopenia occurred in 69% of 218 patients in the pooled safety population, including Grade in 13%, Grade in 10%, and Grade in 17% [see Adverse Reactions (6.1)]. The median time to onset of the first thrombocytopenic event was 26.5 days. Thrombocytopenia resulted in dose reduction, dose interruption, or discontinuation in 9%, 2.8%, and 0.5% of patients, respectively.Grade to bleeding events occurred in 6% of patients, including Grade in patient. Fatal adverse reactions included cerebral hemorrhage in patients.Perform complete blood cell counts at baseline and during treatment as clinically indicated. Consider withholding and/or reducing the dose based on severity [see Dosage and Administration (2.3)].. 5.4 Infusion-Related Reactions. Infusion-related reactions occurred in 18% of 218 patients in the pooled safety population, including Grade in 1.8% [see Adverse Reactions (6.1)].Monitor patients for infusion-related reactions. For Grade or reactions, interrupt the infusion and provide supportive treatment. Once symptoms resolve, resume at lower infusion rate [see Dosage and Administration (2.3)]. Administer premedication for all subsequent infusions. Discontinue BLENREP for life-threatening infusion-related reactions and provide appropriate emergency care.. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action, BLENREP can cause fetal harm when administered to pregnant woman because it contains genotoxic compound (the microtubule inhibitor, monomethyl auristatin [MMAF]) and it targets actively dividing cells.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with BLENREP and for months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BLENREP and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].