• Parenteral 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 .
Dilution
• Withdraw the calculated volume of BLENREP from the appropriate number of vials and dilute in a 250-mL infusion bag of 0.9 % Sodium Chloride Injection , USP , to a final concentration of 0.2 mg / mL to 2 mg / mL . The infusion bags must be made of polyvinylchloride ( PVC ) or polyolefin ( PO ).
• Mix the diluted solution by gentle inversion . Do not shake .
• Discard any unused reconstituted solution of BLENREP left in the vial ( s ).
• If the diluted infusion solution is not used immediately , store refrigerated at 36 º F to 46 º F ( 2 º C to 8 º C ) for up to 24 hours . Do not freeze . Once removed from refrigeration , administer the diluted infusion solution of BLENREP within 6 hours ( including infusion time ).
• Parenteral 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 .
Administration
• If refrigerated , allow the diluted infusion solution to equilibrate to room temperature ( 68 º F to 77 º F [ 20 º C to 25 º C ]) prior to administration . Diluted infusion solution may be kept at room temperature for no more than 6 hours ( including infusion time ).
• Administer by intravenous infusion over approximately 30 minutes using an infusion set made of polyvinyl chloride ( PVC ) or polyolefin ( PO ).
• Filtration of the diluted solution is not required ; however , if the diluted solution is filtered , use a polyethersulfone ( PES ) -based filter ( 0.2 micron ).
Do not mix or administer BLENREP as an infusion with other products . The product does not contain a preservative .
4 CONTRAINDICATIONS None .
5 WARNINGS AND PRECAUTIONS 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 2 or more lines on Snellen Visual Acuity in any eye ), and 34 % had both ocular symptoms and visual acuity changes .
Keratopathy
Keratopathy was reported as Grade 1 in 7 % of patients , Grade 2 in 22 %, Grade 3 in 45 %, and Grade 4 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 2 treatment cycles ( cumulative incidence of 65 % by Cycle 2 ). Of the patients with Grade 2 to 4 keratopathy ( n = 149 ), 39 % of patients recovered to Grade 1 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 2 months ( range : 11 days to 8.3 months ).
Visual Acuity Changes
A clinically significant decrease in visual acuity of worse than 20 / 40 in the betterseeing 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 : 7 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 Instruction
Conduct ophthalmic examinations ( visual acuity and slit lamp ) at baseline , prior to each dose , and promptly for worsening symptoms . Perform baseline examinations within 3 weeks prior to the first dose . Perform each follow-up examination at least 1 week after the previous dose and within 2 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 4 times a 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 a restricted program under a REMS [ see Warnings and Precautions ( 5.2 )].
5.2 BLENREP REMS
BLENREP is available only through a restricted program under a 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 :
• Prescribers must be certified with the program by enrolling and completing training in the BLENREP REMS .
• Prescribers must counsel patients receiving BLENREP about the risk of ocular toxicity and the need for ophthalmic examinations prior to each dose .
• Patients must be enrolled in the BLENREP REMS and comply with monitoring .
• Healthcare facilities must be certified with the program and verify that patients are authorized to receive BLENREP .
• Wholesalers and distributers must only distribute BLENREP to certified healthcare facilities .
Further information is available , at www . BLENREPREMS . com and 1-855-209-9188 .
5.3 Thrombocytopenia
Thrombocytopenia occurred in 69 % of 218 patients in the pooled safety population , including Grade 2 in 13 %, Grade 3 in 10 %, and Grade 4 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 3 to 4 bleeding events occurred in 6 % of patients , including Grade 4 in 1 patient . Fatal adverse reactions included cerebral hemorrhage in 2 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 3 in 1.8 % [ see Adverse Reactions ( 6.1 )].
Monitor patients for infusion-related reactions . For Grade 2 or 3 reactions , interrupt the infusion and provide supportive treatment . Once symptoms resolve , resume at a lower infusion rate [ see Dosage and Administration ( 2.3 )]. Administer premedication for all subsequent infusions . Discontinue BLENREP for life-threatening infusionrelated 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 a pregnant woman because it contains a genotoxic compound ( the microtubule inhibitor , monomethyl auristatin F [ MMAF ]) and it targets actively dividing cells .
Advise pregnant women of the potential risk to a fetus . Advise females of reproductive potential to use effective contraception during treatment with BLENREP 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 [ see Use in Specific Populations ( 8.1 , 8.3 )].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling :
• Ocular toxicity [ see Warnings and Precautions ( 5.1 )].
• Thrombocytopenia [ see Warnings and Precautions ( 5.3 )].
• Infusion-related reactions [ see Warnings and Precautions ( 5.4 )]. 6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a 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 a dosage of 2.5 mg / kg or 3.4 mg / kg ( 1.4 times the recommended dose ) administered intravenously once every 3 weeks in 218 patients in DREAMM-2 . Of these patients , 194 received a liquid formulation ( not the approved dosage form ) rather than the lyophilized powder . Among the 218 patients , 24 % were exposed for 6 months or longer .
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