BLENREP Powder for solution for injection Ref.[9941] Active ingredients: Belantamab mafodotin

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 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: 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 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 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)].

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)].

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.

Relapsed or Refractory Multiple Myeloma

The safety of BLENREP as a 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 3 weeks (n=95). Among these patients, 22% were exposed for 6 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 a 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 a 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 3 or 4 (≥5%) laboratory abnormalities were lymphocytes decreased, platelets decreased, hemoglobin decreased, neutrophils decreased, creatinine increased, and gamma-glutamyl transferase increased.

Table 3 summarizes the adverse reactions in DREAMM-2 for patients who received the recommended dosage of 2.5 mg/kg once every 3 weeks.

Table 3. Adverse Reactions (≥10%) in Patients Who Received BLENREP in DREAMM-2:

^a Keratopathy was based on slit lamp eye examination, characterized as corneal epithelium changes with or without symptoms.
^b Visual acuity changes were determined upon eye examination.
^c Blurred vision included diplopia, vision blurred, visual acuity reduced, and visual impairment.
^d Dry eyes included dry eye, ocular discomfort, and eye pruritus.
^e Fatigue included fatigue and asthenia.
^f Infusion-related reactions included infusion-related reaction, pyrexia, chills, diarrhea, nausea, asthenia, hypertension, lethargy, tachycardia.
^g Upper respiratory tract infection included upper respiratory tract infection, nasopharyngitis, rhinovirus infections, and sinusitis.

Clinically 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 4 summarizes the laboratory abnormalities in DREAMM-2.

Table 4. Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received BLENREP in DREAMM-2:

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 2 patients tested positive for neutralizing anti-belantamab mafodotin antibodies following 4 weeks on therapy. Due to the limited number of patients with antibodies against belantamab mafodotin-blmf, no conclusions can be drawn concerning a potential effect of immunogenicity on pharmacokinetics, efficacy, or safety.

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 [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)]. 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 drug-associated 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.

Data

Animal 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.

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.

BLENREP can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].

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 [see Nonclinical Toxicology (13.1)].

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)].

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

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.

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)].

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) [see Clinical Pharmacology (12.3)].