Zenbexus Capsule
FDA Label NDC 0003-5710

EMBRYO-FETAL TOXICITY

ZENBEXUS is contraindicated in pregnancy. ZENBEXUS is embryo-fetal toxic in animals and can cause birth defects or embryo-fetal death in humans. In females of reproductive potential, obtain 2 negative pregnancy tests before starting ZENBEXUS treatment [Contraindications (4), see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].

Females of reproductive potential must use 2 effective forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after last dose of ZENBEXUS treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].

Because of the risk of embryo-fetal toxicity, ZENBEXUS is only available through a restricted distribution program called ZENBEXUS REMS [see Warnings and Precautions (5.2)].

Information about ZENBEXUS REMS is available at www.ZENBEXUSREMS.com or by calling the REMS Call Center at 1-888-423-5436.

SERIOUS VENOUS AND ARTERIAL THROMBOEMBOLISM

Increased risk of deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke in patients with multiple myeloma receiving ZENBEXUS with daratumumab and hyaluronidase-fihj and dexamethasone. Anti-thrombotic prophylaxis is recommended [see Warnings and Precautions (5.3)].

ZENBEXUS is indicated, in combination with daratumumab and hyaluronidase-fihj and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.

This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete response (CR) at any time [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Females of reproductive potential must have negative pregnancy testing and use effective contraception methods before initiating ZENBEXUS [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].

The recommended dosage of ZENBEXUS is 1 mg orally once daily with or without food [see Clinical Pharmacology (12.3)] on Days 1 to 21 of a 28-day cycle, until disease progression or unacceptable toxicity, in combination with daratumumab and hyaluronidase-fihj and dexamethasone.

The recommended dosage modifications for adverse reactions are provided in Table 1.

Avoid concomitant use of ZENBEXUS with strong or moderate CYP3A inhibitors.

If concomitant use with strong CYP3A inhibitors is unavoidable, reduce ZENBEXUS dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

If concomitant use with moderate CYP3A inhibitors is unavoidable, reduce ZENBEXUS dose to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. If dose modification is needed due to adverse events, reduce ZENBEXUS dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle.

In patients with eGFR less than 30 mL/min/1.73 m² not receiving dialysis, reduce ZENBEXUS dose to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle. If dose modification is needed due to adverse events, reduce ZENBEXUS dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle.

In patients with eGFR greater than 30 mL/min/1.73 m² or eGFR less than 30 mL/min/1.73 m² receiving intermittent hemodialysis, no dose adjustment is recommended [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

ZENBEXUS is a hazardous drug. Follow applicable special handling and disposal procedures.1

Take ZENBEXUS at approximately the same time each day with or without food [see Clinical Pharmacology (12.3)].

Swallow ZENBEXUS capsules whole with water. Do not open, break, or chew the capsules. Direct contact with the capsule contents should be avoided. In case of capsule breakage, avoid raising dust during clean-up. If contact occurs, wash thoroughly with soap and water.

If a dose is missed and it has been less than 12 hours since the missed dose, take the missed dose as soon as possible. If it has been more than 12 hours since the missed dose, skip the missed dose. Do not double the next dose.

ZENBEXUS capsules are available as follows:

• 0.75 mg of iberdomide: light gray opaque cap imprinted with “BMS” in white ink and dark brown opaque body imprinted with “0.75 mg” in white ink.
• 1 mg of iberdomide: light gray opaque cap imprinted with “BMS” in white ink and ivory opaque body imprinted with “1 mg” in black ink.

Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, ZENBEXUS can cause birth defects or embryo-fetal death in humans [see Boxed Warning, Warnings and Precautions (5.1), and Use in Specific Populations (8.1)]. ZENBEXUS is contraindicated in females who are pregnant. Iberdomide causes adverse developmental outcomes in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.

Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animal studies, ZENBEXUS can cause birth defects or embryo-fetal death in humans and is contraindicated for use during pregnancy. Oral administration of iberdomide in pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities [see Use in Specific Populations (8.1)]. ZENBEXUS is only available through ZENBEXUS REMS [see Warnings and Precautions (5.2)].

Females of reproductive potential must avoid pregnancy while taking ZENBEXUS and for at least 4 weeks after completing therapy.

Advise females of reproductive potential of the potential risk to a fetus and to use 2 methods of effective contraception for at least 4 weeks before beginning ZENBEXUS therapy, during therapy, during dose interruptions and for at least 4 weeks after last dose of ZENBEXUS therapy [see Contraindications (4) and Use in Specific Populations (8.1)].

Two negative pregnancy tests with a sensitivity of at least 25 mIU/mL must be obtained prior to initiating therapy. Pregnancy testing should be performed weekly during the first 4 weeks of treatment. Thereafter, testing should occur every 4 weeks in patients with regular menstrual cycles, or every 2 weeks in patients with irregular menstrual cycles [see Use in Specific Populations (8.3)].

Females of reproductive potential taking ZENBEXUS must not donate eggs during treatment and for 4 weeks after completion [see Use in Specific Populations (8.3)].

ZENBEXUS may pass into human semen. Advise patients who can impregnate partners to use effective contraception during treatment and for 4 weeks following the discontinuation of ZENBEXUS therapy [see Use in Specific Populations (8.1, 8.3)].

Male patients taking ZENBEXUS must not donate sperm during treatment and for 4 weeks after completion [see Use in Specific Populations (8.3)].

Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking ZENBEXUS and for at least 4 weeks after discontinuing ZENBEXUS, even if they have undergone a successful vasectomy.

Male patients taking ZENBEXUS must not donate sperm during treatment and for 4 weeks after discontinuing ZENBEXUS [see Warnings and Precautions (5.1)].

Patients must not donate blood during treatment with ZENBEXUS and for 4 weeks following discontinuation of ZENBEXUS therapy.

ZENBEXUS is available only through a restricted program called ZENBEXUS REMS, because of the risk of embryo-fetal toxicity [see Warnings and Precautions (5.1)].

Notable requirements of the ZENBEXUS REMS Program include the following:

• Prescribers must be certified by enrolling in the ZENBEXUS REMS Program.
• Patients must enroll in the ZENBEXUS REMS Program and comply with ongoing monitoring and contraception requirements [see Boxed Warning, Warnings and Precautions (5.1), and Use in Specific Populations (8.3)].
• Pharmacies must be certified by enrolling in the ZENBEXUS REMS Program and must only dispense to patients who are authorized to receive ZENBEXUS.
• Wholesalers and distributors must only distribute to certified pharmacies.

Further information about ZENBEXUS REMS is available at www.ZENBEXUSREMS.com or by telephone at 1-888-423-5436.

ZENBEXUS can cause serious and life-threatening venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke). In the EXCALIBER-RRMM study evaluating ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd), venous thromboembolic events occurred in 6.4% of patients despite mandatory thromboembolism prophylaxis in the IberDd arm (N=204). The incidence of deep venous thrombosis was 3.4% and the incidence of pulmonary embolism was 1.5%.

Arterial thromboembolic events occurred in 3.4% of patients. The incidence of myocardial infarction was 2.0%, and the incidence of stroke (CVA) was 1.5%.

Monitor patients for signs and symptoms of thromboembolic events during treatment with ZENBEXUS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient's underlying risk factors. In patients who develop a thromboembolism, interrupt ZENBEXUS and initiate anticoagulant therapy according to guidelines [see Dosage and Administration (2.3)].

ZENBEXUS can cause severe neutropenia [see Adverse Reactions (6.1)].

In the EXCALIBER-RRMM study, neutropenia All Grades was reported in 90.2% and Grade 3 in 30.9% and Grade 4 in 53.4% of patients in the IberDd arm (N=204).

Febrile neutropenia occurred in 5.4% of patients.

The median time to Grade 3 or 4 neutropenia was 21 days. The median duration of Grade 3 or 4 neutropenia was 8 days. Treatment interruption due to neutropenia occurred in 51.5% of patients in the IberDd arm, and discontinuation due to neutropenia was required in 1% of patients in the IberDd arm.

Monitor complete blood count throughout treatment with ZENBEXUS. Interrupt, reduce dosage, or discontinue ZENBEXUS, as necessary [see Dosage and Administration (2.3)]. Initiate GCSF as appropriate per guidelines.

ZENBEXUS can cause serious infections, including life-threatening or fatal infections [see Adverse Reactions (6.1)]. Patients with active or uncontrolled infection should not start ZENBEXUS treatment until the infection is controlled.

In the EXCALIBER-RRMM study, infections, including opportunistic infections, were reported in 78.9%, Grade 3 in 35.8%, Grade 4 in 3.4%, and fatal infections occurred in 2% of patients in the IberDd arm (N=204). Serious infections occurred in 40% of patients. Discontinuations due to infections occurred in 1.5% of patients.

Monitor patients for signs and symptoms of infection prior to and during treatment with ZENBEXUS and treat appropriately. Withhold or reduce the dose based on severity [see Dosage and Administration (2.3)].

Consider prophylactic anti-infective medications according to current practice guidelines.

In the EXCALIBER-RRMM study, at a median follow-up time of 16 months, second primary malignancies (SPM) occurred in 6.9% of patients in the IberDd arm and in 4.9% of patients in the daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) arm [see Adverse Reactions (6.1)].

Monitor patients for the development of second primary malignancies.

The following clinically significant adverse reactions are described elsewhere in the labeling.

• Serious Venous and Arterial Thromboembolism [see Warnings and Precautions (5.3)]
• Neutropenia [see Warnings and Precautions (5.4)]
• Infections [see Warnings and Precautions (5.5)]
• Second Primary Malignancies [see Warnings and Precautions (5.6)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in EXCALIBER-RRMM, a two-stage, phase 3, randomized, multicenter open-label study in patients with relapsed or refractory multiple myeloma (RRMM) after 1 or 2 prior lines of therapy [see Clinical Studies (14)]. Patients were randomized to receive ZENBEXUS (at 1 of 3 dose levels) in combination with daratumumab and hyaluronidase-fihj and dexamethasone or daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) in stage 1, and ZENBEXUS 1 mg in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) or DVd in stage 2. The MRD Primary Analysis Group included the first 420 patients randomized to ZENBEXUS 1 mg in combination with Dd (N=207) or DVd (N=213) in stage 1 and stage 2. Safety was assessed in patients in the MRD Primary Analysis Group who received at least one dose of the study drug (IberDd: N=204; DVd: N=204). Among patients who received ZENBEXUS, 86% were exposed for 6 months or longer and 73% were exposed for greater than one year.

Serious adverse reactions occurred in 58.3% of patients who received ZENBEXUS. Serious adverse reactions in ≥2% of patients included pneumonia (26%), upper respiratory tract infection (6.4%), second primary malignancy (5.9%), neutropenia (4.9%), febrile neutropenia (3.9%), COVID-19 (4.4%), and sepsis (2.9%). Fatal adverse reactions occurred in 10 patients (4.9%) who received ZENBEXUS. Sepsis (1.5%) was the only fatal drug reaction that occurred in more than 1 patient. The following fatal adverse reactions occurred in one patient each: listeria encephalitis, influenza, lung adenocarcinoma, cardiac arrest, large intestine perforation, metabolic acidosis, and respiratory failure.

Permanent discontinuation of ZENBEXUS due to an adverse reaction occurred in 7.8% of patients. The most frequent adverse reaction which resulted in permanent ZENBEXUS discontinuation was neutropenia (1%).

Dosage interruption of ZENBEXUS due to an adverse reaction occurred in 84% of patients. Adverse reactions which required dosage interruption in >10% of patients included neutropenia, upper respiratory tract infection, pneumonia and COVID-19.

Dosage reductions of ZENBEXUS due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dose reductions in >2% of patients included neutropenia, fatigue, pneumonia, and sensory neuropathy.

The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorder, hypogammaglobulinemia, COVID-19, and constipation.

The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased neutrophils, decreased white blood cells, and decreased lymphocytes.

Tables 2 and 3 summarize adverse reactions and laboratory abnormalities, respectively, in the EXCALIBER-RRMM study.

Clinically relevant adverse reactions in <10% of patients who received ZENBEXUS (in combination with daratumumab and hyaluronidase-fihj and dexamethasone) included:

• Venous thromboembolic event (includes retinal vein occlusion, pulmonary embolism, deep vein thrombosis, embolism venous, post thrombotic syndrome, superficial vein thrombosis, and thrombophlebitis).
• Arterial thromboembolic event (includes myocardial infarction, stress cardiomyopathy, ischemic stroke, lacunar infarction, peripheral arterial occlusive disease).
• Second primary malignancy
• Febrile neutropenia
• Sepsis
• Hepatotoxicity

Table 3: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline

The denominator used to calculate the rate varied from 201 to 204 for both IberDd and DVd arms based on the number of patients with a baseline value and at least one post-treatment value.

in Patients Who Received ZENBEXUS in EXCALIBER-RRMM

Laboratory Abnormality	ZENBEXUS + Daratumumab and hyaluronidase-fihj + Dexamethasone (IberDd)		Daratumumab and hyaluronidase-fihj + Bortezomib + Dexamethasone (DVd)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Neutrophil count decreased	97	77	48	11
White blood cell count decreased	95	69	64	18
Lymphocytes count decreased	91	62	81	51
Platelet count decreased	62	9	92	46
Hemoglobin decreased	58	6	63	6
Chemistry
Blood calcium decreased	44	2	28	1
Blood alkaline phosphatase increased	33	0.5	26	0.5

Avoid concomitant use of strong or moderate CYP3A inhibitors with ZENBEXUS. If concomitant use cannot be avoided, reduce ZENBEXUS dose [see Dosage and Administration (2.4)].

Iberdomide is primarily metabolized by CYP3A. Concomitant use with strong or moderate CYP3A inhibitors increases iberdomide exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.

Avoid concomitant use of strong or moderate CYP3A inducers with ZENBEXUS.

Iberdomide is primarily metabolized by CYP3A. Concomitant use with a strong or moderate CYP3A inducer decreases iberdomide exposure [see Clinical Pharmacology (12.3)], which may decrease efficacy.

There is a pregnancy exposure registry that monitors outcomes in patients exposed to ZENBEXUS during pregnancy. Report any suspected fetal exposure to ZENBEXUS to the FDA via the MedWatch program at 1-800-FDA-1088 and to the REMS Call Center at 1-888-423-5436.

Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies, ZENBEXUS can cause birth defects or embryo-fetal death in humans when administered to a pregnant female and is contraindicated during pregnancy [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].

ZENBEXUS has a shared mechanism of action with thalidomide. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented, and mortality at or shortly after birth has been reported in about 40% of infants.

There are no available data on the use of ZENBEXUS in pregnant women to evaluate for drug associated risk. Oral administration of iberdomide in pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities. Iberdomide crossed the placenta after administration to pregnant rats and rabbits (see Data). Advise patients of the potential risk to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to ZENBEXUS to the REMS Call Center at 1-888-423-5436.

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.

There is no information regarding the presence of iberdomide or its metabolites in human milk, the effects of ZENBEXUS on the breastfed child, or the effects of ZENBEXUS on milk production. Iberdomide was excreted in the milk of lactating rats (see Data). Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from ZENBEXUS, advise women not to breastfeed during treatment with ZENBEXUS. Refer to daratumumab and hyaluronidase-fihj or dexamethasone prescribing information for additional information.

Iberdomide caused adverse developmental outcomes in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis.

Pregnant rats were administered oral doses of 0.6, 50, or 300 mg/kg/day. At 300 mg/kg/day, adverse effects included increased post-implantation loss, fetal resorptions, reduced numbers of viable fetuses, lower fetal body weights, and the occurrence of external and skeletal malformations in the head (acephaly, dome shaped, meningoencephalocele), eyes (malpositioned, microphthalmia), mouth (cleft lip, small tongue, misshapen palate), ear(s) (misshapen or small), cervical vertebrae (fused or misshapen neural arches), pectoral girdle (bent scapula), skull (fused or misshapen bones), and sternum (sternoschisis).

Pregnant rabbits were administered oral doses of 0.3, 50 or 300 mg/kg/day. At doses of 300 mg/kg/day, increased abortions were observed. At doses of ≥50 mg/kg/day developmental effects included increased post-implantation loss, fetal resorptions, reduced numbers of viable fetuses, decreased fetal body weights, and external, skeletal, and visceral malformations in the entire body and hindlimbs (edema), tail (short), gallbladder and thyroid (absent), aortic arch (small), interventricular septum (discontinuous), cervical vertebrae (fused, misshapen neural arches), skull (fused or misshapen bones), and sternum (fused).

In rats, fetal plasma concentration levels on gestation day (GD) 17 were 17 to 22% of the maternal concentration at 2 hours post-dosing, and in rabbits, fetal plasma concentration levels on GD 17 were 2 to 4% of the maternal concentration at 2 hours post-dosing. This indicates that iberdomide crossed the placenta.

Following a single oral administration of iberdomide to lactating rats, the milk to plasma concentration ratios ranged from 12 to 32 for iberdomide over the 12 hour post-dose period, indicating iberdomide is excreted into rat milk.

ZENBEXUS can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)].

Verify the pregnancy status of females of reproductive potential prior to initiating ZENBEXUS therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking ZENBEXUS, during dose interruptions and for at least 4 weeks after last dose of ZENBEXUS therapy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Females of reproductive potential must have 2 negative pregnancy tests before initiating ZENBEXUS. The first test should be performed within 10 to 14 days, and the second test within 24 hours prior to prescribing ZENBEXUS. Pregnancy testing should be performed weekly during the first 4 weeks of treatment. Thereafter, testing should occur every 4 weeks in patients with regular menstrual cycles, or every 2 weeks in patients with irregular menstrual cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. ZENBEXUS treatment must be discontinued during this evaluation.

Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 effective forms of contraception simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner's vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with ZENBEXUS, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of ZENBEXUS therapy. Effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.

Based on findings in animals, ZENBEXUS may impair male or female fertility. The effects of iberdomide on fertility were reversible in males [see Nonclinical Toxicology (13.1)].

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

Of the 207 patients who were randomized to IberDd and included in the minimal residual disease (MRD) analysis group in EXCALIBER-RRMM study, 39% of adult patients were younger than 65 years of age, 43% were 65 years of age to younger than 75 years of age, and 19% were 75 years and over [see Clinical Studies (14)]. No overall differences in effectiveness were observed between elderly patients and younger patients.

In patients treated with IberDd, the incidence of serious adverse reactions was 53%, 56%, and 74% in adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age, and 75 years of age and older, respectively [see Adverse Reactions (6.1)].

Reduce ZENBEXUS dose in patients with eGFR less than 30 mL/min/1.73 m² not on dialysis [see Dosage and Administration (2.5)].

Iberdomide exposure increased in subjects with eGFR less than 30 mL/min/1.73 m² not on dialysis [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions.

ZENBEXUS capsules contain iberdomide hydrochloride, iberdomide is a cereblon-modulating protein degrader. The chemical name of iberdomide hydrochloride is (3S)-3-[4-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione hydrochloride and the chemical structure is as follows:

Chemical Structure (Chem Structure)

The molecular formula for iberdomide hydrochloride is C₂₅H₂₇N₃O₅HCl and the molecular weight is 485.97.

ZENBEXUS capsules contain 0.75 mg or 1 mg of iberdomide (equivalent to 0.81 mg or 1.08 mg respectively of iberdomide hydrochloride) in HPMC capsules and the following inactive ingredients: anhydrous lactose, pregelatinized starch, and stearic acid.

The HPMC capsule shell contain hypromellose, iron oxide black, iron oxide yellow, and titanium dioxide. The 0.75 mg capsule shell also contains iron oxide red. The 0.75 mg capsule is imprinted with white ink that contains povidone, propylene glycol, shellac, sodium hydroxide, and titanium dioxide. The 1 mg capsule is imprinted with white and black ink that contains iron oxide black, potassium hydroxide, povidone, propylene glycol, shellac, sodium hydroxide, strong ammonia solution, and titanium dioxide.

Iberdomide is a cereblon-modulating protein degrader that binds to cereblon, a substrate recognition component of an E3 ubiquitin ligase complex. Iberdomide engages cereblon and facilitates recruitment, ubiquitination, and proteasomal degradation of the transcription factors, Aiolos and Ikaros, resulting in anti‑tumor and immunomodulatory activity.

In vitro and in vivo, iberdomide treatment showed anti-tumor activity in multiple myeloma (MM) cells and xenografts including in lenalidomide- and pomalidomide-resistant MM cell lines. Immunomodulatory properties of iberdomide include increased secretion of the immune stimulatory cytokines (interleukin-2 and interferon-gamma), inhibition of proinflammatory cytokine release (interleukin-6), enhanced immune mediated killing of MM cells, and prevention of T-cell exhaustion. In vitro, the combination of iberdomide and daratumumab produced an increase in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) activity of daratumumab against multiple myeloma cells. In vivo, iberdomide showed increased anti-tumor activity in combination with dexamethasone or daratumumab compared to iberdomide, dexamethasone or daratumumab alone.

In patients with relapsed or refractory multiple myeloma, at a dose of 1 mg, iberdomide in combination with daratumumab and dexamethasone decreases B cells, natural killer (NK) cells, and naïve CD8⁺ T cells, and increases effector memory CD8⁺ T cells, HLA-DR expression on CD8⁺ T cells, and Ki-67–positive CD4+ and CD8+ T cells and NK cells.

Iberdomide exposure-response analyses demonstrated no clinically relevant relationship between systemic iberdomide exposure level and efficacy following iberdomide dose of 1 to 1.6 mg (1 to 1.6 times the recommended dosage). Increasing iberdomide exposure was associated with higher risk of Grade 3+ neutropenia and at least 1 dose modification due to treatment-emergent adverse events (TEAE).

At 2.6-times the mean maximum concentration produced by the recommended ZENBEXUS dosage, a clinically relevant QT interval prolongation was not observed.

Iberdomide pharmacokinetic parameters for patients with multiple myeloma receiving the recommended approved dosage at steady state are presented as mean (% CV), unless otherwise specified.

Iberdomide maximum plasma concentration (C_max) is 6.35 ng/mL (30%) and area under the concentration-time curve (AUC) is 82.6 ng*h/mL (32%). Drug accumulation is approximately two-fold. Iberdomide C_max and AUC are approximately dose-proportional over the dose range of 0.1 mg to 6 mg (0.1 to 6 times the recommended dosage) following a single oral dose in healthy subjects.

Iberdomide median (min, max) time to C_max (T_max) at steady state is 2 (2, 10) hours.

No clinically significant difference in iberdomide PK is expected following administration of ZENBEXUS with food.

Iberdomide volume of distribution (V_ss/F) is 415 L (40%). In vitro plasma protein binding is 75% and is not concentration-dependent. In vitro blood-to-plasma ratio is 0.78.

Iberdomide terminal elimination half-life (t_1/2) is 37 hours (51%) and apparent oral clearance (CL/F) is 12.3 L/h (38%).

Iberdomide is metabolized primarily by CYP3A.

Following a single oral administration of [¹⁴C] iberdomide to healthy subjects, approximately 46% of the dose was eliminated in urine (16% as unchanged drug) and 43% of the dose was eliminated in feces (11% as unchanged drug).

No clinically significant differences in the pharmacokinetics of iberdomide were observed based on age (36 to 90 years), sex (45% female), race (65% White, 27% Asian, and 4% African American), body weight (37.6 kg to 137 kg), body mass index (16.7 to 49.7 kg/m²), body surface area (1.27 to 2.60 m²), or hepatic impairment (Child-Pugh Class A, B, and C).

Subjects with eGFR less than 30 mL/min/1.73 m² not on dialysis exhibited 1.8-fold higher AUC and comparable C_max compared to healthy subjects.

No clinically significant differences in the pharmacokinetics of iberdomide were observed based on eGFR in patients with eGFR greater than 30 mL/min/1.73 m² or in subjects with eGFR less than 30 mL/min/1.73 m² requiring intermittent hemodialysis. Dialysis clearance (3.07 L/hr) was 16% of total clearance in subjects with kidney failure requiring intermittent hemodialysis.

Strong CYP3A Inhibitors: Itraconazole (strong CYP3A inhibitor) increased iberdomide AUC to 2.4-fold in healthy subjects.

Moderate CYP3A Inhibitors: Fluconazole or diltiazem (moderate CYP3A inhibitors) is predicted to increase iberdomide C_max to 1.5-fold and AUC to 1.7-fold in patients with cancer.

Strong CYP3A Inducers: Rifampin (strong CYP3A inducer) decreased iberdomide C_max to 29% and AUC to 10% in healthy subjects.

Moderate CYP3A Inducers: Efavirenz (moderate CYP3A inducer) is predicted to decrease iberdomide C_max to approximately 50% and AUC to approximately 30% in patients with cancer.

Other Drugs: Coadministration of iberdomide with daratumumab and dexamethasone, mild CYP3A inhibitors and inducers, or P-gp inhibitors is not predicted to have clinically significant effect on iberdomide PK.

Cytochrome P450 (CYP) Enzymes: Iberdomide does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. Iberdomide does not induce CYP1A2, CYP2B6, or CYP3A.

Transporter Systems: Iberdomide is a substrate of P-gp and BCRP. Iberdomide is not a substrate of OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or MRP2. Iberdomide does not inhibit P-gp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, MRP2, MATE1, or MATE2-K.

Carcinogenicity studies have not been conducted for iberdomide.

Iberdomide was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay but was clastogenic in the in vitro assay using human peripheral blood lymphocytes. Subsequently, iberdomide was negative in the in vivo micronucleus assay and DNA damage in liver (Comet assay) in rats and, therefore, iberdomide is not genotoxic.

In the 9-month monkey study, animals were treated with oral doses of up to 0.4 mg/kg/day. Testicular hypospermatogenesis and intraluminal cell debris in the epididymis occurred at the high dose of 0.40 mg/kg/day (approximately 3-fold greater than the human exposure at the recommended dose based on AUC at steady state).

In a fertility and early embryonic development toxicity study in rabbits, males and females were treated with oral doses of up to 50 mg/kg and 15 mg/kg, respectively, and were mated with untreated rabbits. Treatment in males began 65 days prior to mating, continued during mating and for up to 81 days post-mating. In females, treatment began 14 days prior to mating, continued during mating and until GD 7. Males treated with ≥5 mg/kg/day (approximately 32-fold greater than the human exposure at the recommended dose based on AUC steady state) had epithelial cell degeneration in seminiferous tubules, cellular debris in epididymal lumen, and abnormal sperm morphology. These effects were reversible after stopping dosing. Due to mortality in males at doses ≥5 mg/kg/day, mating and effects on fertility were not evaluated. Female rabbits had reduced fertility and increased pre- and post-implantation loss at ≥5 mg/kg/day (approximately 50-fold greater than the human exposure at the recommended dose based on AUC at steady state).

The efficacy of ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) compared with daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) was evaluated in adult patients with relapsed or refractory multiple myeloma (RRMM) in a phase 3, two-stage, randomized, multicenter open-label study (EXCALIBER-RRMM) (NCT04975997). The study included patients who had previously received one or two prior lines of therapy. Patients who had disease refractory to a prior anti-CD38 monoclonal antibody therapy, or to prior bortezomib were excluded.

Patients received ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone (Dd) as follows:

Dosing in IberDd arm (28-day cycles):

• Iberdomide (oral): 1 mg, Day 1-21;
• Daratumumab and hyaluronidase-fihj (subcutaneous): 1800 mg Cycles 1-2 on Days 1, 8, 15 and 22; Cycles 3-6 on Days 1 and 15; Cycles 7+ on Days 1;
• Dexamethasone (oral): 20 or 40 mg on Days 1, 8, 15 and 22.

Treatment in both arms was administered until disease progression or unacceptable toxicity.

The major efficacy outcome measure was minimal residual disease (MRD) negative complete response (CR) at any time.

A total of 939 patients were randomized to 1 of 3 dose levels of ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) or to daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) across stage 1 (n=279), or to ZENBEXUS 1 mg in combination with Dd or DVd in stage 2 (n=660) in EXCALIBER-RRMM. The primary efficacy population for MRD negativity included the first 420 patients randomized to ZENBEXUS 1 mg in combination with Dd in stage 1 and stage 2 (N=207) or (DVd) in stage 1 and stage 2 (N=213).

In the primary efficacy population for MRD negativity, the median age was 68 years (range: 35 to 87); 42% were female; 61% were White, 1% were Black, 35% were Asian, and 2% were Hispanic or Latino. Sixty-three percent had International Staging System (ISS) Stage I, 25% had ISS Stage II and 12% had ISS Stage III disease. High-risk cytogenetics presence of del(17p), t(4;14), or t(14; 16) were present in 22% of patients. Extramedullary disease was present in 11% of patients.

The median number of prior lines of therapy was 1 (range 1 to 2), with 67% who received one prior line of therapy, and 33% who received 2 prior lines of therapy. Ninety percent of patients received prior immunomodulatory agents (70% received prior lenalidomide, 34% received prior thalidomide, and 5% received prior pomalidomide), and 95% received a prior proteasome inhibitor. Four percent of patients received a prior anti-CD38 monoclonal antibody. There is limited data with ZENBEXUS in combination with daratumumab and dexamethasone in patients who have received or are refractory to prior anti-CD38 monoclonal antibody therapy.

The efficacy results are shown in Table 4.

Table 4: Efficacy Results in EXCALIBER-RRMM in the Primary Efficacy Population for MRD Negativity

Endpoint	ZENBEXUS + Daratumumab and Hyaluronidase-fihj + Dexamethasone (IberDd) (N=207)	Daratumumab and hyaluronidase-fihj + Bortezomib + Dexamethasone (DVd) (N=213)
Response was based on Independent Review Committee (IRC) assessment per International Myeloma Working Group (IMWG) 2016 criteria.
Minimal Residual Disease (MRD) negative complete response (≥ CR) at any time, n(%) Based on a threshold of 10-5 using a Hematogenix Next Generation Flow Cytometry assay.	85 (41)	44 (21)
(95% CI)	(34, 48)	(15, 27)
p-value The 2-stage combined one-sided p-value based on Miettinen-Nurminen with CMH weights, stratified by number of prior lines (1 vs 2), Age (≤70 vs >70) and ISS staging (I and II vs III).	<0.0001

In the iberdomide arm, among patients who achieved a CR, 89% (85/95) were MRD negative; whereas, in the control arm, among patients who achieved a CR, 83% (44/53) were MRD negative.

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/hazardous-drugs

ZENBEXUS™ (iberdomide) capsules, 0.75 mg, light gray opaque cap imprinted with “BMS” in white ink and dark brown opaque body imprinted with “0.75 mg” in white ink, are supplied as follows:

• Bottle of 21 capsules (NDC 0003-5700-21).

ZENBEXUS™ (iberdomide) capsules, 1 mg, light gray opaque cap imprinted with “BMS” in white ink and ivory opaque body imprinted with “1 mg” in black ink, are supplied as follows:

• Bottle of 21 capsules (NDC 0003-5710-21).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Store and dispense in the original bottle with desiccant. Replace the cap securely each time after opening. Do not discard the desiccant.

The capsules should not be removed until just prior to dosing.

ZENBEXUS is a hazardous drug. Follow applicable special handling and disposal procedures.1

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

Embryo-Fetal Toxicity

Advise patients that ZENBEXUS is contraindicated in pregnancy and can cause birth defects or embryo-fetal death in humans [see Boxed Warning and Contraindications (4)].

• Advise females of reproductive potential that they must avoid pregnancy while taking ZENBEXUS and for at least 4 weeks after completing therapy.
• Initiate ZENBEXUS treatment in females of reproductive potential only following two negative pregnancy tests.
• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during ZENBEXUS therapy, during dose interruption and for 4 weeks after she has completely finished taking ZENBEXUS. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch, or implants) and a partner's vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm, and cervical cap.
• Instruct patient to immediately stop taking ZENBEXUS and contact her healthcare provider if patient becomes pregnant while taking this drug, if patient misses her menstrual period, or experiences unusual menstrual bleeding, stops taking birth control, or thinks FOR ANY REASON that the patient may be pregnant.
• Advise patient that if her healthcare provider is not available, she should call the REMS Call Center at 1-888-423-5436 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].
• ZENBEXUS may pass into human semen. Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking ZENBEXUS and for at least 4 weeks after discontinuing ZENBEXUS, even if they have undergone a successful vasectomy.
• Advise male patients taking ZENBEXUS that they must not donate sperm while taking ZENBEXUS and for 4 weeks after discontinuing ZENBEXUS [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].
• Advise females of reproductive potential taking ZENBEXUS that they must not donate eggs [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].
• All patients must be instructed to not donate blood while taking ZENBEXUS and for 4 weeks following discontinuation of ZENBEXUS [see Warnings and Precautions (5.1)].

ZENBEXUS REMS Program

Because of the risk of embryo-fetal toxicity, ZENBEXUS is only available through a restricted program called the ZENBEXUS REMS Program [see Warnings and Precautions (5.2)].

Patients must sign a Patient Enrollment Form and comply with the requirements to receive ZENBEXUS. In particular, females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Warnings and Precautions (5.2) and Use in Specific Populations (8.3)].

ZENBEXUS is available only from pharmacies that are certified in the ZENBEXUS REMS program.

Pregnancy Exposure Registry

Inform females that there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to ZENBEXUS during pregnancy and advise them to contact the REMS Call Center by calling 1-888-423-5436 [see Use in Specific Populations (8.1)].

Serious Thromboembolic Events

Inform patients of the risk of venous and arterial thromboembolic events including DVT, PE, MI and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation [see Warnings and Precautions (5.3)].

Neutropenia

Advise patients to contact their healthcare provider if they have a fever [see Warnings and Precautions (5.4)].

Infections

Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection [see Warnings and Precautions (5.5)].

Second Primary Malignancies

Inform patients of the risk of developing SPM during treatment with ZENBEXUS [see Warnings and Precautions (5.6)].

Administration

Advise patients to swallow ZENBEXUS capsules whole and not to open, break, or chew the capsule. Advise patients to wash their hands immediately if they come in contact with the capsule contents.

Storage Instructions

Advise patients to keep ZENBEXUS in the original container.

Manufactured by:

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

ZENBEXUS is a trademark of Bristol-Myers Squibb Company.

21 Capsules

NDC 0003-5700-21

Zenbexus™

(iberdomide) capsules

0.75 mg

WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS

Dispense with accompanying Medication Guide.

Rx Only

Bristol Myers Squibb^®

Zenbexus 0.75 mg Respresentative Packaging (Zenbexus 0.75mg Label.jpg)

21 Capsules

NDC 0003-5710-21

Zenbexus™

(iberdomide) capsules

1 mg

WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS

Dispense with accompanying Medication Guide.

Rx Only

Bristol Myers Squibb^®

Zenbexus 1 mg Representative Packaging (Zenbexus 1mg Label)