Zenbexus
Iberdomide · Capsule · Oral
Uses
1 INDICATIONS AND USAGE 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). ZENBEXUS is a cereblon-modulating protein degrader 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. (1) This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete response (CR) at any time. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Dosage and administration
• Recommended dosage: 1 mg orally once daily with or without food on Days 1 to 21 of repeated 28-day cycles until disease progression or unacceptable toxicity. (2.2)
• See Full Prescribing Information for recommended ZENBEXUS dosage modifications. (2.3 , 2.4 , 2.5) 2.1 Pregnancy Testing Prior to Administration 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) ] . 2.2 Recommended Dosage 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. 2.3 Dosage Modifications The recommended dosage modifications for adverse reactions are provided in Table 1. Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Dosage Modification Refer to daratumumab and hyaluronidase-fihj and dexamethasone Prescribing Information for information about dosage modifications for daratumumab and hyaluronidase-fihj and dexamethasone. Neutropenia (Absolute neutrophil count [ANC] <500 cells/mcL) [see Warnings and Precautions (5.4) ] Grade 4
• Interrupt ZENBEXUS.
• Consider initiating granulocyte colony-stimulating factor (GCSF), as appropriate.
• Follow complete blood count (CBC) at least weekly.
• ANC must return to ≥1,000 cells/mcL before restarting.
• The dose of ZENBEXUS may be maintained if neutropenia was the only ZENBEXUS-related toxicity requiring a dose modification and GCSF treatments are continued.
• If a dose reduction is clinically appropriate, decrease ZENBEXUS to 0.75 mg once daily when restarting treatment. Febrile Neutropenia (ANC <1,000 cells/mcL with a single temperature of >38.3°C [101°F] or with a sustained temperature of ≥38°C [100.4°F] for more than 1 hour) Grade 3 Thrombocytopenia (platelet count <25,000/mcL) Grade 4
• Withhold ZENBEXUS for the remainder of the cycle.
• Platelet count must return to ≥50,000/mcL before restarting.
• Decrease ZENBEXUS to 0.75 mg once daily when restarting treatment. Thrombocytopenia with bleeding or any requirement for a platelet transfusion Grade 3 Thromboembolism [see Warnings and Precautions (5.3) ] ≥ Grade 3
• Interrupt ZENBEXUS.
• Initiate anticoagulant therapy.
• Restart treatment at a decreased ZENBEXUS dose to 0.75 mg once daily when acute symptoms of thrombosis/embolism have been resolved, at the discretion of the treating physician. Other ZENBEXUS related adverse reactions [see Adverse Reactions (6.1) ] ≥ Grade 3
• Interrupt ZENBEXUS.
• Restart ZENBEXUS when adverse event has resolved or improved to ≤ Grade 2.
• If a dose reduction is clinically appropriate, decrease ZENBEXUS to 0.75 mg once daily when restarting treatment. 2.4 Dosage Modifications for CYP3A Inhibitors 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. 2.5 Recommended Dosage in Patients with Renal Impairment In patients with eGFR less than 30 mL/min/1.73 m 2 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 m 2 or eGFR less than 30 mL/min/1.73 m 2 receiving intermittent hemodialysis, no dose adjustment is recommended [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.6 Administration 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. Delayed or Missed Doses 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.
Dosage forms and strengths
3 DOSAGE FORMS AND STRENGTHS 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.
• Capsules: 0.75 and 1 mg. (3)
Contraindications
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.
• Pregnancy (Boxed Warning , 4 , 5.1 , 8.1)
Warnings and precautions
• Neutropenia : Monitor complete blood counts at baseline and throughout treatment. Interrupt, reduce, or discontinue ZENBEXUS and initiate growth factor support as appropriate. (2.3 , 5.4)
• Infections : Can cause severe, life-threatening, or fatal infections. Monitor patients for signs and symptoms of infection, including opportunistic infections, and treat appropriately. (5.5)
• Second Primary Malignancies : Monitor patients for the development of second primary malignancies. (5.6) 5.1 Embryo-Fetal Toxicity 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 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) ] . Males 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) ] . Blood Donation Patients must not donate blood during treatment with ZENBEXUS and for 4 weeks following discontinuation of ZENBEXUS therapy. 5.2 ZENBEXUS REMS 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. 5.3 Serious Venous and Arterial Thromboembolism 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) ] . 5.4 Neutropenia 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. 5.5 Infections 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.
Side effects
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) ] Most common (≥20%) adverse reactions with ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone are upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorder, hypogammaglobulinemia, COVID-19, and constipation. The most common Grade 3 or 4 (≥30%) laboratory abnormalities are neutrophil count decreased, white blood cell count decreased, and lymphocyte count decreased. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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. Table 2: Adverse Reactions (≥10%) in Patients Who Received ZENBEXUS in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone in EXCALIBER-RRMM Adverse reactions were graded according to NCI CTCAE Version 5.0. Adverse Reaction ZENBEXUS + Daratumumab and Hyaluronidase-fihj + Dexamethasone (IberDd) (n=204) Daratumumab and Hyaluronidase-fihj + Bortezomib + Dexamethasone (DVd) (n=204) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, sinusitis, and other related terms. 54 Includes fatal adverse reaction: IberDd (n=1). 6 52 6 Pneumonia Pneumonia includes atypical pneumonia, bacterial pneumonia, lower respiratory tract infection, lung consolidation, viral pneumonia and other related terms. 34 25 17 10 COVID-19 Includes other related terms. 23 3.9 16 2.9 General disorders and administration site conditions Fatigue 36 3.4 33 2.5 Edema 17 0.5 24 1 Pyrexia 14 1 15 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 35 1.5 33 2.9 Bone pain 11 1 13 0.5 Gastrointestinal disorders Diarrhea 33 4.9 36 6 Constipation 20 0 22 1 Nausea 14 0.5 6 0 Nervous system disorders Motor dysfunction Motor dysfunction includes ataxia, balance disorder, gait disturbance, muscle contracture, muscle spasms, muscular weakness, myopathy, paralysis, peripheral motor neuropathy and other related terms. 26 1.5 17 2.5 Sensory neuropathy Sensory neuropathy includes anosmia, hypoesthesia, mononeuropathy, neuralgia, paresthesia, peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy, radiculopathy and other related terms.
Drug interactions
• Strong or moderate CYP3A inhibitors: Avoid concomitant use with ZENBEXUS or, if concomitant use is unavoidable, reduce dose. (2.3 , 7.1)
• Strong or moderate CYP3A inducers: Avoid concomitant use with ZENBEXUS. (7.1) 7.1 Effects of Other Drugs on ZENBEXUS Strong or Moderate CYP3A Inhibitors 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. Strong or Moderate CYP3A Inducers 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.
Use in specific populations
• Lactation: Advise not to breastfeed. (8.2)
• Renal impairment: Reduce dose in patients with eGFR less than 30 mL/min/1.73 m 2 not on dialysis. (2.5) 8.1 Pregnancy Pregnancy Exposure Registry 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. Risk Summary 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. Data Animal Data 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. 8.2 Lactation Risk Summary 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. Data Animal Data 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. 8.3 Females and Males of Reproductive Potential ZENBEXUS can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1) ] . Pregnancy Testing 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.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry 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. Risk Summary 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. Data Animal Data 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.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of ZENBEXUS have not been established in pediatric patients.
Geriatric use
8.5 Geriatric Use 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) ] .
Description
11 DESCRIPTION ZENBEXUS capsules contain iberdomide hydrochloride, iberdomide is a cereblon-modulating protein degrader. The chemical name of iberdomide hydrochloride is (3 S )-3-[4-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1-oxo-2,3-dihydro-1 H -isoindol-2-yl]piperidine-2,6-dione hydrochloride and the chemical structure is as follows: The molecular formula for iberdomide hydrochloride is C 25 H 27 N 3 O 5 HCl 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. chemical structure
Mechanism of action
12.1 Mechanism of Action 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.
How supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 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
Patient information
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.
Label text from the FDA structured product label by E.R. Squibb & Sons, L.L.C. (revised Aug 13, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Iberdomide Hydrochloride in 2 products
Zenbexus NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0003-5700 | Iberdomide Hydrochloride .75 mg/1 Capsule | E.R. Squibb & Sons, L.L.C. | NDA |
| 0003-5710 | Iberdomide Hydrochloride 1 mg/1 Capsule | E.R. Squibb & Sons, L.L.C. | NDA |
Frequently asked questions
What is Zenbexus used for?
1 INDICATIONS AND USAGE 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…
What are the side effects of Zenbexus?
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) ] Most common (≥20%) adverse reactions with… See the full label for the complete list.
Who makes Zenbexus?
Zenbexus is listed by 1 labeler in the FDA NDC directory, including E.R. Squibb & Sons, L.L.C..