ZENBEXUS Capsule Ref.[116893] Active ingredients: Iberdomide

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.

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.

5.6 Second Primary Malignancies

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.

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.
^* Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, sinusitis, and other related terms.
^† Includes fatal adverse reaction: IberDd (n=1).
^‡ Pneumonia includes atypical pneumonia, bacterial pneumonia, lower respiratory tract infection, lung consolidation, viral pneumonia and other related terms.
^§ Includes other related terms.
^¶ Motor dysfunction includes ataxia, balance disorder, gait disturbance, muscle contracture, muscle spasms, muscular weakness, myopathy, paralysis, peripheral motor neuropathy and other related terms.
^# Sensory neuropathy includes anosmia, hypoesthesia, mononeuropathy, neuralgia, paresthesia, peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy, radiculopathy and other related terms.
^Þ Sleep disorder includes insomnia, restless legs syndrome, sleep disorder and other related terms.
^ß Hypogammaglobulinemia includes hypogammaglobulinemia, hypoglobulinemia, and other related terms.
^à Hemorrhage includes epistaxis, gastrointestinal hemorrhage, hematuria, injection site hemorrhage, rectal hemorrhage, subarachnoid hemorrhage, subdural hematoma and other related terms.

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* in Patients Who Received ZENBEXUS in EXCALIBER-RRMM:

^* 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.

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.

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.

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.

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. 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.

Contraception

Females

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.

Males

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)].

Infertility

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.