umbralisib (Discontinued)

Brand and Other Names:Ukoniq
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Dosing & Uses

AdultPediatric

Marginal Zone Lymphoma or Follicular Lymphoma

In April 2022, umbralisib was voluntarily withdrawn for marginal zone lymphoma and follicular lymphoma

The decision was based on recently updated overall survival (OS) data from the UNITY-CLL Phase 3 trial that showed an increasing imbalance in OS

Dosage Modifications

Dose reductions for adverse reactions

  • First dose reduction: 600 mg qDay
  • Second dose reduction: 400 mg qDay
  • Unable to tolerate 400 mg/day: Permanently discontinue

Neutropenia

  • Absolute neutrophil count (ANC) 0.5-1 x 109/L
    • Maintain dose
    • If recurs or persistent, then withhold until ANC ≥1 x 109/L, then resume at same dose
  • ANC <0.5 x 109/L
    • Withhold until ANC ≥0.5 x 109/L, then resume at same dose
    • If recurs, then resume at reduced dose

Thrombocytopenia

  • Platelet count 25 to <50 x 109/L with bleeding OR <25 x 109/L
  • Withhold until platelet count ≥25 x 109/L and bleeding resolved (if applicable), then resume at same dose
  • If recurs, withhold until resolved, then resume at reduced dose

Infection

Includes opportunistic infection

  • Grade 3 or 4 infection
    • Withhold until resolved, then resume at same or reduced dose
  • Pneumocystis jirovecii pneumonia (PJP)
    • Suspected PJP: Withhold until evaluated
    • Confirmed PJP: Permanently discontinue
  • Cytomegalovirus (CMV) infection
    • Withhold until infection or viremia resolves, then resume at same or reduced dose
    • Monitor for CMV reactivation by polymerase chain reaction or antigen test at least monthly

Elevated ALT/AST

  • ALT/AST >5x to <20x ULN: Withhold until AST/ALT <3x ULN, then resume at reduced dose
  • ALT/AST >20x ULN: Discontinue

Diarrhea or noninfectious colitis

  • Withhold until resolved, then resume at same or reduced dose
    • Persistent mild or moderate diarrhea (≤6 stools/day over baseline) OR
    • Persistent asymptomatic (Grade 1) colitis
    • If recurs, withhold until resolved, then resume at reduced dose
  • Withhold until resolved, then resume at reduced dose
    • Severe diarrhea (>6 stools/day over baseline) OR
    • Abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs
  • Discontinue
    • Recurrent severe diarrhea or colitis (any grade)
    • Life-threatening diarrhea or noninfectious colitis

Severe cutaneous reactions

  • Severe
    • Withhold until resolved, then resume at reduced dose or discontinue
    • If recurs after rechallenge, discontinue
  • Discontinue
    • Life-threatening cutaneous reactions
    • Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (any grade)

Other adverse reactions

  • Severe: Withhold until resolved, then resume at same or reduced dose
  • Life-threatening: Discontinue

Renal impairment

  • Mild or moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
  • Severe (CrCl <30 mL/min): Not studied

Hepatic impairment

  • Mild (total bilirubin ≤1.5x ULN and any AST): No dosage adjustment necessary
  • Moderate or severe (total bilirubin >1.5x ULN and any AST): Not studied

Dosing Considerations

Verify pregnancy status in females of reproductive potential before initiation

Prophylaxis

  • Provide prophylaxis for PJP during treatment
  • Consider prophylactic antivirals during treatment to prevent CMV infection, including CMV reactivation

Monitoring parameter

  • Hepatic function: Baseline, during treatment
  • Neutrophil counts
    • First 2 months: At least every 2 weeks
    • Patients with neutrophil count <1 x 109: At least weekly

Safety and efficacy not established

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Interactions

Interaction Checker

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                    Adverse Effects

                    >10%

                    All grades

                    • Creatinine increased (79%)
                    • Diarrhea (58%)
                    • Fatigue (41%)
                    • Nausea (38%)
                    • Neutrophils decreased (33%)
                    • ALT increased (33%)
                    • AST increased (32%)
                    • Hemoglobin decreased (27%)
                    • Musculoskeletal pain (27%)
                    • Platelets decreased (26%)
                    • Potassium decreased (21%)
                    • Vomiting (21%)
                    • Upper respiratory tract infection (21%)
                    • Abdominal pain (19%)
                    • Decreased appetite (19%)
                    • Rash (18%)
                    • Edema (14%)
                    • Insomnia (14%)

                    Grade 3 or 4

                    • Neutrophil decreased (16%)

                    1-10%

                    All grades

                    • Pyrexia (10%)
                    • Urinary tract infection (9%)
                    • Dyspnea (7%)
                    • Pneumonia (6%)
                    • Sepsis (3%)
                    • Colitis (2%)

                    Grade 3 or 4

                    • Diarrhea (10%)
                    • ALT increased (8%)
                    • AST increased (7%)
                    • Platelets decreased (4%)
                    • Potassium decreased (4%)
                    • Hemoglobin decreased (3%)
                    • Rash (3%)
                    • Fatigue (3%)
                    • Abdominal pain (3%)
                    • Musculoskeletal pain (2%)
                    • Decreased appetite (2%)

                    <1%

                    Grade 3 or 4

                    • Pneumonitis
                    • Exfoliative dermatitis
                    • Nausea
                    • Vomiting
                    • Edema
                    • Upper respiratory tract infection
                    • Insomnia
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                    Warnings

                    Contraindications

                    None

                    Cautions

                    Serious neutropenia reported; monitor and consider appropriate supportive care

                    Serious diarrhea or noninfectious colitis occurred; monitor for development of diarrhea or colitis and provide supportive care (ie, antidiarrheals, enteric-acting steroids) as appropriate

                    Serious hepatotoxicity occurred; median time to onset for grade ≥3 elevated AST/ALT monitor hepatic function

                    Contains FD&C yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma); incidence of sensitivity frequently seen in patients who also have aspirin hypersensitivity

                    Can cause fetal harm when administered to pregnant females

                    Infections

                    • Serious, including fatal, infections occurred
                    • Monitor for fever, CMV infection, and any new or worsening signs and symptoms of infection
                    • Evaluate promptly and treat as needed
                    • Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and consider prophylactic antivirals for CMV prevention during treatment

                    Severe cutaneous reactions

                    • Severe cutaneous reactions, including a fatal case of exfoliative dermatitis
                    • Monitor for new or worsening cutaneous reactions
                    • Review all concomitant medications and discontinue any potentially contributing medications
                    • Provide supportive care as appropriate

                    Increased risk of death

                    • February 2, 2022: FDA is investigating possible increased risk of death with umbralisib
                    • FDA determined that initial findings from a clinical trial showed or reported a possible increased risk of death in treated patients taking the medicine
                    • FDA is re-evaluating this risk against the benefits of umbralisib for its approved uses; results from UNITY trial will continue to be evaluated and a future public meeting will discuss findings and explore continued marketing of umbralisib
                    • Enrollment of new patients in other ongoing umbralisib clinical trials has been suspended while findings are being reviewed
                    • Review patients’ progress on umbralisib and discuss the risks and benefits of continuing treatment in the context of other available treatments

                    Drug interaction overview

                    • Substrate of CYP1A2, CYP2C9, and CYP3A4
                    • Inhibits CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-gp; induces CYP3A4
                    • Coadministration with strong CYP3A4 or CYP2C9 inhibitors and inducers: Not studied
                    • Coadministration with sensitive substrates of CYP3A4, CYP2C8, CYP2C9 and CYP2C19, or P-gp substrates: Not fully characterized
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                    Pregnancy & Lactation

                    Pregnancy

                    May cause fetal harm when administered to pregnant females

                    Data are not available on use in pregnant females

                    Verify pregnancy status in females of reproductive potential before initiation

                    Animal data

                    • Administration to pregnant mice during organogenesis resulted in adverse developmental outcomes (eg, alterations to growth, embryofetal mortality, structural abnormalities) at maternal exposures (AUC) comparable to 800-mg dose

                    Contraception

                    • Females of reproductive potential: Use effective contraception during treatment and for 1 month after last dose
                    • Males with female partners of reproductive potential: Use effective contraception during treatment and for 1 month after last dose

                    Infertility

                    • Based on findings from mice and dogs, male fertility may be impaired
                    • Trend for reversibility noted in dogs 30 days after last dose

                    Lactation

                    No data available on presence in milk, effects on breastfed children, or milk production

                    Pregnancy Categories

                    A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                    B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                    C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                    D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                    X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                    NA: Information not available.

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                    Pharmacology

                    Mechanism of Action

                    Dual inhibitor of phosphatidylinositol-3-kinase (PI3K) delta and casein kinase (CK1) 1-epsilon expressed on malignant B cells

                    PI3K-delta plays an important role in supporting cell proliferation and survival, cell differentiation, intercellular trafficking and immunity

                    CK1-epsilon is a regulator of oncoprotein translation and has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies

                    Absorption

                    Peak plasma concentration (steady-state): 7.3 mcg/mL

                    Peak plasma time: ~4 hr

                    AUC (steady-state): 141 mcg⋅hr/mL

                    Effect of food

                    • A single dose with a high-fat, high-calorie meal (~917 calories [171 calories from protein, 232 calories from carbohydrate, and 502 calories from fat]) increased AUC and peak plasma concentration

                    Distribution

                    Protein bound: ≥99.7%

                    Vd (central): 312 L

                    Mean blood-to-plasma ration: 0.6

                    Metabolism

                    Metabolized by CYP2C9, CYP3A4, and CYP1A2

                    Elimination

                    Half-life: 91 hr

                    Clearance: 15.5 L/hr

                    Excretion: ~81% (feces [17% unchanged]); 3% (urine [0.02% unchanged])

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                    Administration

                    Oral Administration

                    Take with food at same time each day

                    Swallow tablet whole; do not crush, break, cut, or chew

                    Provide prophylaxis (ie, antivirals) for PJP during treatment

                    Missed dose

                    • Vomited dose: Skip dose; wait for next scheduled dose
                    • Missed dose ≥12 hr from next dose: Take as soon as possible
                    • Missed dose <12 hr from next dose: Skip dose; wait for next scheduled dose

                    Storage

                    Store at 68-77ºF (20-25ºC); excursions permitted to 59-86ºF (15-30ºC)

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                    Images

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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.