umbralisib (Discontinued)

>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

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

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.

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])

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)