Umbralisib is a dual phosphatidylinositol 3-kinase (PI3K)-delta and casein kinase-1 (CK1)-epsilon inhibitor. On February 3, 2022, the FDA suspended enrollment of new patients in ongoing clinical trials of umbralisib and on June 1, 2022 FDA approval for the treatment of marginal zone lymphoma and follicular lymphoma was withdrawn due to a possible increased risk of death with an umbralisib-containing regimen compared with standard treatment in patients with chronic lymphocytic leukemia in a randomized, phase 3 (UNITY-CLL) trial. Health care professionals should stop prescribing umbralisib and switch patients to alternative treatments; TG Therapeutics plans to make it available under expanded access under limited circumstances in which a patient may be receiving benefit from umbralisib.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer umbralisib with food at the same time each day.
-Swallow tablets whole; do not crush, break, cut, or chew tablets.
-If a dose is missed, take it within 12 hours of the time it is usually taken. After more than 12 hours, skip the dose and resume dosing on the following day at the usual time.
-If vomiting occurs, do not administer an additional dose; resume dosing the following day at the usual time.
Diarrhea or noninfectious colitis occurred in 53% (grade 3, 9%) of patients with hematologic malignancies who received single-agent umbralisib (n = 335) in clinical studies;. Monitor patients for signs and symptoms of diarrhea or colitis. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop diarrhea or colitis. Give supportive care (e.g., antidiarrheals or enteric acting steroids) as appropriate. In a pooled safety population, diarrhea (58%; grade 3 or 4, 10%), colitis (2%), nausea (38%; grade 3 or 4, less than 1%), vomiting (21%; grade 3 or 4, less than 1%), abdominal pain (19%; grade 3 or 4, 3%), and decreased appetite/anorexia (19%; grade 3 or 4, 2%) were reported in patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
In a pooled safety population, fatigue was reported in 41% (grade 3 or 4, 3%) of patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies. The term fatigue included asthenia and lethargy.
In a pooled safety population, edema was reported in 14% (grade 3 or 4, less than 1%) of patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies. The term edema included peripheral edema, face edema, pulmonary edema, and fluid overload.
In a pooled safety population, fever was reported in 10% of patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
In a pooled safety population, musculoskeletal pain was reported in 27% (grade 3 or 4, 2%) of patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies. The term musculoskeletal pain included back pain, myalgia, extremity pain, bone pain (e.g., neck pain and spinal pain) musculoskeletal chest pain, and musculoskeletal discomfort.
Grade 3 or higher infection occurred in 10% of patients with hematologic malignancies who received single-agent umbralisib (n = 335) in clinical studies; fatal infections were reported in less than 1% of patients. Monitor patients for fever or other signs and symptoms of infection; treat promptly. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop severe infection. Hold umbralisib therapy in patients with suspected Pneumocystis jirovecii pneumonia (PJP) infection; permanently discontinue therapy in patients with confirmed PJP. Evaluate patients with a history of cytomegalovirus (CMV) infection for signs and symptoms of CMV reactivation during therapy; consider CMV prophylaxis. If therapy is resumed in patients who had confirmed CMV, monitor for CMV reactivation (i.e., PCR or antigen test) at least monthly. In a pooled safety population, respiratory tract infection (21%; grade 3 or 4, less than 1%), urinary tract infection (9%), pneumonia (6%), and sepsis (3%) were reported in patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies. The term respiratory tract infection included sinusitis, naso-pharyngitis, and rhinitis.
Grade 3 cutaneous reactions occurred in 2% of patients with hematologic malignancies who received single-agent umbralisib (n = 335) in clinical studies; 1 case of fatal exfoliative dermatitis was reported. Monitor patients for the development of new or worsening cutaneous reactions. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop severe cutaneous reactions; provide supportive care as indicated and monitor weekly until resolution. Discontinue umbralisib in patients diagnosed with Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS). In a pooled safety population, rash (18%; grade 3 or 4, 3%) and exfoliative dermatitis (less than 1%) were reported in patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies. The term rash included maculopapular rash, erythematous rash/erythema, pruritic rash/pruritus, and exfoliative dermatitis.
In a pooled safety population, insomnia was reported in 14% (grade 3 or 4, less than 1%) of patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
In a pooled safety population, dyspnea (7%) and pneumonitis (less than 1%) were reported in patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
Grade 3 or 4 neutropenia occurred in 18% of patients with hematologic malignancies who received single-agent umbralisib (n = 335) in clinical studies. Monitor complete blood counts at least every 2 weeks for the first 2 months of therapy, and at least weekly if neutrophil counts are less than 1 x 109 cells/L. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop severe myelosuppression. Provide supportive care as indicated. In a pooled safety population, neutropenia (33%; grade 3 or 4, 16%), anemia (27%; grade 3 or 4, 3%), and thrombocytopenia (26%; grade 3 or 4, 4%) were reported in patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
Severe elevated hepatic enzymes occurred in 8% (grade 3) and less than 1% (grade 4) of patients with hematologic malignancies who received single-agent umbralisib (n = 335) in clinical studies. Monitor hepatic function (e.g., liver function tests) prior to and during umbralisib treatment. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop hepatic disease/impairment. Increased ALT (33%; grade 3 or 4, 8%) and AST (32%; grade 3 or 4, 7%) levels were reported in patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
In a pooled safety population, nephrotoxicity, specifically increased serum creatinine level, was reported in 79% of patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
In a pooled safety population, hypokalemia was reported in 21% (grade 3 or 4, 4%) of patients with marginal zone lymphoma and follicular lymphoma who received single-agent umbralisib (n = 221) in clinical studies.
Serious infection has been reported with umbralisib therapy including sepsis; some infections were fatal. Monitor patients for fever or other signs and symptoms of infection; treat promptly. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop severe infection. Administer Pneumocystis jirovecii pneumonia (PJP) prophylaxis in all patients during umbralisib therapy. Hold umbralisib therapy in patients with suspected PJP infection; permanently discontinue therapy in patients with confirmed PJP. Evaluate patients with a history of cytomegalovirus (CMV) infection for signs and symptoms of CMV reactivation during therapy; consider CMV prophylaxis. If therapy is resumed in patients who had confirmed CMV, monitor for CMV reactivation (i.e., PCR or antigen test) at least monthly.
Severe neutropenia has been reported with umbralisib therapy. Monitor complete blood counts at least every 2 weeks for the first 2 months of therapy, and at least weekly if neutrophil counts are less than 1 x 109 cells/L. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop severe myelosuppression. Provide supportive care as indicated.
Serious diarrhea or colitis has been reported with umbralisib therapy. Monitor patients for signs and symptoms of diarrhea or colitis. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop diarrhea or colitis. Give supportive care (e.g., antidiarrheals or enteric acting steroids) as appropriate.
Severe hepatotoxicity has been reported with umbralisib therapy. Monitor liver function tests prior to and during umbralisib treatment. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop hepatic disease/impairment.
Serious rash including exfoliative dermatitis has been reported with umbralisib therapy. Monitor patients for the development of new or worsening cutaneous reactions. Therapy interruption, dosage reduction, or discontinuation may be necessary in patients who develop severe cutaneous reactions; provide supportive care as indicated. Discontinue umbralisib in patients diagnosed with Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms.
Umbralisib contains tartrazine dye (FD&C yellow no. 5). Patients with tartrazine dye hypersensitivity who take umbralisib may be at risk for developing allergic reactions (e.g., bronchial asthma). Tartrazine sensitivity frequently occurs in patients who also have aspirin hypersensitivity.
Geriatric patients aged 65 years and older who received umbralisib had more serious adverse reactions (23% vs. 12%) including infection (13% vs. 4%) compared with younger patients.
Umbralisib may cause fetal harm if administered during pregnancy based on its mechanism of action and data from animal studies. Apprise pregnant women of the potential hazard to the fetus if umbralisib is used during pregnancy. In an animal study, umbralisib caused embryo-fetal toxicity (e.g., folded retina, delayed ossification of sternebrae and vertebrae, increased resorptions, and increased post-implantation loss) when given to pregnant mice during organogenesis at doses that resulted in exposures comparable to human exposure at the recommended dose of 800 mg.
Counsel patients about the reproductive risk and contraception requirements during umbralisib treatment. Pregnancy testing prior to starting umbralisib therapy is recommended for females of reproductive potential. These patients should avoid pregnancy and use effective contraception during therapy and for 1 month after the last umbralisib dose. Women who become pregnant while receiving umbralisib should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, men with female partners of reproductive potential should use effective contraception during umbralisib therapy and for 1 month after the last dose. Women who become pregnant while receiving umbralisib should be apprised of the potential hazard to the fetus. Umbralisib may cause infertility in men based on animal data. There was a trend for reversibility 30 days after the last dose in data from a study in dogs.
It is not known if umbralisib is present in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in the breast-fed child, women should discontinue breast-feeding during umbralisib therapy and for 1 month after the last dose.
For the treatment of non-Hodgkin's lymphoma (NHL)*:
NOTE: FDA approval was removed for this indication in June 2022 after initial accelerated approval due to a possible increased risk of death in the UNITY-CLL trial.
-for the treatment of relapsed or refractory marginal zone lymphoma (MZL) in patients who have received at least 1 prior anti-CD20-based regimen:
NOTE: FDA approval was removed for this indication in June 2022 after initial accelerated approval due to a possible increased risk of death in the UNITY-CLL trial.
Oral dosage:
Adults: Dosage not established.
-for the treatment of relapsed or refractory follicular lymphoma (FL) in patients who have received at least 3 prior lines of systemic therapy:
NOTE: FDA approval was removed for this indication in June 2022 after initial accelerated approval due to a possible increased risk of death in the UNITY-CLL trial.
Oral dosage:
Adults: Dosage not established.
Maximum Dosage Limits:
-Adults
Dosage not established.
-Geriatric
Dosage not established.
-Adolescents
Dosage not established.
-Children
Dosage not established.
-Infants
Dosage not established.
-Neonates
Dosage not established.
Patients with Hepatic Impairment Dosing
Dosage not established.
Patients with Renal Impairment Dosing
Dosage not established.
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Umbralisib is a dual phosphatidylinositol 3-kinase (PI3K)-delta and casein kinase-1 (CK1)-epsilon inhibitor. PI3K-delta is expressed in both normal and malignant B-cells; CK1-epsilon may contribute to the pathogenesis of cancer cells, including in lymphoid malignancies. Umbralisib also inhibited a mutated form of ABL1 in biochemical assays. In vitro, it inhibited cell proliferation, CXCL12-mediated cell adhesion, and CCL19-mediated cell migration in lymphoma cell lines.
Umbralisib is administered orally. It is 99.7% or greater bound to plasma proteins, without dependence on concentration. The mean blood-to-plasma ratio is 0.6. Following umbralisib administration, the mean apparent central volume of distribution is 312 L (coefficient of variance (CV), 185%), the mean apparent clearance is 15.5 L/hour (CV, 52%), and the effective half-life is 91 hours (CV, 42%). Following a single radiolabeled dose of umbralisib 800 mg orally, 81% of the dose was recovered in the feces (17% unchanged) and 3% of the dose was recovered in the urine (0.02% unchanged).
Affected cytochrome P450 isoenzymes and transporters: none known in vivo
In vitro, umbralisib is metabolized by CYP2C9, CYP3A4, and CYP1A2. It inhibits CYP2C8, CYP2C9, CYP2C19, and CYP3A4; induces CYP3A4; and inhibits P-glycoprotein (P-gp) in vitro. There was no clinically significant impact on the pharmacokinetic parameters of umbralisib when umbralisib was administered with the proton pump inhibitor, omeprazole. Otherwise, coadministration with CYP450 substrates, inhibitors, and inducers or drug transporters (e.g., P-gp) has not been studied or fully characterized.
-Route-Specific Pharmacokinetics
Oral Route
Umbralisib exposure increases in a dose-proportional manner at a dosage range of 200 to 1,000 mg once daily. The mean steady-state Cmax and AUC values were 7.3 mcg/mL (CV, 39%) and 141 mcg x hour/mL (CV, 46%), respectively, following umbralisib 800 mg once daily. The median Tmax of umbralisib is about 4 hours. A 3.8-fold and 6.4-fold accumulation of Cmax and AUC values, respectively, occurs at the recommended dosage.
Effect of food: Administration of a single dose of umbralisib with a high-fat, high-calorie meal (approximately 917 calories; with 171 calories from protein, 232 calories from carbohydrates, and 502 calories from fat) increased the Cmax by 115% and the AUC by 61% relative to fasting conditions.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin level at or below the ULN and AST level more than the ULN OR a total bilirubin level of more than 1 to 1.5 times the ULN and any AST level) had no clinically significant impact on the pharmacokinetic parameters of umbralisib. The effect of moderate to severe hepatic impairment on the PK parameters of umbralisib has not been evaluated.
Renal Impairment
Mild and moderate renal impairment (creatinine clearance (CrCl) of 30 to 89 mL/min) had no clinically significant impact on the pharmacokinetic (PK) parameters of umbralisib. The effect of severe renal impairment (CrCl of 15 to 29 mL/min) or dialysis on the PK parameters of umbralisib has not been evaluated.
Geriatric
Age (range, 18 to 87 years) had no clinically significant impact on the pharmacokinetic parameters of umbralisib.
Gender Differences
Sex had no clinically significant impact on the pharmacokinetic parameters of umbralisib.
Ethnic Differences
Race (White and Black) had no clinically significant impact on the pharmacokinetic parameters of umbralisib. The effect of other races or ethnicities on the PK parameters of umbralisib has not been evaluated.
Obesity
Body weight (range, 44 to 165 kg) had no clinically significant impact on the pharmacokinetic parameters of umbralisib.