Umbralisib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]
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Overview
Umbralisib is a a kinase inhibitor that is FDA approved for the treatment of adult patients with:
- Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen.
- Relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.
These indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. Common adverse reactions include increased creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, Nausea and vomiting\ vomiting, abdominal pain, decreased appetite, and rash.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Marginal Zone Lymphoma
UKONIQ is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen. This indication is approved under accelerated approval based on overall response rate . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
Follicular Lymphoma
UKONIQ is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy. This indication is approved under accelerated approval based on overall response rate.Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
DOSAGE AND ADMINISTRATION
Recommended Dosage
- The recommended dosage of UKONIQ is 800 mg taken orally once daily with food until disease progression or unacceptable toxicity.
Advise patients of the following:
- Swallow tablets whole. Do not crush, break, cut, or chew tablets.
- Take UKONIQ at the same time each day.
- If vomiting occurs, do not take an additional dose; continue with the next scheduled dose.
- If a dose is missed, take a missed dose unless it is less than 12 hours until the next scheduled dose.
Recommended Prophylaxis
Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) during treatment with UKONIQ.
Consider prophylactic antivirals during treatment with UKONIQ to prevent cytomegalovirus (CMV) infection, including CMV reactivation.
Dosage Modifications for Adverse Reactions
- Recommended dosage modifications of UKONIQ for adverse reactions are presented in Table 1
- The recommended dose reductions of UKONIQ for adverse reactions are presented in Table 2
DOSAGE FORMS AND STRENGTH
Tablets: 200 mg, green film-coated, oval-shaped with “L474” on one side and plain on the other side.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Umbralisib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Umbralisib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Umbralisib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Umbralisib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Umbralisib in pediatric patients.
Contraindications
None.
Warnings
Infections
- Serious, including fatal, infections occurred in patients treated with UKONIQ. Grade 3 or higher infections occurred in 10% of 335 patients, with fatal infections occurring in <1%. The most frequent Grade ≥3 infections included pneumonia, sepsis, and urinary tract infection. The median time to onset of Grade ≥3 infection was 2.4 months (range: 1 day to 21 months).
- Monitor for any new or worsening signs and symptoms of infection. For Grade 3 or 4 infection, withhold UKONIQ until infection has resolved. Resume UKONIQ at the same or a reduced dose.
- Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) during treatment with UKONIQ.
- Withhold UKONIQ in patients with suspected PJP of any grade and permanently discontinue in patients with confirmed PJP.
- Monitor for cytomegalovirus (CMV) infection during treatment with UKONIQ in patients with a history of CMV infection. Consider prophylactic antivirals during treatment with UKONIQ to prevent CMV infection, including CMV reactivation.
- For clinical CMV infection or viremia, withhold UKONIQ until infection or viremia resolves. If UKONIQ is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.
Neutropenia
- Serious neutropenia occurred in patients treated with UKONIQ. Grade 3 neutropenia developed in 9% of 335 patients and Grade 4 neutropenia developed in 9% .The median time to onset of Grade 3 or 4 neutropenia was 45 days.
- Monitor neutrophil counts at least every 2 weeks for the first 2 months of UKONIQ and at least weekly in patients with neutrophil counts (Grade 3-4). Consider supportive care as appropriate. Withhold, reduce dose, or discontinue UKONIQ depending on the severity and persistence of neutropenia.
Diarrhea or Non-infectious Colitis
- Serious diarrhea or non-infectious colitis occurred in patients treated with UKONIQ. Any grade diarrhea or colitis occurred in 53% of 335 patients and Grade 3 occurred in 9%.
- The median time to onset for any grade diarrhea or colitis was 1 month (range: 1 day to 23 months), with 75% of cases occurring by 2.9 months.
- For patients with severe diarrhea (Grade 3, i.e., >6stools per day over baseline) or abdominal pain, stool with mucus or blood, change in bowel habits, or peritoneal signs, withhold UKONIQ until resolved and provide supportive care with antidiarrheals or enteric acting steroids as appropriate. Upon resolution, resume UKONIQ at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue UKONIQ. Discontinue UKONIQ for lifethreatening diarrhea or colitis
Hepatotoxicity
- Serious hepatotoxicity occurred in patients treated with UKONIQ. Grade 3 and 4 transaminase elevations (ALT and/or AST) occurred in 8% and<1%,respectively, in 335 patients. The median time to onset for Grade 3 or higher transaminase elevations was 2.2 months (range: 15 days to 4.7 months).
- Monitor hepatic function at baseline and during treatment with UKONIQ. For ALT/AST greater than 5 to less than 20 times ULN, withhold UKONIQ until return to less than 3 times ULN, then resume at a reduced dose. For ALT/AST elevation greater than 20 times ULN, discontinue UKONIQ.
Severe Cutaneous Reactions
- Severe cutaneous reactions, including a fatal case of exfoliative dermatitis, occurred in patients treated with UKONIQ. Grade 3 cutaneous reactions occurred in 2% of 335 patients and included exfoliative dermatitis, erythema, and rash (primarily maculo-papular) The median time to onset of Grade 3 or higher cutaneous reaction was 15 days (range: 9 days to 6.4 months).
- Monitor patients for new or worsening cutaneous reactions. Review all concomitant medications and discontinue any potentially contributing medications. Withhold UKONIQ for severe (Grade 3) cutaneous reactions until resolution. Monitor at least weekly until resolved. Upon resolution, resume UKONIQ at a reduced dose. Discontinue UKONIQ if severe cutaneous reaction does not improve, worsens, or recurs. Discontinue UKONIQ for life-threatening cutaneous reactions or SJS, TEN, or DRESS of any grade.Provide supportive care as appropriate.
Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5
- UKONIQ contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Embryo-Fetal Toxicity
- Based on findings in animals and its mechanism of action, UKONIQ can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of umbralisib to pregnant mice during the period of organogenesis caused adverse developmental outcomes including embryo-fetal mortality and fetal malformations at maternal exposures comparable to those in patients at the recommended dose of 800 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose.
Adverse Reactions
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 compared to rates in the clinical trials of another drug and may not reflect the rates observed in the general patient population.
- The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to UKONIQ as monotherapy at a dosage of 800 mg orally once daily in 335 adults with hematologic malignancies in studies TGR-1202-101, TGR-1202-202, UTX-TGR-205, and UTXTGR-501. Among these 335 patients who received UKONIQ, 52% were exposed for 6 months or longer and 30% were exposed for greater than one year.
Relapsed or Refractory Follicular Lymphoma and Marginal Zone Lymphoma
- The safety of UKONIQ was evaluated in a pooled safety population that included 221 adults with marginal zone lymphoma (37%) and follicular lymphoma (63%) enrolled in three singlearm, open-label trials (Study TGR-1202-101, TGR-1202-202, and UTX-TGR-205) and one open-label extension trial (Study UTX-TGR-501). These trials required hepatic transaminases ≤ 2.5 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and creatinine clearance ≥ 30 mL/min. No patients had prior exposure to a PI3K inhibitor. Patients received UKONIQ 800 mg orally once daily. Among these 221 patients who received UKONIQ, 60% were exposed for 6 months or longer and 34% were exposed for greater than one year.
- The median age was 66 years (range: 29 to 88 years), 43% were female, and 97% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Race was reported in 92% of patients; of these patients, 89% were White, 6% were Black, and 3% were Asian. Patients had a median of 2 prior therapies (range 1 to 10).
- Serious adverse reactions occurred in 18% of patients who received UKONIQ. Serious adverse reactions that occurred in ≥2% of patients were diarrhea-colitis (4%), pneumonia (3%), sepsis (2%), and urinary tract infection (2%). Fatal adverse reactions occurred in <1% of patients who received UKONIQ, including exfoliative dermatitis.
- Permanent discontinuation of UKONIQ due to an adverse reaction occurred in 14% of patients. Adverse reactions which resulted in permanent discontinuation of UKONIQ in ≥5% of patients included diarrhea-colitis (6%) and transaminase elevation (5%).
- Dose reductions of UKONIQ due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dose reductions in ≥4% of patients included diarrhea-colitis (4%). Dosage interruptions of UKONIQ due to an adverse reaction occurred in 43% of patients. Adverse reactions which required dosage interruption in ≥5% of patients included diarrheacolitis (18%), transaminase elevation (7%), neutropenia (5%), vomiting (5%), and upper respiratory tract infection (5%).
- The most common (≥15%) adverse reactions, including laboratory abnormalities, were increased creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash.
Clinically relevant adverse reactions in <10% of patients who received UKONIQ included urinary tract infection (9%), dyspnea (7%), pneumonia (6%), sepsis (3%), colitis (2%), pneumonitis (<1%) and exfoliative dermatitis (<1%)
Postmarketing Experience
There is limited information regarding Umbralisib Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Umbralisib Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Risk Summary
- Based on findings from animal studies and the mechanism of action. UKONIQ can cause fetal harm when administered to a pregnant woman. There are no available data on UKONIQ use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, administration of umbralisib to pregnant mice during organogenesis resulted in adverse developmental outcomes, including alterations to growth, embryo-fetal mortality, and structural abnormalities at maternal exposures (AUC) comparable to those in patients at the recommended dose of 800 mg (see Data). Advise pregnant women of the potential risk to a fetus.
- 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
- In an embryo-fetal development study in mice, pregnant animals were administered oral doses of umbralisib at 100, 200, and 400 mg/kg/day during the period of organogenesis. Malformations were observed at doses of 200 mg/kg/day (cleft palate) and 400 mg/kg/day (cleft palate and nasopharyngeal fistula). Additional findings occurred starting at the dose of 100 mg/kg/day and included folded retina, delayed ossification of sternebrae and vertebrae, increased resorptions, and increased post-implantation loss. The exposure (AUC) at a dose of 100 mg/kg/day in mice is approximately equivalent to the human exposure at the recommended dose of 800 mg.
- In an embryo-fetal development study in rabbits, pregnant animals were administered oral doses of umbralisib at 30, 100, and 300 mg/kg/day during the period of organogenesis. Administration at 300 mg/kg/day resulted in maternal toxicity (decreased food consumption and body weight) and reduced fetal weights. The exposure (AUC) at 300 mg/kg/day in rabbits is approximately 0.03 times the exposure in human patients at the recommended dose of 800 mg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Umbralisib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Umbralisib during labor and delivery.
Nursing Mothers
Risk Summary
There are no data on the presence of umbralisib in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions from umbralisib in the breastfed child, advise women not to breastfeed during treatment with UKONIQ and for one month after the last dose.
Pediatric Use
Safety and effectiveness of UKONIQ have not been established in pediatric patients.
Geriatic Use
Of the 221 patients with MZL or FL who received UKONIQ in clinical studies, 56% of patients were 65 years of age and older, while 19% were 75 years of age and older. No overall differences in effectiveness or pharmacokinetics were observed between these patients and younger patients. In patients 65 years of age and older, 23% experienced serious adverse reactions compared to 12% in patients younger than 65 years of age. There was a higher incidence of infectious serious adverse reactions in patients 65 years of age or older (13%) compared to patients younger than 65 years of age (4%).
Gender
There is no FDA guidance on the use of Umbralisib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Umbralisib with respect to specific racial populations.
Renal Impairment
No dose adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault equation). . UKONIQ has not been studied in patients with severe renal impairment ([CLcr] < 30 mL/min).
Hepatic Impairment
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin >1 to 1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)]. UKONIQ has not been studied in patients with moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin > 3 × ULN and any AST).
Females of Reproductive Potential and Males
UKONIQ may cause fetal harm when administered to a pregnant woman.
Pregnancy Testing
- Verify pregnancy status in females of reproductive potential prior to initiating UKONIQ.
Contraception
Females
- Advise females of reproductive potential to use effective contraception during treatment with
UKONIQ and for one month after the last dose.
Males
- Advise males with female partners of reproductive potential to use effective contraception during
treatment with UKONIQ and for one month after the last dose.
Infertility
Males
- Based on the findings from mice and dogs, UKONIQ may impair male fertility. Trend for reversibility was noted in dogs 30 days after the last dose.
Immunocompromised Patients
There is no FDA guidance one the use of Umbralisib in patients who are immunocompromised.
Follicular Lymphoma
The efficacy of UKONIQ was evaluated in a single-arm cohort of Study UTX-TGR-205, an open-label, multi-center, multi-cohort trial (NCT02793583). Patients with relapsed or refractory FL were required to have received at least two prior systemic therapies, including an anti-CD20 monoclonal antibody and an alkylating agent. The trial excluded patients with Grade 3b FL, large cell transformation, prior allogeneic transplant, history of CNS lymphoma, and prior exposure to a PI3K inhibitor. Patients received UKONIQ 800 mg orally once daily until disease progression or unacceptable toxicity. A total of 117 patients with FL were enrolled in this cohort. The median age was 65 years (range: 29 to 87 years), 38% were female, 80% were White, 4% were Black, 73% had Stage IIIIV disease, 38% had bulky disease and 97% had a baseline ECOG performance status of 0 to 1. Patients had a median of 3 prior lines of therapy (range: 1 to 10), with 36% refractory to their last therapy. Efficacy was based on overall response rate as assessed by an Independent Review Committee (IRC) using criteria adopted from the International Working Group criteria for malignant lymphoma. The median follow-up time was 20.1 months (range: 13.5 to 29.6 months). Efficacy results are shown in Table 6.
Administration and Monitoring
Administration
Recommended Dosage
- The recommended dosage of UKONIQ is 800 mg taken orally once daily with food until disease progression or unacceptable toxicity.
Advise patients of the following:
- Swallow tablets whole. Do not crush, break, cut, or chew tablets.
- Take UKONIQ at the same time each day.
- If vomiting occurs, do not take an additional dose; continue with the next scheduled dose.
- If a dose is missed, take a missed dose unless it is less than 12 hours until the next scheduled dose.
Recommended Prophylaxis
- Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) during treatment with UKONIQ.
- Consider prophylactic antivirals during treatment with UKONIQ to prevent cytomegalovirus (CMV) infection, including CMV reactivation.
Dosage Modifications for Adverse Reactions
Recommended dosage modifications of UKONIQ for adverse reactions are presented in Table 1
and the recommended dose reductions of UKONIQ for adverse reactions are presented in Table 2
DOSAGE FORMS AND STRENGTH
Tablets: 200 mg, green film-coated, oval-shaped with “L474” on one side and plain on the other side.
Monitoring
Monitor for fever and any new or worsening signs and symptoms of infection. Evaluate promptly and treat as needed.
IV Compatibility
There is limited information regarding the compatibility of Umbralisib and IV administrations.
Overdosage
There is limited information regarding Umbralisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Umbralisib Pharmacology in the drug label.
Mechanism of Action
Umbralisib inhibits multiple kinases. In biochemical and cell-based assays, umbralisib inhibited PI3Kδ and casein kinase CK1ε. PI3Kδ is expressed in normal and malignant B-cells; CK1ε has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies. Umbralisib also inhibited a mutated form of ABL1 in biochemical assays. Umbralisib inhibited cell proliferation, CXCL12-mediated cell adhesion, and CCL19-mediated cell migration in lymphoma cell lines in studies conducted in vitro.
Structure
Umbralisib is a kinase inhibitor. The active pharmaceutical ingredient is umbralisib tosylate with the molecular formula C38H32F3N5O6S and a molecular weight of 743.75 g/mol. The chemical name for umbralisib tosylate is ( S ) -2- ( 1- ( 4-amino-3- ( 3-fluoro-4-isopropoxyphenyl ) -1H-pyrazolo [ 3, 4-d ] pyrimidin-1-yl ) -ethyl ) -6-fluoro-3- ( 3-fluorophenyl ) -4H-chromen-4-one 4 methylbenzenesulfonate and has the following structure:
Umbralisib tosylate is white to light brown powder that is freely soluble in dimethyl sulfoxide, soluble in methanol, and practically insoluble in water. The ionization constant (pKa) of umbralisib tosylate is 2.71. UKONIQ tablets are for oral administration. Each tablet contains 200 mg of umbralisib free base equivalent to 260.2 mg of umbralisib tosylate. The tablets also contain inactive ingredients: croscarmellose sodium, hydroxypropyl betadex, hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose. The tablet coating film consists of FD&C Blue No. 1, FD&C Yellow No. 5, ferric oxide yellow, hypromellose 2910, polydextrose, polyethylene glycol 8000, titanium dioxide and triacetin.
Pharmacodynamics
Exposure-Response Relationships
- An exposure-response relationship between umbralisib and overall response rate was observed in patients with FL. The time course of pharmacodynamic response is unknown. A relationship between higher umbralisib steady state exposures and higher incidence of adverse reactions, including diarrhea (any grade) and elevated AST/ALT (any grade and Grade ≥ 3), was
observed.
Cardiac Electrophysiology
- The effect of UKONIQ on QT interval has not been fully characterized.
Pharmacokinetics
Umbralisib exposures increased proportionally over a dose range of 200 mg to 1000 mg once daily (0.25 to 1.25 times the recommended dosage). A 6.4- and 3.8-fold accumulation of AUC and Cmax of umbralisib, respectively, were observed at the recommended dosage. The mean (CV%) steady-state AUC and Cmax were 141 µg*h/mL (46%) and 7.3 µg/mL (39%), respectively, at the recommended dosage.
Absorption
- The median time to reach peak plasma concentration (tmax) is approximately 4 hours.
Effect of Food
- Administration of a single dose of UKONIQ with a high-fat, high calorie meal (approximately
917 calories with 171 calories from protein, 232 calories from carbohydrate, and 502 calories from fat) in healthy subjects increased AUC and Cmax of umbralisib by 61% and 115%, respectively, relative to fasting conditions.
Distribution
- The mean (CV%) apparent central volume of distribution of umbralisib is 312 (185%) L.
- The plasma protein binding is ≥99.7% and was independent of concentration between 2 and 5
µM. Mean blood-to-plasma ratio is 0.6.
Elimination
- The mean (CV%) apparent clearance of umbralisib is 15.5 (52%) L/h with effective half-life of
91 (42%) hours.
Metabolism
- Umbralisib is metabolized by CYP2C9, CYP3A4, and CYP1A2 in vitro.
Excretion
- Approximately 81% of the dose was recovered in feces (17% unchanged) and 3% in urine
(0.02% unchanged) following a single radiolabeled dose of umbralisib 800 mg to healthy subjects.
Specific Populations
- No clinically significant differences in the pharmacokinetics of umbralisib were observed based
on age (18 to 87 years old), sex, race (White and Black), body weight (44 to 165 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 × ULN and any AST), or mild and moderate renal impairment (CLcr 30 to 89 mL/min, estimated by the Cockcroft-Gault equation). The effect of other race/ethnicity, severe renal impairment (CLcr 15 to 29 mL/min) and dialysis, or moderate to severe hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > ULN and any AST) on umbralisib pharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies
- No clinically significant differences in umbralisib pharmacokinetics were observed when used.
- concomitantly with omeprazole, a proton pump inhibitor.
- Coadministration of UKONIQ with strong CYP3A4 inhibitors and inducers or moderate
CYP2C9 inhibitors and inducers have not been studied.
- Coadministration of UKONIQ with sensitive substrates of CYP3A4, CYP2C8, CYP2C9 and
CYP2C19, or P-gp substrates have not been fully characterized.
In Vitro Studies
- Cytochrome P450 (CYP) Enzymes: Umbralisib is a substrate of CYP1A2, CYP2C9, and
CYP3A4, but is not a substrate of CYP2B6, CYP2C8, CYP2C19, CYP2D6, and UGT1A1.
- Umbralisib inhibits CYP2C8, CYP2C9, CYP2C19, and CYP3A4, but does not inhibit CYP1A2,
CYP2B6, and CYP2D6. Umbralisib induces CYP3A4.
Transporter Systems:
Umbralisib is not a substrate to P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2-K. Umbralisib inhibits P-gp.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been conducted with umbralisib.
Umbralisib was not mutagenic in a bacterial mutagenicity (Ames) assay. Umbralisib was not clastogenic in an in vitro micronucleus assay using human (TK6) lymphoblast cells or in an in vivo micronucleus assay in mice at doses up to 1000 mg/kg. In a repeat-dose toxicology study in dogs, adverse findings in reproductive organs were observed in males and included findings in the testis (decreased weight, tubular degeneration, tubular atrophy) and epididymis (decreased weight, luminal debris) at doses ≥100 mg/kg, which is approximately 0.1 times the human exposure (AUC) at the recommended dose of 800 mg. In a combined male and female fertility study in mice, umbralisib was administered orally at doses of 50, 150, or 300 mg/kg/day, starting 28 days prior to pairing and through mating in males and starting 14 days prior to pairing through Gestation Day 7 in females. Adverse findings were observed at doses of 150 and 300 mg/kg/day and included decreased testicular and epididymis weights, decreased sperm mobility and counts, increased post-implantation loss, and increased resorption. The dose of 150 mg/kg results in an exposure approximately 1.3 times the human exposure (AUC) at the recommended dose of 800 mg.
Clinical Studies
Marginal Zone Lymphoma
- The efficacy of UKONIQ was evaluated in a single-arm cohort of Study UTX-TGR-205 (NCT02793583), an open-label, multi-center, multi-cohort trial. Patients with MZL were required to have received at least one prior therapy, including an anti-CD20 containing regimen. The trial excluded patients with prior exposure to a PI3K inhibitor. Patients received UKONIQ 800 mg orally once daily until disease progression or unacceptable toxicity.
- A total of 69 patients with MZL [extranodal (N=38), nodal (N=20), and splenic (N=11)] were enrolled in this cohort. The median age was 67 years (range: 34 to 88 years), 52% were female, 83% were White, 7% were Black, 3% were Asian, 7% were Other, and 97% had a baseline ECOG performance status of 0 or 1. Patients had a median number of prior lines of therapy of 2 (range: 1 to 6), with 26% being refractory to their last therapy.
- Efficacy was based on overall response rate as assessed by an Independent Review Committee (IRC) using criteria adopted from the International Working Group criteria for malignant lymphoma. The median follow-up time was 20.3 months (range: 15.0 to 28.7 months). Efficacy results are shown in Table 5.
The median time to response was 2.8 months (range: 1.8 to 21.2 months). Overall response rates were 44.7%, 60.0%, and 45.5% for the 3 MZL sub-types (extranodal, nodal, and splenic, respectively).
How Supplied
UKONIQ tablets are supplied as follows:
Storage
Store tablets at 68°F to 77°F (20°C to 25°C). Excursions permitted between 59°F and 86°F (15°C and 30°C) [see USP Controlled Room Temperature].
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Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Infections
- Advise patients that UKONIQ can cause serious infections that may be fatal. Advise patients to immediately report any signs or symptoms of infection (e.g., fever, chills, weakness).
Neutropenia
- Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop a fever or any signs of infection.
Diarrhea or Non-Infectious Colitis
- Advise patients that they may experience loose stools or diarrhea and should contact their healthcare provider with any persistent or worsening diarrhea. Advise patients to maintain adequate hydration. Advise patients of the possibility of colitis and to notify their healthcare provider of any abdominal pain/distress.
Hepatotoxicity
- Advise patients that UKONIQ may cause significant elevations in liver enzymes and the need for periodic monitoring of liver tests. Advise patients to report symptoms of liver dysfunction including jaundice (yellow eyes or yellow skin), abdominal pain, bruising, or bleeding.
Severe Cutaneous Reactions
Advise patients that UKONIQ may cause a severe skin rash and to notify their healthcare provider immediately if they develop a new or worsening skin rash.
Embryo-Fetal Toxicity
- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.
- Advise females of reproductive potential to use effective contraceptive during treatment with UKONIQ and for one month after the last dose. Advise males with female partners of reproductive potential to use effective contraceptive during treatment with UKONIQ and for one month after the last dose.
Lactation
Advise women not to breastfeed during treatment with UKONIQ and for one month after the last dose.
Infertility
- Advise males of reproductive potential that UKONIQ may impair fertility.
Allergic Reactions Due to Inactive Ingredient FD&C Yellow No. 5
- Advise patients that UKONIQ contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions in certain susceptible persons.
Administration
- Inform patients to take UKONIQ orally once daily at approximately the same time each day with food and how to make up a missed or vomited dose. Advise patients to swallow tablets whole. Advise patients not to crush, break, cut or chew tablets.
Precautions with Alcohol
Alcohol-Umbralisib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
UKONIQ
Look-Alike Drug Names
There is limited information regarding Umbralisib Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.