UKONIQ: Package Insert and Label Information

UKONIQ- umbralisib tosylate tablet, film coated
TG Therapeutics, Inc.

1 INDICATIONS AND USAGE

1.1 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 [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

1.2 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 [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of UKONIQ is 800 mg taken orally once daily with food [see Clinical Pharmacology (12.3)] 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.

2.2 Recommended Prophylaxis

Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) during treatment with UKONIQ [see Warnings and Precautions (5.1)].

Consider prophylactic antivirals during treatment with UKONIQ to prevent cytomegalovirus (CMV) infection, including CMV reactivation [see Warnings and Precautions (5.1)].

2.3 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.

Table 1: Recommended Dosage Modifications of UKONIQ for Adverse Reactions

ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; CMV, cytomegalovirus; PJP, Pneumocystis jirovecii pneumonia; ULN, upper limit of normal; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS, drug reaction with eosinophilia and systemic symptoms. a National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Adverse Reactions Severity a Dosage Modification
Hematologic Adverse Reactions
Neutropenia[see Warnings and Precautions (5.2)] ANC 0.5 to 1 ×109 /L
  • Maintain UKONIQ.
  • If ANC 0.5 to 1 × 109 /L recurs or is persistent, then withhold UKONIQ until ANC 1 × 109 /L or greater, then resume at same dose.
ANC less than 0.5 × 109 /L
  • Withhold UKONIQ until ANC 0.5 × 109 /L or greater, then resume at same dose.
  • If recurrence, then resume at reduced dose.
Thrombocytopenia[see Adverse Reactions (6.1)] Platelet count 25 to less than 50 × 109 /L with bleedingORPlatelet count less than 25 × 109 /L Withhold UKONIQ until platelet count 25 × 109 /L or greater and resolution of bleeding (if applicable), then resume at same dose. If recurrence, withhold until resolution and then resume at reduced dose.
Nonhematologic Adverse Reactions
Infection, including opportunistic infection[see Warnings and Precautions (5.1)] Grade 3 or 4 Withhold UKONIQ until resolved, then resume at same or reduced dose.
PJP
  • For suspected PJP, withhold UKONIQ until evaluated.
  • For confirmed PJP, discontinue UKONIQ.
CMV infection or viremia Withhold UKONIQ until infection or viremia resolves, then resume at same or reduced dose.
ALT or AST Elevation[see Warnings and Precautions (5.4)] AST or ALT greater than 5 to less than 20 times ULN Withhold UKONIQ until return to less than 3 times ULN, then resume at reduced dose.
AST or ALT greater than 20 timesULN Discontinue UKONIQ.
Diarrhea or Noninfectious Colitis[see Warnings and Precautions (5.3)] Mild or moderate diarrhea (up to 6 stools per day over baseline)ORAsymptomatic (Grade 1) colitis
  • If persistent, withhold UKONIQ until resolved, then resume at same or reduced dose.
  • If recurrence, withhold until resolution and then resume at reduced dose.
Adverse Reactions Severity a Dosage Modification
Severe diarrhea (greater than 6 stools per day over baseline)ORAbdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs
  • Withhold UKONIQ until resolved, then resume at reduced dose.
  • For recurrent severe diarrhea or recurrent colitis of any grade, discontinue UKONIQ.
Life-threatening Discontinue UKONIQ.
Severe CutaneousReactions [see Warnings and Precautions (5.5)] Severe
  • Withhold UKONIQ until resolved, then resume at reduced dose or discontinue.
  • If recurrence after re-challenge, discontinue UKONIQ.
Life-threatening Discontinue UKONIQ.
SJS, TEN, DRESS (any grade) Discontinue UKONIQ.
Other AdverseReactions [see Adverse Reactions (6.1)] Severe Withhold UKONIQ until resolved, then resume at the same or reduced dose.
Life-threatening Discontinue UKONIQ.
Table 2: Recommended Dose Reductions of UKONIQ for Adverse Reactions
Dose Reduction Dosage
First 600 mg orally daily
Second 400 mg orally daily
Subsequent Permanently discontinue UKONIQ in patients unable to tolerate 400 mg orally daily

3 DOSAGE FORMS AND STRENGTH

Tablets: 200 mg, green film-coated, oval-shaped with “L474” on one side and plain on the other side.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 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) [see Adverse Reactions (6.1)].

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 [see Dosage and Administration (2.3)].

Provide prophylaxis for Pneumocystis jirovecii pneumonia (PJP) during treatment with UKONIQ [see Dosage and Administration (2.2)]. Withhold UKONIQ in patients with suspected PJP of any grade and permanently discontinue in patients with confirmed PJP [see Dosage and Administration (2.2)].

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 [see Dosage and Administration (2.2)]. 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 [see Dosage and Administration (2.2)].

5.2 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% [see Adverse Reactions (6.1)]. 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 <1 ×109 /L (Grade 3-4). Consider supportive care as appropriate. Withhold, reduce dose, or discontinue UKONIQ depending on the severity and persistence of neutropenia [see Dosage and Administration (2.3)].

5.3 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% [see Adverse Reactions (6.1)]. 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., > 6 stools 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 [see Dosage and Administration (2.3)].

5.4 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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.3)].

5.5 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) [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.3)]. Provide supportive care as appropriate.

5.6 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.

5.7 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 [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Infections [see Warnings and Precautions (5.1)]
  • Neutropenia [see Warnings and Precautions (5.2)]
  • Diarrhea and Non-infectious Colitis [see Warnings and Precautions (5.3)]
  • Hepatotoxicity [see Warnings and Precautions (5.4)]
  • Severe Cutaneous Reactions [see Warnings and Precautions (5.5)]

6.1 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 UTX-TGR-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 single-arm, open-label trials (Study TGR-1202-101, TGR-1202-202, and UTX-TGR-205) and one open-label extension trial (Study UTX-TGR-501) [see Clinical Studies (14.1, 14.2)]. 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 diarrhea-colitis (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.

Table 3 provides the adverse reactions in the pooled safety population of 221 patients with marginal zone lymphoma and follicular lymphoma who received the recommended dosage.

Table 3: Adverse Reactions Reported (≥10%) in Patients With Marginal Zone Lymphoma and Follicular Lymphoma Who Received UKONIQ in Pooled Safety Population

a Abdominal pain includes Abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort

b Fatigue includes Fatigue, asthenia, lethargy

c Edema includes Edema peripheral, face edema, pulmonary edema, fluid overload, generalized edema d Musculoskeletal pain includes Back pain, myalgia, pain in extremity, musculoskeletal pain, neck pain, spinal pain, musculoskeletal chest pain, musculoskeletal discomfort

e Upper respiratory tract infection includes Upper respiratory tract infection, sinusitis, nasopharyngitis, rhinitis

f Rash includes Rash, rash maculo-papular, rash erythematous, rash pruritic, rash macular, exfoliative dermatitis

Adverse Reactions UKONIQ N=221
All Grades (%) Grade 3 or 4 (%)
Gastrointestinal Disorders
Diarrhea 58 10
Nausea 38 <1
Vomiting 21 <1
Abdominal paina 19 3
General Disorders and Administration Site Conditions
Fatigueb 41 3
Edemac 14 <1
Pyrexia 10 0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal paind 27 2
Infections
Upper respiratory tract infectione 21 <1
Metabolism and Nutrition Disorders
Decreased appetite 19 2
Skin and Subcutaneous Tissue Disorders
Rashf 18 3
Psychiatric Disorders
Insomnia 14 <1

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%).

Table 4 provides the laboratory abnormalities in the pooled safety population of 221 patients with marginal zone lymphoma and follicular lymphoma who received the recommended dosage.

Table 4: Select Laboratory Abnormalities (>20%) That Worsened from Baseline in Patients with Marginal Zone Lymphoma and Follicular Lymphoma Who Received UKONIQ in Pooled Safety Population

a Laboratory values were categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 grading system.

Laboratory Parameter UKONIQ N=221
All Grades a (%) Grade 3 or 4 (%)
Hematologic
Neutrophil decreased 33 16
Hemoglobin decreased 27 3
Platelets decreased 26 4
Chemistry
Creatinine increased 79 0
Alanine aminotransferase increased 33 8
Aspartate aminotransferase increased 32 7
Potassium decreased 21 4
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