BRIEF SUMMARY

UMBRALISIB- (Feb 2021)

Indn- For the treatment of certain patients with marginal zone lymphoma and follicular lynphoma      

Comp-  • Recommended dosage: 800 mg orally once daily with food.                              a kinase inhibitor 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

.• Relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy  .

ADR-  most common  adverse reactions, including laboratory abnormalities, were increased creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection,

CI-  None 

WARNINGS-

 • Infections: Monitor for fever and any new or worsening signs and symptoms of infection. Evaluate promptly and treat as needed 

• Neutropenia: Monitor blood counts during treatment 

Pat inform-

Infections -Advise patients that it 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.                                 

==================================================================

U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 5

Name of the Drug-    UKONIQ

Active Ingredient -     Umbralisib

Pharmacological Classification-   For the treatment of certain patients with                                                                       marginal zone lymphoma and follicular                                                                           lynphoma                                                                         

Date of Approval-          2/5/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                          UKONIQ safely and effectively.                                                                                        See full prescribing information for UKONIQ. UKONIQ™ (umbralisib) tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

UKONIQ is a kinase inhibitor 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

. • Relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy (1.2). 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.

DOSAGE AND ADMINISTRATION

 • Recommended dosage: 800 mg orally once daily with food

. • Manage toxicity using treatment interruption, dose reduction, or discontinuation

DOSAGE FORMS AND STRENGTHS

 Tablets: 200 mg 

ADVERSE REACTIONS

 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

CONTRAINDICATIONS_

 None (4).

WARNINGS AND PRECAUTIONS

 • Infections: Monitor for fever and any new or worsening signs and symptoms of infection. Evaluate promptly and treat as needed 

• Neutropenia: Monitor blood counts during treatment 

• Diarrhea or Non-infectious colitis: Monitor for the development of diarrhea or colitis and provide supportive care as appropriate

. • Hepatotoxicity: Monitor hepatic function

 • Severe cutaneous reactions: Withhold treatment, reduce dose, or discontinue treatment depending on severity and persistence of severe cutaneous reaction

 • 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

. • Embryo-fetal toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception 

 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 Use in Specific Populations 

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 

Distributed by: TG Therapeutics, Inc. 343 Thornall Street, Suite 740 Edison, NJ 08837

CLINICAL PHARMACOLOGY

1. Mechanism of Action Umbralisib inhibits multiple kinases. In biochemical and cell-based assays, umbralisib inhibited PI3Kd and casein kinase CK1e. PI3Kd is expressed in normal and malignant B-cells; CK1e has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies.

2. 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.

3. 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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.

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.

2 Lactation 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

3. Females and Males of Reproductive Potential -                                               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 .

4. Pediatric Use Safety and effectiveness of UKONIQ have not been established in pediatric patients.

8.5 Geriatric 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%).

6. 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).

7. 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