Denileukin Diftitox

LYMPHIR is indicated for the treatment of adult patients with relapsed or refractory Stage I-III cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy. LYMPHIR is an IL2-receptor-directed cytotoxin indicated for the treatment of adult patients with relapsed or refractory Stage I-III cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy. ( 1 )

For injection: 300 mcg/vial, sterile, white lyophilized cake in a single-dose vial for reconstitution and further dilution. For injection: 300 mcg lyophilized cake in a single-dose vial.

None. None. ( 4 )

Visual Impairment: Monitor and evaluate for visual impairment throughout treatment. Withhold LYMPHIR until visual impairment resolves or permanently discontinue based on severity. ( 5.2 ) Infusion-Related Reactions: Monitor patients closely during infusions. Interrupt or discontinue for infusion-related reactions based on severity. ( 5.3 ) Hepatotoxicity: Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. ( 5.4 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 )

5.1 Capillary Leak Syndrome LYMPHIR can cause capillary leak syndrome (CLS), including life-threatening or fatal reactions. CLS was defined in the clinical trials as the occurrence of at least 2 of the following symptoms at any time during LYMPHIR therapy: hypotension, edema, and serum albumin <3 g/dL. These symptoms were not required to occur simultaneously to be characterized as capillary leak syndrome. As defined, CLS occurred in 27% of patients in the pooled population across 3 clinical trials, including 8% with Grade 3. There was one (0.8%) fatal occurrence of CLS. Of the patients with CLS, 22% had recurrence. The majority of CLS events (81%) occurred within the first 2 cycles of treatment. The median time to onset from Cycle 1, Day 1 was 6.5 days (range: 1 to 77), the median duration of CLS was 14 days (range: 2 to 40), and 75% of patients had resolution. The most common symptoms included edema, hypoalbuminemia, and hypotension. Pleural effusion, pericardial effusion, and dehydration also occurred. Regularly assess patients for weight gain, new onset or worsening of edema, dyspnea, and hypotension (including orthostatic changes). Monitor serum albumin levels prior to the initiation of each cycle of therapy and more often as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity. If LYMPHIR is withheld, resume LYMPHIR following resolution of CLS and when serum albumin is greater than or equal to 3 g/dL [see Dosage and Administration ( 2.1 and 2.4 )] .

5.2 Visual Impairment LYMPHIR can cause serious visual impairment, including changes in visual acuity and color vision. In the pooled population across 3 clinical trials, visual impairment occurred in 9%, with Grade 1 in 8% and Grade 2 in 1%. The most commonly reported symptom was blurred vision. Of the patients with visual impairment, 67% had resolution of their visual impairment. Perform baseline ophthalmic examination and monitor as clinically indicated. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, or blurred vision, refer for ophthalmologic evaluation. Withhold LYMPHIR until visual impairment resolves or permanently discontinue based on severity [see Dosage and Administration ( 2.4 )] . 5. 3 Infusion-Related Reactions LYMPHIR can cause serious infusion-related reactions. Infusion-related reactions were reported in 69% of patients in the pooled population across 3 clinical trials of patients who received LYMPHIR, with Grade 3 infusion-related reactions in 3.4% [see Adverse Reactions ( 6.1 )] . Eighty-three percent of infusion-related reactions occurred in Cycles 1 and 2. The most common symptoms included nausea, fatigue, chills, musculoskeletal pain, vomiting, fever, and arthralgia. Premedicate patients for the first three cycles prior to starting a LYMPHIR infusion [see Dosage and Administration ( 2.3 )] . Monitor patients frequently during infusion. For Grade 2 or higher infusion reactions, premedicate at least 30 minutes prior to each subsequent infusion with a systemic steroid for at least 3 cycles [see Dosage and Administration ( 2.3 )] . Interrupt or discontinue LYMPHIR based on severity [see Dosage and Administration ( 2.4 )]. Institute appropriate medical management. 5. 4 Hepatotoxicity LYMPHIR can cause hepatotoxicity. In the pooled safety population, elevated ALT occurred in 70% of patients, with Grade 3 ALT occurring in 22%; elevated AST occurred in 64% of patients, with Grade 3 AST elevation occurring in 9%. For Grade 3 events, median time to onset was 8 days (range: 1 to 15 days); median time to resolution was 15 days (range: 7 to 50 days); all cases of Grade 3 ALT or AST elevations resolved [see Adverse Reactions ( 6.1 )]. Elevated total bilirubin occurred in 5% of patients, with Grade 3 occurring in 0.9%. Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold, reduce dose, or permanently discontinue LYMPHIR based on severity [see Dosage and Administration ( 2.4 )] .

5.5 Embryo-Fetal Toxicity Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to the initiation of LYMPHIR. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 days following the last dose of LYMPHIR [see Use in Specific Populations ( 8.1 , 8.3 )] .

The following adverse reactions are discussed in greater detail in other sections of the label: Capillary Leak Syndrome [see Warnings and Precautions ( 5.1 )] Visual Impairment [see Warnings and Precautions ( 5.2 )] Infusion-Related Reactions [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (≥20%), including laboratory abnormalities, are increased transaminases, albumin decreased, nausea, edema, hemoglobin decreased, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Citius Oncology, Inc. at 1-844-459-6744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LYMPHIR as a single agent in 119 patients with CTCL across 3 clinical trials. Patients received treatment with LYMPHIR as an intravenous infusion at 9 mcg/kg daily from Day 1 through Day 5 of each 21-day cycle until disease progression or unacceptable toxicity. Among 119 patients who received LYMPHIR the median number of cycles received was 5 (range: 1 to 42), with 13% exposed for 6 months or longer. In this pooled safety population, the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were increased transaminases (70%), albumin decreased (53%), nausea (40%), edema (35%), hemoglobin decreased (34%), fatigue (30%), musculoskeletal pain (26%), rash (23%), chills (22%), constipation (22%), pyrexia (21%), and capillary leak syndrome (20%). Relapsed or Refractory Stage I-III CTCL Study 302 The safety of LYMPHIR was evaluated in Study 302, an open-label, single-arm, multicenter trial that included 69 patients with relapsed or refractory Stage I-III CTCL [see Clinical Studies ( 14 )] . Patients received treatment with LYMPHIR 9 mcg/kg daily from Day 1 through Day 5 of each 21-day cycle. Treatment was administered until disease progression or unacceptable toxicity. The median number of LYMPHIR cycles was 6 (range: 1 to 42). The median age of patients was 64 years (range: 28 to 87 years), 49% were 65 years of age or older, 65% were men, 72% were White, 19% were Black or African American, 1.4% were Asian, and 14% were Hispanic or Latino. Serious adverse reactions occurred in 38% of patients who received LYMPHIR. Serious adverse reactions in > 2% of patients included capillary leak syndrome (10%), infusion-related reaction (9%), sepsis (7%), skin infection (2.9%), pyrexia (2.9%), and rash (2.9%). Permanent discontinuation of LYMPHIR due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of LYMPHIR included capillary leak syndrome, infusion-related reaction, renal insufficiency, respiratory failure, and sepsis. Dosage interruptions of LYMPHIR due to an adverse reaction occurred in 38% of patients. Adverse reactions requiring dosage interruption of LYMPHIR included capillary leak syndrome, infusion-related reaction, weight increase, nausea, and tachycardia. Table 3 summarizes the adverse reactions in Study 302. Table 3: Adverse Reactions (≥ 10%) in Patients with Relapsed or Refractory Stage I-III CTCL Who Received LYMPHIR in Study 302 Adverse Reaction LYMPHIR N=69 All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Nausea 43 1.4 # Diarrhea 19 0 Vomiting 13 0 Constipation 12 0 General disorders and administration site conditions Fatigue a 38 0 Edema b 33

1.4 Chills 27

1.4 Pyrexia 16

1.4 Musculoskeletal and connective tissue disorders Musculoskeletal pain c 27

2.9 Arthralgia 12 0 Nervous system disorders Headache d 25 0 Dizziness 13 0 Mental status changes e 13 0 Injury, poisoning and procedural complications Infusion-related reaction 25 6 Skin and subcutaneous tissue disorders Rash f 23 6 Pruritis 19 6 Vascular disorders Capillary leak syndrome 17 6 Metabolism and nutrition disorders Decreased appetite 13

1.4 Eye disorders Blurred vision 13 0 Investigations Weight increased 13 0 Infections and infestations Skin infection g 13

1.4 Renal and urinary disorders Renal insufficiency h 12

2.9 Psychiatric disorders Insomnia 10 0 # Only Grade 3 adverse reaction occurred a Includes fatigue, asthenia, and lethargy b Includes edema, edema peripheral, generalized edema, face edema, swelling face, peripheral swelling c Includes musculoskeletal pain, back pain, neck pain, pain in extremity, myalgia, bone pain d Includes headache, migraine e Includes amnesia, confusional state, delirium, memory impairment, disturbance in attention, somnolence, cognitive disorder f Includes rash, drug eruption, erythema, rash maculo-papular, rash papular, rash pustular, rash pruritic, dermatitis exfoliative generalized, acute generalized exanthematous pustulosis g Includes skin infection, skin bacterial infection, staphylococcal skin infection, impetigo h Includes acute kidney injury, blood creatinine increased Clinically relevant adverse reactions in < 10% of patients who received LYMPHIR included sepsis and peripheral neuropathy. Table 4 summarizes select laboratory abnormalities in Study 302. Table 4: Select Laboratory Abnormalities (≥ 10%) that Worsened from Baseline in Patients with Relapsed or Refractory Stage I-III CTCL who Received LYMPHIR in Study 302 Laboratory Abnormality a,b Any Grade c (%) b Grade 3 or 4 c (%) Chemistry Alanine aminotransferase increased 66 13 Aspartate aminotransferase increased 60

4.5 Albumin decreased 43

1.5 Creatine phosphokinase increased d 22 3 Alkaline phosphatase increased 18 0 Hematology Lymphocyte count decreased 52 20 Hemoglobin decreased 34 1.5 a Graded according to NCI CTCAE version 5.0 b The denominator used to calculate the rate was 67 based on the number of patients with a baseline value and at least one post-treatment value c Percentage of patients with an increase of at least 1 CTCAE grade from baseline to the worst post-baseline value of any grade, or to the worst post-baseline value that is Grade 3 or 4 d The denominator used to calculate the rate was based on 36 patients with a baseline value and at least one post-treatment value. 6. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of denileukin diftitox. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Thyroid conditions: hyperthyroidism, thyroiditis, thyrotoxicosis, and hypothyroidism.

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )]. There are no available data on the use of LYMPHIR in pregnant women to evaluate for a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with denileukin diftitox. Denileukin diftitox-cxdl causes depletion of regulatory T lymphocytes (Treg), immune activation, and capillary leak syndrome, compromising pregnancy maintenance. 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 are 2-4% and 15-20%, respectively. 8. 2 Lactation Risk Summary No data are available regarding the presence of denileukin diftitox-cxdl in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LYMPHIR and for 7 days after the last dose.

8.3 Females and Males of Reproductive Potential Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating LYMPHIR [see Use in Specific Populations ( 8.1 )] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with LYMPHIR and for 7 days after the last dose. Infertility Males Based on findings in rats, male fertility may be compromised by treatment with LYMPHIR [see Nonclinical Toxicology ( 13.1 )] . The reversibility of the effect on fertility is unknown.

8.4 Pediatric Use Safety and effectiveness of LYMPHIR in pediatric patients have not been established.

8.5 Geriatric Use Of the 69 patients with Stage I-III relapsed or refractory CTCL who received LYMPHIR, 34 patients (49%) were 65 years of age and older and 10 patients (14%) were 75 years of age and older [see Clinical Studies ( 14 )] . Clinical studies of LYMPHIR did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Denileukin diftitox-cxdl is a fusion protein designed to direct the cytocidal action of diphtheria toxin (DT) to cells which express the IL-2 receptor. After uptake into the cell, the DT fragment is cleaved and the free DT fragments inhibit protein synthesis, resulting in cell death. Denileukin diftitox-cxdl demonstrated the ability to deplete immunosuppressive regulatory T lymphocytes (Tregs) and antitumor activity through a direct cytocidal action on IL-2R-expressing tumors.