1 INDICATIONS AND USAGE POTELIGEO is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.

POTELIGEO is a CC chemokine receptor type 4 (CCR4)-directed monoclonal antibody indicated for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome after at least one prior systemic therapy ( 1 ).

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Dermatologic Toxicity [ see Warnings and Precautions (5.1) ].

Infusion Reactions [ see Warnings and Precautions (5.2) ].

Infections [ see Warnings and Precautions (5.3) ].

Autoimmune Complications [ see Warnings and Precautions (5.4) ].

Complications of Allogeneic HSCT after POTELIGEO [ see Warnings and Precautions (5.5) ].

The most common adverse reactions (reported in ≥20% of patients) are rash, infusion related reactions, fatigue, diarrhea, musculoskeletal pain, and upper respiratory tract infection ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Kyowa Kirin, Inc.

at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trial 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 data described below reflect exposure to POTELIGEO in Study 0761-010, a randomized, open-label, actively controlled clinical trial for adult patients with MF or SS who received at least one prior systemic therapy [ see Clinical Studies (14) ].

Of 370 patients treated, 184 (57% with MF, 43% with SS) received POTELIGEO as randomized treatment and 186 (53% with MF, 47% with SS) received vorinostat.

In the vorinostat arm, 135 patients (73%) subsequently crossed over to POTELIGEO for a total of 319 patients treated with POTELIGEO.

POTELIGEO was administered at 1 mg/kg intravenously over at least 60 minutes on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of subsequent 28-day cycles.

Premedication (diphenhydramine, acetaminophen) was optional and administered to 65% of randomized patients for the first infusion.

The comparator group received vorinostat 400 mg orally once daily, given continuously in 28-day cycles.

Treatment continued until unacceptable toxicity or progressive disease.

The median age was 64 years (range, 25 to 101 years), 58% of patients were male, 70% were white, and 99% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Patients had a median of 3 prior systemic therapies.

The trial required an absolute neutrophil count (ANC) ≥1,500/µL (≥1,000/µL if bone marrow was involved), platelet count ≥100,000/µL (≥75,000/µL if bone marrow was involved), creatinine clearance >50 mL/min or serum creatinine ≤1.5 mg/dL, and hepatic transaminases ≤2.5 times upper limit of normal (ULN) (≤5 times ULN if lymphomatous liver infiltration).

Patients with active autoimmune disease, active infection, autologous HSCT within 90 days, or prior allogeneic HSCT were excluded.

During randomized treatment, the median duration of exposure to POTELIGEO was 5.6 months, with 48% (89/184) of patients with at least 6 months of exposure and 23% (43/184) with at least 12 months of exposure.

The median duration of exposure to vorinostat was 2.8 months, with 22% (41/186) of patients with at least 6 months of exposure.

Fatal adverse reactions within 90 days of the last dose occurred in 2.2% (7/319) of patients who received POTELIGEO as randomized or crossover treatment.

Serious adverse reactions were reported in 36% (66/184) of patients randomized to POTELIGEO and most often involved infection (16% of patients; 30/184).

Serious adverse reactions reported in >2% of patients randomized to POTELIGEO were pneumonia (5%), sepsis (4%), pyrexia (4%), and skin infection (3%); other serious adverse reactions, each reported in 2% of patients, included hepatitis, pneumonitis, rash, infusion related reaction, lower respiratory tract infection, and renal insufficiency.

POTELIGEO was discontinued for adverse reactions in 18% of randomized patients, most often due to rash or drug eruption (7.1%).

The most common adverse reactions (reported in ≥20% of patients randomized to POTELIGEO) were rash (including drug eruption), infusion related reactions, fatigue, diarrhea, upper respiratory tract infection and musculoskeletal pain.

Other common adverse reactions (reported in ≥10% of patients randomized to POTELIGEO) included skin infection, pyrexia, nausea, edema, thrombocytopenia, headache, constipation, mucositis, anemia, cough and hypertension.

Table 1 summarizes common adverse reactions having a ≥2% higher incidence with POTELIGEO than with vorinostat in Study 0761-010.

Table 1: Common Adverse Reactions (≥10%) with ≥2% Higher Incidence in the POTELIGEO Arm Adverse Reactions by Body System Adverse reactions include groupings of individual preferred terms.

, Includes adverse reactions reported up to 90 days after randomized treatment.

POTELIGEO (N=184) Vorinostat (N=186) All Grades (%) ≥Grade 3 (%) All Grades (%) ≥Grade 3 (%) Rash/Drug Eruption includes: dermatitis (allergic, atopic, bullous, contact, exfoliative, infected), drug eruption, palmoplantar keratoderma, rash (generalized, macular, maculopapular, papular, pruritic, pustular), skin reaction, toxic skin eruption Upper Respiratory Tract Infection includes: laryngitis viral, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral upper respiratory tract infection Skin Infection includes: cellulitis, dermatitis infected, erysipelas, impetigo, infected skin ulcer, periorbital cellulitis, skin bacterial infection, skin infection, staphylococcal skin infection Musculoskeletal Pain includes: back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity Mucositis includes: aphthous stomatitis, mouth ulceration, mucosal inflammation, oral discomfort, oral pain, oropharyngeal pain, stomatitis Skin and Subcutaneous Tissue Disorders Rash, Including Drug Eruption 35 5 11 2 Drug Eruption 24 5 <1 0 Procedural Complications Infusion Related Reaction 33 2 0 0 Infections Upper Respiratory Tract Infection 22 0 16 1 Skin Infection 19 3 13 4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Pain 22 <1 17 3 General Disorders Pyrexia 17 <1 7 0 Gastrointestinal Mucositis 12 1 6 0 Other Common Adverse Reactions in ≥10% of POTELIGEO Arm Includes grouped terms , From 184 patients randomized to POTELIGEO General disorders: fatigue (31%), edema (16%) Gastrointestinal disorders: diarrhea (28%), nausea (16%), constipation (13%) Blood and lymphatic system disorders : thrombocytopenia (14%), anemia (12%) Nervous system disorders: headache (14%) Vascular disorders: hypertension (10%) Respiratory disorders: cough (11%) Adverse Reactions in ≥5% but <10% of POTELIGEO Arm , Infections: candidiasis (9%), urinary tract infection (9%), folliculitis (8%), pneumonia (6%), otitis (5%), herpesvirus infection (5%) Investigations: renal insufficiency (9%), hyperglycemia (9%), hyperuricemia (8%), weight increase (8%), weight decrease (6%), hypomagnesemia (6%) Psychiatric disorders: insomnia (9%), depression (7%) Skin and subcutaneous disorders: xerosis (8%), alopecia (7%) Nervous system disorders: dizziness (8%), peripheral neuropathy (7%) Metabolism and nutrition disorders: decreased appetite (8%) Respiratory disorders: dyspnea (7%) General disorders: chills (7%) Gastrointestinal disorders: vomiting (7%), abdominal pain (5%) Injury, poisoning and procedural complications: fall (6%) Musculoskeletal disorders: muscle spasms (5%) Cardiovascular disorders: arrhythmia (5%) Eye disorders: conjunctivitis (5%) Selected Other Adverse Reactions , Tumor lysis syndrome (<1%) Myocardial ischemia or infarction (<1%) Cardiac failure (<1%) Cytomegalovirus infection (<1%) Table 2 summarizes common treatment-emergent laboratory abnormalities having a ≥2% higher incidence with POTELIGEO than with vorinostat.

Table 2: Common New or Worsening Laboratory Abnormalities (≥10%) with ≥2% Higher Incidence in the POTELIGEO Arm Laboratory Test Includes laboratory abnormalities, reported up to 90 days after treatment, that are new or worsening in grade or with worsening from baseline unknown.

POTELIGEO (N=184) Vorinostat (N=186) All Grades (%) ≥Grade 3 (%) All Grades (%) ≥Grade 3 (%) Chemistry Albumin Decreased 34 2 27 3 Calcium Decreased 30 3 20 2 Uric Acid Increased 29 29 11 11 Phosphate Decreased 27 5 26 5 Magnesium Decreased 17 <1 8 <1 Glucose Decreased 14 0 8 <1 Calcium Increased 12 <1 8 <1 Hematology CD4 Lymphocytes Decreased Out of 99 evaluable recipients of POTELIGEO and 36 evaluable recipients of vorinostat.

63 43 17 8 Lymphocytes Decreased 31 16 12 4 White Blood Cells Decreased 33 2 18 2 Other common treatment-emergent laboratory abnormalities in the POTELIGEO arm included hyperglycemia (52%; 4% Grade 3-4), anemia (35%; 2% Grade 3-4), thrombocytopenia (29%, none Grade 3-4), aspartate transaminase (AST) increased (25%; 2% Grade 3-4), alanine transaminase (ALT) increased (18%; 1% Grade 3-4), alkaline phosphatase increased (17%; 0% Grade 3-4), and neutropenia (10%; 2% Grade 3-4).

Grade 4 treatment-emergent laboratory abnormalities observed in ≥1% of the POTELIGEO arm included lymphopenia (5%), leukopenia (1%), and hypophosphatemia (1%).

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of POTELIGEO.

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.

Gastrointestinal disorders: Immune-mediated colitis Infections: Hepatitis B virus reactivation Cardiac disorders: Stress cardiomyopathy Skin and subcutaneous disorders: Granuloma