CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. TREMFYA is contraindicated in patients with history of serious hypersensitivity reaction to guselkumab or to any of the excipients [see Warnings and Precautions (5.1)].. Serious hypersensitivity reactions to guselkumab or to any of the excipients. (4).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of labeling:Infections [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.1)] Infections [see Warnings and Precautions (5.2)] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.1)] Most common (>=1%) adverse reactions associated with TREMFYA include upper respiratory infections, headache, injection site reactions, arthralgia, bronchitis, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections. (6)To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Plaque PsoriasisIn clinical trials, total of 1823 subjects with moderate-to-severe plaque psoriasis received TREMFYA. Of these, 1393 subjects were exposed to TREMFYA for at least months and 728 subjects were exposed for at least year.Data from two placebo- and active-controlled trials (PsO1 and PsO2) in 1441 subjects (mean age 44 years; 70% males; 82% white) were pooled to evaluate the safety of TREMFYA (100 mg administered subcutaneously at Weeks and 4, followed by every weeks).. Weeks to 16:In the 16-week placebo-controlled period of the pooled clinical trials (PsO1 and PsO2), adverse events occurred in 49% of subjects in the TREMFYA group compared to 47% of subjects in the placebo group and 49% of subjects in the U.S. licensed adalimumab group. Serious adverse events occurred in 1.9% of subjects in the TREMFYA group (6.3 events per 100 subject-years of follow-up) compared to 1.4% of subjects in the placebo group (4.7 events per 100 subject-years of follow-up), and in 2.6% of subjects in U.S. licensed adalimumab group (9.9 events per 100 subject-years of follow-up).Table summarizes the adverse reactions that occurred at rate of at least 1% and at higher rate in the TREMFYA group than in the placebo group during the 16-week placebo-controlled period.Table 1:Adverse Reactions Occurring in >=1% of Subjects through Week 16 in PsO1 and PsO2TREMFYASubjects receiving 100 mg of TREMFYA at Week 0, Week 4, and every weeks thereafter 100 mg N=823 (%)AdalimumabU.S. licensed adalimumab N=196 (%)Placebo N=422 (%)Upper respiratory infectionsUpper respiratory infections include nasopharyngitis, upper respiratory tract infection (URTI), pharyngitis, and viral URTI. 118 (14.3)21 (10.7)54 (12.8)HeadacheHeadache includes headache and tension headache. 38 (4.6)2 (1.0)14 (3.3)Injection site reactionsInjection site reactions include injection site erythema, bruising, hematoma, hemorrhage, swelling, edema, pruritus, pain, discoloration, induration, inflammation, and urticaria. 37 (4.5)15 (7.7)12 (2.8)Arthralgia22 (2.7)4 (2.0)9 (2.1)Diarrhea13 (1.6)3 (1.5)4 (0.9)GastroenteritisGastroenteritis includes gastroenteritis and viral gastroenteritis. 11 (1.3)4 (2.0)4 (0.9)Tinea infectionsTinea infections include tinea pedis, tinea cruris, tinea infection, and tinea manuum infections. (1.1)00Herpes simplex infectionsHerpes simplex infections include oral herpes, herpes simplex, genital herpes, genital herpes simplex, and nasal herpes simplex. (1.1)02 (0.5)Adverse reactions that occurred in 1% but 0.1% of subjects in the TREMFYA group and at higher rate than in the placebo group through Week 16 in PsO1 and PsO2 were migraine, candida infections, and urticaria.. Specific Adverse Reactions. InfectionsInfections occurred in 23% of subjects in the TREMFYA group compared to 21% of subjects in the placebo group.The most common (>= 1%) infections were upper respiratory infections, gastroenteritis, tinea infections, and herpes simplex infections; all cases were mild to moderate in severity and did not lead to discontinuation of TREMFYA.. Elevated Liver EnzymesElevated liver enzymes were reported more frequently in the TREMFYA group (2.6%) than in the placebo group (1.9%). Of the 21 subjects who were reported to have elevated liver enzymes in the TREMFYA group, all events except one were mild to moderate in severity and none of the events led to discontinuation of TREMFYA.. Safety through Week 48Through Week 48, no new adverse reactions were identified with TREMFYA use and the frequency of the adverse reactions was similar to the safety profile observed during the first 16 weeks of treatment.. Psoriatic ArthritisTREMFYA was studied in two placebo-controlled trials in subjects with psoriatic arthritis (748 subjects on TREMFYA and 372 subjects on placebo). Of the 748 subjects who received TREMFYA, 375 subjects received TREMFYA 100 mg at Week 0, Week 4, and every weeks thereafter and 373 subjects received TREMFYA 100 mg every weeks. The overall safety profile observed in subjects with psoriatic arthritis treated with TREMFYA is generally consistent with the safety profile in subjects with plaque psoriasis with the addition of bronchitis and neutrophil count decreased. In the 24-week placebo-controlled period, combined across the two studies, bronchitis occurred in 1.6% of subjects in the TREMFYA q8w group and 2.9% of subjects in the TREMFYA q4w group compared to 1.1% of subjects in the placebo group. Neutrophil count decreased occurred in 0.3% of subjects in the TREMFYA q8w and 1.6% of subjects in the TREMFYA q4w group compared to 0% of subjects in the placebo group. The majority of events of neutrophil count decreased were mild, transient, not associated with infection and did not lead to discontinuation.. 6.2 Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity with TREMFYA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to guselkumab across indications or with the incidences of antibodies to other products may be misleading.. Plaque PsoriasisUp to Week 52, approximately 6% of subjects treated with TREMFYA developed antidrug antibodies. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing antibodies. Among the 46 subjects who developed antibodies to guselkumab and had evaluable data, 21 subjects exhibited lower trough levels of guselkumab, including one subject who experienced loss of efficacy after developing high antibody titers. Up to Week 156, approximately 9% of subjects treated with TREMFYA developed antidrug antibodies and of these subjects approximately 6% were classified as neutralizing antibodies. However, antibodies to guselkumab were generally not associated with changes in clinical response or development of injection-site reactions.. Psoriatic ArthritisUp to Week 24, 2% (n=15) of subjects treated with TREMFYA developed antidrug antibodies. Of these subjects, had antibodies that were classified as neutralizing antibodies. Overall, the small number of subjects who were positive for antibodies to guselkumab limits definitive conclusion of the effect of immunogenicity on the pharmacokinetics, efficacy and safety of guselkumab.. 6.3 Postmarketing Experience. The following adverse reactions have been reported during post-approval of TREMFYA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to TREMFYA exposure.Immune system disorders: Hypersensitivity, including anaphylaxis [see Warnings and Precautions (5.1)] Skin and subcutaneous tissue disorders: Rash [see Warnings and Precautions (5.1)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of TREMFYA.No effects on fertility parameters were observed after male guinea pigs were subcutaneously administered guselkumab at dose of 25 mg/kg twice weekly (15 times the MRHD based on mg/kg comparison).No effects on fertility parameters were observed after female guinea pigs were subcutaneously administered guselkumab at doses up to 100 mg/kg twice weekly (60 times the MRHD based on mg/kg comparison).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Guselkumab is human monoclonal IgG1 antibody that selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.. 12.2 Pharmacodynamics. In evaluated subjects with plaque psoriasis, guselkumab reduced serum levels of IL-17A, IL-17F and IL-22 relative to pre-treatment levels based on exploratory analyses of the pharmacodynamic markers.In evaluated subjects with psoriatic arthritis, serum levels of acute phase proteins C-reactive protein, serum amyloid and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 were elevated at baseline. Serum levels of these proteins measured at Week and Week 24 were decreased compared to baseline following guselkumab treatment at Week 0, Week and every weeks thereafter.The relationship between these pharmacodynamic markers and the mechanism(s) by which guselkumab exerts its clinical effects is unknown.. 12.3 Pharmacokinetics. Guselkumab exhibited linear pharmacokinetics in healthy subjects and subjects with plaque psoriasis following subcutaneous injections. In subjects with plaque psoriasis, following subcutaneous administration of 100 mg of TREMFYA at Weeks and 4, and every weeks thereafter, mean steady-state trough serum guselkumab concentration was approximately 1.2 mcg/mL.The pharmacokinetics of guselkumab in subjects with psoriatic arthritis was similar to that in subjects with plaque psoriasis. Following subcutaneous administration of 100 mg of TREMFYA at Weeks 0, 4, and every weeks thereafter, mean steady-state trough serum guselkumab concentration was approximately 1.2 mcg/mL.. AbsorptionFollowing single 100 mg subcutaneous injection in healthy subjects, guselkumab reached mean (+- SD) maximum serum concentration of 8.09 +- 3.68 mcg/mL by approximately 5.5 days post dose. The absolute bioavailability of guselkumab following single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects.. DistributionIn subjects with plaque psoriasis, apparent volume of distribution was 13.5 L.. EliminationApparent clearance in subjects with plaque psoriasis was 0.516 L/day. Mean half-life of guselkumab was approximately 15 to 18 days in subjects with plaque psoriasis across trials.. MetabolismThe exact pathway through which guselkumab is metabolized has not been characterized. As human IgG monoclonal antibody, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.. Specific PopulationsNo apparent differences in clearance were observed in subjects >= 65 years of age compared to subjects 65 years of age, suggesting no dose adjustment is needed for elderly subjects. Clearance and volume of distribution of guselkumab increases as body weight increases, however, observed clinical trial data indicate that dose adjustment for body weight is not warranted. No specific trials have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab.. Drug InteractionsPopulation pharmacokinetic analyses indicated that concomitant use of NSAIDs, oral corticosteroids and conventional DMARDs such as methotrexate, did not affect the clearance of guselkumab.. Cytochrome P450 SubstratesThe effects of guselkumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), dextromethorphan (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in an exploratory study with to 12 evaluable subjects with moderate-to-severe plaque psoriasis. Changes in AUCinf of midazolam, S-warfarin, omeprazole, and caffeine after single dose of guselkumab were not clinically relevant. For dextromethorphan, changes in AUCinf after guselkumab were not clinically relevant in out of 10 subjects; however, 2.9-fold change in AUCinf was observed in one individual [see Drug Interactions (7.1)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Plaque Psoriasis. Four multicenter, randomized, double-blind trials (PsO1 [NCT02207231], PsO2 [NCT02207244], PsO3 [NCT02203032], and PsO4 [NCT02905331]) enrolled subjects 18 years of age and older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had an Investigators Global Assessment (IGA) score of >=3 (moderate) on 5-point scale of overall disease severity, Psoriasis Area and Severity Index (PASI) score >=12, and minimum affected body surface area (BSA) of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded.. Trials PsO1 and PsO2In PsO1 and PsO2, 1443 subjects were randomized to either TREMFYA (100 mg at Weeks and and every weeks thereafter) administered with prefilled syringe, placebo or U.S. licensed adalimumab (80 mg at Week and 40 mg at Week 1, followed by 40 mg every other week thereafter).Both trials assessed the responses at Week 16 compared to placebo for the two co-primary endpoints:the proportion of subjects who achieved an IGA score of (cleared) or (minimal);the proportion of subjects who achieved at least 90% reduction from baseline in the PASI composite score (PASI 90).Comparisons between TREMFYA and U.S. licensed adalimumab were secondary endpoints at the following time points:at Week 16 (PsO1 and PsO2), the proportions of subjects who achieved an IGA score of or 1, PASI 90, and PASI 75 response;at Week 24 (PsO1 and PsO2), and at Week 48 (PsO1), the proportions of subjects achieving an IGA score of 0, an IGA score of or 1, and PASI 90 response.Other evaluated outcomes included improvement in psoriasis symptoms assessed on the Psoriasis Symptoms and Signs Diary (PSSD) and improvements in psoriasis of the scalp at Week 16.In both trials, subjects were predominantly men and white, with mean age of 44 years and mean weight of 90 kg. At baseline, subjects had median affected BSA of approximately 21%, median PASI score of 19, and 18% had history of psoriatic arthritis. Approximately 24% of subjects had an IGA score of severe. In both trials, 23% had received prior biologic systemic therapy.. the proportion of subjects who achieved an IGA score of (cleared) or (minimal);. the proportion of subjects who achieved at least 90% reduction from baseline in the PASI composite score (PASI 90).. at Week 16 (PsO1 and PsO2), the proportions of subjects who achieved an IGA score of or 1, PASI 90, and PASI 75 response;. at Week 24 (PsO1 and PsO2), and at Week 48 (PsO1), the proportions of subjects achieving an IGA score of 0, an IGA score of or 1, and PASI 90 response.. Clinical ResponseTable presents the efficacy results at Week 16 in PsO1 and PsO2.Table 2:Efficacy Results at Week 16 in Adults with Plaque Psoriasis (NRINRI Non-Responder Imputation)PsO1PsO2EndpointTREMFYA (N=329) (%)Placebo (N=174) (%)TREMFYA (N=496) (%)Placebo (N=248) (%)IGA response of 0/1Co-Primary Endpoints IGA response of (cleared) or (minimal) 280 (85)12 (7)417 (84)21 (8)PASI 90 response 241 (73)5 (3)347 (70)6 (2)Table presents the results of an analysis of all the North America sites (i.e., U.S. and Canada), demonstrating superiority of TREMFYA to U.S. licensed adalimumab.Table 3:Efficacy Results in Adults with Plaque Psoriasis (NRINRI Non-Responder Imputation)PsO1PsO2EndpointTREMFYA (N=115)Subjects from sites in the United States and Canada (%)AdalimumabU.S. licensed adalimumab (N=115) (%)TREMFYA (N=160) (%)Adalimumab (N=81) (%)IGA response of 0/1 (cleared or minimal) Week 1697 (84)70 (61)119 (74)50 (62) Week 2497 (84)62 (54)119 (74)46 (57) Week 4891 (79)62 (54)NANAIGA response of (cleared) Week 2461 (53)27 (23)76 (48)23 (28) Week 4854 (47)28 (24)NANAPASI 75 response Week 16105 (91)80 (70)132 (83)51 (63)PASI 90 response Week 1684 (73)47 (41)102 (64)34 (42) Week 2492 (80)51 (44)113 (71)41 (51) Week 4884 (73)53 (46)NANAAn improvement was seen in psoriasis involving the scalp in subjects randomized to TREMFYA compared to placebo at Week 16.Examination of age, gender, race, body weight, and previous treatment with systemic or biologic agents did not identify differences in response to TREMFYA among these subgroups.. Maintenance and Durability of ResponseTo evaluate maintenance and durability of response (PsO2), subjects randomized to TREMFYA at Week and who were PASI 90 responders at Week 28 were re-randomized to either continue treatment with TREMFYA every weeks or be withdrawn from therapy (i.e. receive placebo).At Week 48, 89% of subjects who continued on TREMFYA maintained PASI 90 compared to 37% of subjects who were re-randomized to placebo and withdrawn from TREMFYA. For responders at Week 28 who were re-randomized to placebo and withdrawn from TREMFYA, the median time to loss of PASI 90 was approximately 15 weeks.. Patient Reported OutcomesGreater improvements in symptoms of psoriasis (itch, pain, stinging, burning and skin tightness) at Week 16 in TREMFYA compared to placebo were observed in both trials based on the Psoriasis Symptoms and Signs Diary (PSSD). Greater proportions of subjects on TREMFYA compared to U.S. licensed adalimumab achieved PSSD symptom score of (symptom-free) at Week 24 in both trials.. Trial PsO3PsO3 [NCT02203032] evaluated the efficacy of 24 weeks of treatment with TREMFYA in subjects (N=268) who had not achieved an adequate response, defined as IGA >=2 at Week 16 after initial treatment with U.S. licensed ustekinumab (dosed 45 mg or 90 mg according to the subjects baseline weight at Week and Week 4). These subjects were randomized to either continue with U.S. licensed ustekinumab treatment every 12 weeks or switch to TREMFYA 100 mg at Weeks 16, 20, and every weeks thereafter. Baseline characteristics for randomized subjects were similar to those observed in PsO1 and PsO2.In subjects with an inadequate response (IGA >=2 at Week 16 to U.S. licensed ustekinumab), greater proportions of subjects on TREMFYA compared to U.S. licensed ustekinumab achieved an IGA score of or with >=2 grade improvement at Week 28 (31% vs. 14%, respectively; 12 weeks after randomization).. Trial PsO4PsO4 [NCT02905331] evaluated the efficacy, safety, and pharmacokinetics of TREMFYA administered with the One-Press injector. In this study, 78 subjects were randomized to receive either TREMFYA (100 mg at Weeks and and every weeks thereafter) [N=62], or placebo [N=16]. Baseline characteristics for subjects were comparable to those observed in PsO1 and PsO2. The co-primary endpoints were the same as those for PsO1 and PsO2. Secondary endpoints included the proportion of subjects who achieved an IGA score of at Week 16 and the proportion of subjects who achieved PASI 100 response at Week 16.A greater proportion of subjects in the guselkumab group achieved an IGA score of or or PASI 90 response at Week 16 (81% and 76%, respectively) than in the placebo group (0% for both endpoints). The proportion of subjects who achieved an IGA score of at Week 16 was higher in the guselkumab group compared to the placebo group (56% vs. 0%). The proportion of subjects who achieved PASI 100 response at Week 16 was higher in the guselkumab group compared to the placebo group (50% vs. 0%).. 14.2Psoriatic Arthritis. The safety and efficacy of TREMFYA were assessed in 1120 subjects in randomized, double-blind, placebo-controlled trials (PsA1 [NCT03162796] and PsA2 [NCT03158285]) in adult subjects with active psoriatic arthritis (PsA) (>=3 swollen joints, >=3 tender joints, and C-reactive protein (CRP) level of >=0.3 mg/dL in PsA1 and >=5 swollen joints, >=5 tender joints, and CRP level of >=0.6 mg/dL in PsA2) who had inadequate response to standard therapies (e.g. conventional DMARDs [cDMARDs]), apremilast, or nonsteroidal anti-inflammatory drugs [NSAIDs]). Patients in these trials had diagnosis of PsA for at least months based on the Classification criteria for Psoriatic Arthritis (CASPAR) and median duration of PsA of years at baseline.In PsA1 approximately 31% of subjects had been previously treated with up to anti-tumor necrosis factor alpha (anti-TNF) agents whereas in PsA2 all subjects were biologic naive. Approximately 58% of subjects from both trials had concomitant methotrexate (MTX) use. Patients with different subtypes of PsA were enrolled in both trials, including polyarticular arthritis with the absence of rheumatoid nodules (40%), spondylitis with peripheral arthritis (30%), asymmetric peripheral arthritis (23%), distal interphalangeal involvement (7%) and arthritis mutilans (1%). At baseline, over 65% and 42% of the subjects had enthesitis and dactylitis, respectively and 79% had >=3% body surface area (BSA) psoriasis skin involvement.PsA1 evaluated 381 subjects who were treated with placebo SC, TREMFYA 100 mg SC at Weeks 0, and every weeks (q8w) thereafter, or TREMFYA 100 mg SC every weeks (q4w). PsA2 evaluated 739 subjects who were treated with placebo SC, TREMFYA 100 mg SC at Weeks 0, and q8w thereafter, or TREMFYA 100 mg SC q4w. The primary endpoint in both trials was the percentage of subjects achieving an ACR20 response at Week 24.. Clinical ResponseIn both trials, subjects treated with TREMFYA 100 mg q8w demonstrated greater clinical response including ACR20, compared to placebo at Week 24 (Tables and 5). Similar responses were seen regardless of prior anti-TNF exposure in PsA1, and in both trials similar responses were seen regardless of concomitant cDMARD use, previous treatment with cDMARDs, gender and body weight.Table 4:Percent of Subjects with ACR Responses in PsA1Placebo (N=126)TREMFYA 100 mg q8w (N=127)Response RateResponse RateDifference from Placebo (95% CI)ACR 20 responseSubjects with missing data at visit were imputed as non-responders at that visit. Subjects who met escape criteria (less than 5% improvement in both tender and swollen joint counts) at Week 16 were allowed to initiate or increase the dose of the permitted concomitant medication and remained on the randomized group. Subjects who initiated or increased the dose of non-biologic DMARD or oral corticosteroids over baseline, discontinued study/study medication or initiated protocol prohibited medications/therapies for PsA prior to visit were considered non-responders at that visit. Week 1625%52%27 (15, 38)Week 2422%52%30 (19, 41)ACR 50 response Week 1613%23%10 (1, 19)Week 249%30%21 (12, 31)ACR 70 response Week 166%8%2 (-4, 8)Week 246%12%6 (-0.3, 13)Table 5:Percent of Subjects with ACR Responses in PsA2Placebo (N=246)TREMFYA 100 mg q8w (N=248)Response RateResponse RateDifference from Placebo (95% CI)ACR 20 responseSubjects with missing data at visit were imputed as non-responders at that visit. Subjects who met escape criteria (less than 5% improvement in both tender and swollen joint counts) at Week 16 were allowed to initiate or increase the dose of the permitted concomitant medication and remained on the randomized group. Subjects who initiated or increased the dose of non-biologic DMARD or oral corticosteroids over baseline, discontinued study/study medication or initiated protocol prohibited medications/therapies for PsA prior to visit were considered non-responders at that visit. Week 1634%55%22 (13, 30)Week 2433%64%31 (23, 40)ACR 50 response Week 169%29%19 (13, 26)Week 2414%32%17 (10, 24)ACR 70 response Week 161%14%13 (9, 17)Week 244%19%15 (9, 20)The percentage of subjects achieving ACR20 response in PsA2 by visit is shown in Figure 1.Figure 1: Subjects Achieving ACR 20 Response by Visit Through Week 24 in PsA2The results of the components of the ACR response criteria are shown in Table 6.Table 6:Mean change (SDSD= standard deviation) from Baseline in ACR Component Scores at Week 16 and 24 based on Observed DataPsA1PsA2Placebo (N=126)TREMFYA 100 mg q8w (N=127)Placebo N=246TREMFYA 100 mg q8w (N=248)No. of Swollen JointsBaseline10.1 (7.1)10.9 (9.3)12.3 (6.9)11.7 (6.8)Mean change at Week 16-4.2 (7.0)-7.3 (7.0)-5.8 (7.1)-7.2 (6.0)Mean change at Week 24-5.1 (6.9)-7.3 (8.0)-6.4 (7.2)-8.1 (6.1)No. of Tender JointsBaseline19.8 (14.4)20.2 (14.5)21.6 (13.1)19.8 (11.9)Mean change at Week 16-4.5 (10.8)-10.2 (10.4)-6.8 (10.5)-9.0 (9.4)Mean change at Week 24-6.8 (13.0)-10.5 (12.0)-7.3 (11.2)-10.4 (9.5)Patients Assessment of PainAssessment based on Visual Analog Scale (cm) with the left end indicating no pain (for patients assessment of pain), very well (for patient global assessment), or no arthritis activity (for physician global assessment) and the right end indicating the worst possible pain (for patient assessment of pain), poor (for patient global assessment), or extremely active arthritis (for physician global assessment). Baseline5.8 (2.2)6.0 (2.1)6.3 (1.8)6.3 (2.0)Mean change at Week 16-0.8 (2.3)-1.7 (2.4)-0.9 (2.3)-2.2 (2.5)Mean change at Week 24-0.7 (2.4)-2.2 (2.6)-1.1 (2.4)-2.5 (2.5)Patient Global Assessment Baseline6.1 (2.2)6.5 (2.0)6.5 (1.8)6.5 (1.9)Mean change at Week 16-1.0 (2.3)-2.0 (2.6)-1.0 (2.3)-2.3 (2.6)Mean change at Week 24-0.9 (2.5)-2.5 (2.7)-1.2 (2.6)-2.5 (2.5)Physician Global Assessment Baseline6.3 (1.7)6.2 (1.7)6.7 (1.5)6.6 (1.6)Mean change at Week 16-1.9 (2.2)-2.9 (2.4)-2.1 (2.2)-3.5 (2.3)Mean change at Week 24-2.2 (2.3)-3.5 (2.4)-2.5 (2.3)-3.8 (2.3)Disability Index (HAQ-DI)Disability Index of the Health Assessment Questionnaire; = no difficulty to = inability to perform, measures the patients ability to perform the following: dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living Baseline1.2 (0.7)1.2 (0.6)1.3 (0.6)1.3 (0.6)Mean change at Week 16-0.1 (0.5)-0.3 (0.5)-0.1 (0.5)-0.3 (0.5)Mean change at Week 24-0.1 (0.5)-0.3 (0.6)-0.2 (0.5)-0.4 (0.5)CRP (mg/dL)Baseline1.4 (1.9)1.6 (2.4)2.1 (2.7)2.0 (2.4)Mean change at Week 16-0.2 (1.5)-0.6 (2.2)-0.6 (2.5)-1.0 (2.2)Mean change at Week 24-0.0 (2.8)-0.7 (2.1)-0.5 (2.5)-1.1 (2.2)Treatment with TREMFYA resulted in an improvement in the skin manifestations of psoriasis in subjects with PsA.Treatment with TREMFYA resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.. Figure 1. Physical FunctionTREMFYA treated subjects in the TREMFYA 100 mg q8w group in both PsA1 and PsA2 showed greater mean improvement from baseline in physical function compared to subjects treated with placebo as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Weeks 16 and 24. In both studies, the proportion of HAQ-DI responders (>=0.35 improvement in HAQ-DI score) was greater in the TREMFYA q8w dose group compared to placebo at Weeks 16 and 24.. Other Health-Related OutcomesGeneral health status was assessed by the Short Form health survey (SF-36). At Week 24, subjects in the TREMFYA 100 mg q8w dose group in both PsA1 and PsA2 showed greater improvement from baseline in the SF-36 physical component summary (PCS) compared with placebo. There was not statistically significant improvement observed in the SF-36 MCS. At Week 24, there was numerical improvement in the physical functioning, role-physical, bodily-pain, general health, social-functioning and vitality domains but not in the role-emotional and mental health domains. Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue score (FACIT-F) in Studies PsA1 and PsA2. Treatment with TREMFYA resulted in improvement in fatigue as measured by FACIT-F.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Plaque PsoriasisIn clinical trials, total of 1823 subjects with moderate-to-severe plaque psoriasis received TREMFYA. Of these, 1393 subjects were exposed to TREMFYA for at least months and 728 subjects were exposed for at least year.Data from two placebo- and active-controlled trials (PsO1 and PsO2) in 1441 subjects (mean age 44 years; 70% males; 82% white) were pooled to evaluate the safety of TREMFYA (100 mg administered subcutaneously at Weeks and 4, followed by every weeks).. Weeks to 16:In the 16-week placebo-controlled period of the pooled clinical trials (PsO1 and PsO2), adverse events occurred in 49% of subjects in the TREMFYA group compared to 47% of subjects in the placebo group and 49% of subjects in the U.S. licensed adalimumab group. Serious adverse events occurred in 1.9% of subjects in the TREMFYA group (6.3 events per 100 subject-years of follow-up) compared to 1.4% of subjects in the placebo group (4.7 events per 100 subject-years of follow-up), and in 2.6% of subjects in U.S. licensed adalimumab group (9.9 events per 100 subject-years of follow-up).Table summarizes the adverse reactions that occurred at rate of at least 1% and at higher rate in the TREMFYA group than in the placebo group during the 16-week placebo-controlled period.Table 1:Adverse Reactions Occurring in >=1% of Subjects through Week 16 in PsO1 and PsO2TREMFYASubjects receiving 100 mg of TREMFYA at Week 0, Week 4, and every weeks thereafter 100 mg N=823 (%)AdalimumabU.S. licensed adalimumab N=196 (%)Placebo N=422 (%)Upper respiratory infectionsUpper respiratory infections include nasopharyngitis, upper respiratory tract infection (URTI), pharyngitis, and viral URTI. 118 (14.3)21 (10.7)54 (12.8)HeadacheHeadache includes headache and tension headache. 38 (4.6)2 (1.0)14 (3.3)Injection site reactionsInjection site reactions include injection site erythema, bruising, hematoma, hemorrhage, swelling, edema, pruritus, pain, discoloration, induration, inflammation, and urticaria. 37 (4.5)15 (7.7)12 (2.8)Arthralgia22 (2.7)4 (2.0)9 (2.1)Diarrhea13 (1.6)3 (1.5)4 (0.9)GastroenteritisGastroenteritis includes gastroenteritis and viral gastroenteritis. 11 (1.3)4 (2.0)4 (0.9)Tinea infectionsTinea infections include tinea pedis, tinea cruris, tinea infection, and tinea manuum infections. (1.1)00Herpes simplex infectionsHerpes simplex infections include oral herpes, herpes simplex, genital herpes, genital herpes simplex, and nasal herpes simplex. (1.1)02 (0.5)Adverse reactions that occurred in 1% but 0.1% of subjects in the TREMFYA group and at higher rate than in the placebo group through Week 16 in PsO1 and PsO2 were migraine, candida infections, and urticaria.. Specific Adverse Reactions. InfectionsInfections occurred in 23% of subjects in the TREMFYA group compared to 21% of subjects in the placebo group.The most common (>= 1%) infections were upper respiratory infections, gastroenteritis, tinea infections, and herpes simplex infections; all cases were mild to moderate in severity and did not lead to discontinuation of TREMFYA.. Elevated Liver EnzymesElevated liver enzymes were reported more frequently in the TREMFYA group (2.6%) than in the placebo group (1.9%). Of the 21 subjects who were reported to have elevated liver enzymes in the TREMFYA group, all events except one were mild to moderate in severity and none of the events led to discontinuation of TREMFYA.. Safety through Week 48Through Week 48, no new adverse reactions were identified with TREMFYA use and the frequency of the adverse reactions was similar to the safety profile observed during the first 16 weeks of treatment.. Psoriatic ArthritisTREMFYA was studied in two placebo-controlled trials in subjects with psoriatic arthritis (748 subjects on TREMFYA and 372 subjects on placebo). Of the 748 subjects who received TREMFYA, 375 subjects received TREMFYA 100 mg at Week 0, Week 4, and every weeks thereafter and 373 subjects received TREMFYA 100 mg every weeks. The overall safety profile observed in subjects with psoriatic arthritis treated with TREMFYA is generally consistent with the safety profile in subjects with plaque psoriasis with the addition of bronchitis and neutrophil count decreased. In the 24-week placebo-controlled period, combined across the two studies, bronchitis occurred in 1.6% of subjects in the TREMFYA q8w group and 2.9% of subjects in the TREMFYA q4w group compared to 1.1% of subjects in the placebo group. Neutrophil count decreased occurred in 0.3% of subjects in the TREMFYA q8w and 1.6% of subjects in the TREMFYA q4w group compared to 0% of subjects in the placebo group. The majority of events of neutrophil count decreased were mild, transient, not associated with infection and did not lead to discontinuation.

DESCRIPTION SECTION.

11 DESCRIPTION. Guselkumab, an interleukin-23 blocker, is human immunoglobulin G1 lambda (IgG1) monoclonal antibody. Guselkumab is produced in mammalian cell line using recombinant DNA technology.TREMFYA (guselkumab) injection is sterile, preservative free, clear, colorless to light yellow solution that may contain small translucent particles. TREMFYA is supplied as single-dose solution in 1 mL glass syringe with 27G, half inch fixed needle assembled in passive needle guard delivery system or One-Press patient-controlled injector for subcutaneous use.Each TREMFYA mL prefilled syringe or One-Press patient-controlled injector contains 100 mg guselkumab, L-histidine (0.6 mg), L-histidine monohydrochloride monohydrate (1.5 mg), polysorbate 80 (0.5 mg), sucrose (79 mg) and water for injection at pH 5.8.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Plaque Psoriasis100 mg administered by subcutaneous injection at Week 0, Week and every weeks thereafter. (2.1)Psoriatic Arthritis100 mg administered by subcutaneous injection at Week 0, Week and every weeks thereafter. TREMFYA can be used alone or in combination with conventional DMARD (e.g. methotrexate). (2.2). 2.1Plaque Psoriasis. TREMFYA is administered by subcutaneous injection. The recommended dose is 100 mg at Week 0, Week 4, and every weeks thereafter.. 2.2Psoriatic Arthritis. TREMFYA is administered by subcutaneous injection. The recommended dose is 100 mg at Week 0, Week 4, and every weeks thereafter.TREMFYA may be administered alone or in combination with conventional disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate).. 2.3Important Administration Instructions. Administer TREMFYA subcutaneously. Each prefilled syringe or One-Press injector is for single-dose only. Instruct patients to inject the full amount (1 mL), which provides 100 mg of TREMFYA.Do not inject TREMFYA into areas where the skin is tender, bruised, red, hard, thick, scaly, or affected by psoriasis [see Instructions for Use]. TREMFYA is intended for use under the guidance and supervision of physician. TREMFYA may be administered by health care professional, or patient may self-inject after proper training in subcutaneous injection technique.The TREMFYA Instructions for Use contains more detailed patient instructions on the preparation and administration of TREMFYA [see Instructions for Use].. 2.4Preparation for Use of TREMFYA Prefilled Syringe or One-Press Injector. Before injection, remove TREMFYA prefilled syringe or One-Press injector from the refrigerator and allow TREMFYA to reach room temperature (30 minutes) without removing the needle cap.Inspect TREMFYA visually for particulate matter and discoloration prior to administration. TREMFYA is clear and colorless to light yellow solution that may contain small translucent particles. Do not use if the liquid contains large particles, is discolored or cloudy. TREMFYA does not contain preservatives; therefore, discard any unused product remaining in the prefilled syringe or One-Press injector.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 100 mg/mL in single-dose prefilled syringe or single-dose One-Press patient-controlled injector.TREMFYA is clear and colorless to light yellow solution that may contain small translucent particles.. Injection: 100 mg/mL in single-dose prefilled syringe or single-dose One-Press patient-controlled injector. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1CYP450 Substrates. The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF, interferon) during chronic inflammation.Results from an exploratory drug-drug interaction study in subjects with moderate-to-severe plaque psoriasis suggested low potential for clinically relevant drug interactions for drugs metabolized by CYP3A4, CYP2C9, CYP2C19 and CYP1A2 but the interaction potential cannot be ruled out for drugs metabolized by CYP2D6. However, the results were highly variable because of the limited number of subjects in the study.Upon initiation of TREMFYA in patients who are receiving concomitant CYP450 substrates, particularly those with narrow therapeutic index, consider monitoring for therapeutic effect or drug concentration and consider dosage adjustment as needed [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 3406 subjects with plaque psoriasis or psoriatic arthritis exposed to TREMFYA, total of 185 subjects were 65 years or older, and 13 subjects were 75 years or older. No overall differences in safety or effectiveness were observed between older and younger subjects who received TREMFYA. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. TREMFYA (guselkumab) Injection is clear and colorless to light yellow solution that may contain small translucent particles. TREMFYA is supplied as:Single-dose 100 mg/mL prefilled syringe (NDC: 57894-640-01)Single-dose 100 mg/mL One-Press patient-controlled injector (NDC: 57894-640-11). Single-dose 100 mg/mL prefilled syringe (NDC: 57894-640-01). Single-dose 100 mg/mL One-Press patient-controlled injector (NDC: 57894-640-11). 16.2Storage and Handling. TREMFYA is sterile and preservative-free. Discard any unused portion.Store in refrigerator at 2oC to 8oC (36oF to 46oF).Store in original carton until time of use.Protect from light until use.Do not freeze.Do not shake.Not made with natural rubber latex.Keep out of reach of children.. Store in refrigerator at 2oC to 8oC (36oF to 46oF).. Store in original carton until time of use.. Protect from light until use.. Do not freeze.. Do not shake.. Not made with natural rubber latex.

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity with TREMFYA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to guselkumab across indications or with the incidences of antibodies to other products may be misleading.. Plaque PsoriasisUp to Week 52, approximately 6% of subjects treated with TREMFYA developed antidrug antibodies. Of the subjects who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing antibodies. Among the 46 subjects who developed antibodies to guselkumab and had evaluable data, 21 subjects exhibited lower trough levels of guselkumab, including one subject who experienced loss of efficacy after developing high antibody titers. Up to Week 156, approximately 9% of subjects treated with TREMFYA developed antidrug antibodies and of these subjects approximately 6% were classified as neutralizing antibodies. However, antibodies to guselkumab were generally not associated with changes in clinical response or development of injection-site reactions.. Psoriatic ArthritisUp to Week 24, 2% (n=15) of subjects treated with TREMFYA developed antidrug antibodies. Of these subjects, had antibodies that were classified as neutralizing antibodies. Overall, the small number of subjects who were positive for antibodies to guselkumab limits definitive conclusion of the effect of immunogenicity on the pharmacokinetics, efficacy and safety of guselkumab.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. TREMFYA is an interleukin-23 blocker indicated for the treatment of adult patients with:moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy (1.1)active psoriatic arthritis. (1.2). moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy (1.1). active psoriatic arthritis. (1.2). 1.1Plaque Psoriasis. TREMFYA(R) is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.. 1.2Psoriatic Arthritis. TREMFYA is indicated for the treatment of adult patients with active psoriatic arthritis.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before starting TREMFYA therapy, and each time the prescription is renewed, as there may be new information they need to know.. Hypersensitivity ReactionsAdvise patients to discontinue TREMFYA and seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.1)]. InfectionsInstruct patients of the importance of communicating any history of infections to the healthcare provider and contacting their healthcare provider if they develop any symptoms of an infection [see Warnings and Precautions (5.2)].. Instruction on Injection TechniqueInstruct patients or caregivers to perform the first self-injection under the supervision and guidance of qualified healthcare professional for proper training in subcutaneous injection technique. Instruct patients who are self-administering to inject the full dose of TREMFYA [see Medication Guide and Instructions for Use].Instruct patients or caregivers in the technique of proper needle and syringe disposal. Needles and syringes should be disposed of in puncture-resistant container. Advise patients and caregivers not to reuse needles or syringes.Remind patients if they forget to take their dose of TREMFYA to inject their dose as soon as they remember. They should then take their next dose at the appropriate scheduled time.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. TREMFYA(R) (trem fye ah)(guselkumab)Prefilled SyringeSINGLE-DOSEImportantTREMFYA comes as single-dose prefilled syringe containing one 100 mg dose. Each TREMFYA prefilled syringe can only be used one time. Throw the used prefilled syringe away (See Step 3) after one dose, even if there is medicine left in it. Do not reuse your TREMFYA prefilled syringe.If your healthcare provider decides that you or caregiver may be able to give your injections of TREMFYA at home, you should receive training on the right way to prepare and inject TREMFYA using the prefilled syringe before attempting to inject. Do not try to inject yourself until you have been shown the right way to give the injections by your healthcare provider.Read this Instructions for Use before using your TREMFYA prefilled syringe and each time you get refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.The TREMFYA prefilled syringe is intended for injection under the skin, not into the muscle or vein. After injection, the needle will retract into the body of the device and lock into place.Storage informationStore in refrigerator at 36 to 46F (2 to 8C). Do not freeze TREMFYA prefilled syringe.Keep TREMFYA prefilled syringe and all medicines out of reach of children.Do not shake your TREMFYA prefilled syringe.Keep TREMFYA prefilled syringe in the original carton to protect from light and physical damage.Prefilled syringe partsBefore useAfter useYou will need these supplies:1 TREMFYA prefilled syringeNot provided in the TREMFYA prefilled syringe carton:1 Alcohol swab1 Cotton ball or gauze pad Adhesive bandage1 Sharps container (See Step 3)1. Prepare for your injection Inspect cartonRemove your TREMFYA prefilled syringe carton from the refrigerator.Keep the prefilled syringe in the carton and let it sit on flat surface at room temperature for at least 30 minutes before use.Do not warm the prefilled syringe any other way.Check the expiration date (EXP) on the back panel of the carton.Do not use your prefilled syringe if the expiration date has passed.Do not inject TREMFYA if the perforations on the carton are broken. Call your healthcare provider or pharmacist for refill.Choose injection siteSelect from the following areas for your injection:Front of thighs (recommended)Lower stomach area (lower abdomen), except for 2-inch area right around your navel (belly-button)Back of upper arms (only if someone else is giving you the injection)Do not inject into skin that is tender, bruised, red, hard, thick, scaly or affected by psoriasis.Clean injection siteWash your hands well with soap and warm water.Wipe your chosen injection site with an alcohol swab and allow it to dry.Do not touch, fan, or blow on the injection site after you have cleaned it.Inspect liquidTake your TREMFYA prefilled syringe out of the carton.Check the TREMFYA prefilled syringe liquid in the viewing window. It should be clear to slightly yellow and may contain tiny white or clear particles. You may also see one or more air bubbles. This is normal.Do not inject if the liquid is cloudy or discolored, or has large particles. Call your healthcare provider or pharmacist for refill.2. Inject TREMFYA using prefilled syringe Remove needle coverHold your prefilled syringe by the body and pull needle cover straight off. It is normal to see drop of liquid.Inject TREMFYA within minutes of removing the needle cover.Do not put needle cover back on, as this may damage the needle or cause needle stick injury.Do not touch needle or let it touch any surface.Do not use TREMFYA prefilled syringe if it is dropped. Call your healthcare provider or pharmacist for refill.Position fingers and insert needlePlace your thumb, index and middle fingers directly under the finger flange, as shown.Do not touch plunger or area above finger flange as this may cause the needle safety device to activate.Use your other hand to pinch skin at the injection site. Position syringe at about 45 degree angle to the skin.It is important to pinch enough skin to inject under the skin and not into the muscle.Insert needle with quick, dart-like motion.Release pinch and reposition handUse your free hand to grasp the body of the prefilled syringe.Press plungerPlace thumb from the opposite hand on the plunger and press the plunger all the way down until it stops.Release pressure from plungerThe safety guard will cover the needle and lock into place, removing the needle from your skin.3. After your injection Dispose of your prefilled syringePut your used TREMFYA prefilled syringe in an FDA-cleared sharps disposal container right away after use.Do not throw away (dispose of) your TREMFYA prefilled syringe in your household trash.Do not recycle your used sharps disposal container.For more information, see How should dispose of the used prefilled syringeCheck injection siteThere may be small amount of blood or liquid at the injection site. Hold pressure over your skin with cotton ball or gauze pad until any bleeding stops.Do not rub the injection site.If needed, cover injection site with bandage.Need helpCall your healthcare provider to talk about any questions you may have. For additional assistance or to share your feedback call 800-JANSSEN (800-526-7736).How should dispose of the used prefilled syringeIf you do not have an FDA-cleared sharps disposal container, you may use household container that is: made of heavy-duty plasticcan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come outupright and stable during useleak-resistantproperly labeled to warn of hazardous waste inside the containerWhen your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes.For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: www.fda.gov/safesharpsdisposalThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by:Janssen Biotech, Inc. Horsham, PA 19044US License No. 1864Approved: December 2017. TREMFYA prefilled syringe. Alcohol swab. Cotton ball or gauze pad 1 Adhesive bandage. Sharps container (See Step 3). Front of thighs (recommended). Lower stomach area (lower abdomen), except for 2-inch area right around your navel (belly-button). Back of upper arms (only if someone else is giving you the injection). made of heavy-duty plastic. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out. upright and stable during use. leak-resistant. properly labeled to warn of hazardous waste inside the container. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of guselkumab in human milk, the effects on the breastfed infant, or the effects on milk production. Guselkumab was not detected in the milk of lactating cynomolgus monkeys. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TREMFYA and any potential adverse effects on the breastfed infant from TREMFYA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Guselkumab is human monoclonal IgG1 antibody that selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of TREMFYA.No effects on fertility parameters were observed after male guinea pigs were subcutaneously administered guselkumab at dose of 25 mg/kg twice weekly (15 times the MRHD based on mg/kg comparison).No effects on fertility parameters were observed after female guinea pigs were subcutaneously administered guselkumab at doses up to 100 mg/kg twice weekly (60 times the MRHD based on mg/kg comparison).

OVERDOSAGE SECTION.

10 OVERDOSAGE. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg/mL Syringe Carton. Tremfya(R) (guselkumab)Injection100 mg/mLFOR SUBCUTANEOUS USE ONLYRx onlyNDC 57894-640-11Single-dose One-Presspatient-controlled injectorDiscard unused portionContains no preservativeATTENTION: Dispense the enclosedMedication Guide to each patient. PRINCIPAL DISPLAY PANEL 100 mg/mL Syringe Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of TREMFYA in pediatric patients (less than 18 years of age) have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In evaluated subjects with plaque psoriasis, guselkumab reduced serum levels of IL-17A, IL-17F and IL-22 relative to pre-treatment levels based on exploratory analyses of the pharmacodynamic markers.In evaluated subjects with psoriatic arthritis, serum levels of acute phase proteins C-reactive protein, serum amyloid and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 were elevated at baseline. Serum levels of these proteins measured at Week and Week 24 were decreased compared to baseline following guselkumab treatment at Week 0, Week and every weeks thereafter.The relationship between these pharmacodynamic markers and the mechanism(s) by which guselkumab exerts its clinical effects is unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Guselkumab exhibited linear pharmacokinetics in healthy subjects and subjects with plaque psoriasis following subcutaneous injections. In subjects with plaque psoriasis, following subcutaneous administration of 100 mg of TREMFYA at Weeks and 4, and every weeks thereafter, mean steady-state trough serum guselkumab concentration was approximately 1.2 mcg/mL.The pharmacokinetics of guselkumab in subjects with psoriatic arthritis was similar to that in subjects with plaque psoriasis. Following subcutaneous administration of 100 mg of TREMFYA at Weeks 0, 4, and every weeks thereafter, mean steady-state trough serum guselkumab concentration was approximately 1.2 mcg/mL.. AbsorptionFollowing single 100 mg subcutaneous injection in healthy subjects, guselkumab reached mean (+- SD) maximum serum concentration of 8.09 +- 3.68 mcg/mL by approximately 5.5 days post dose. The absolute bioavailability of guselkumab following single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects.. DistributionIn subjects with plaque psoriasis, apparent volume of distribution was 13.5 L.. EliminationApparent clearance in subjects with plaque psoriasis was 0.516 L/day. Mean half-life of guselkumab was approximately 15 to 18 days in subjects with plaque psoriasis across trials.. MetabolismThe exact pathway through which guselkumab is metabolized has not been characterized. As human IgG monoclonal antibody, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.. Specific PopulationsNo apparent differences in clearance were observed in subjects >= 65 years of age compared to subjects 65 years of age, suggesting no dose adjustment is needed for elderly subjects. Clearance and volume of distribution of guselkumab increases as body weight increases, however, observed clinical trial data indicate that dose adjustment for body weight is not warranted. No specific trials have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab.. Drug InteractionsPopulation pharmacokinetic analyses indicated that concomitant use of NSAIDs, oral corticosteroids and conventional DMARDs such as methotrexate, did not affect the clearance of guselkumab.. Cytochrome P450 SubstratesThe effects of guselkumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), dextromethorphan (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in an exploratory study with to 12 evaluable subjects with moderate-to-severe plaque psoriasis. Changes in AUCinf of midazolam, S-warfarin, omeprazole, and caffeine after single dose of guselkumab were not clinically relevant. For dextromethorphan, changes in AUCinf after guselkumab were not clinically relevant in out of 10 subjects; however, 2.9-fold change in AUCinf was observed in one individual [see Drug Interactions (7.1)].

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been reported during post-approval of TREMFYA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to TREMFYA exposure.Immune system disorders: Hypersensitivity, including anaphylaxis [see Warnings and Precautions (5.1)] Skin and subcutaneous tissue disorders: Rash [see Warnings and Precautions (5.1)].

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy registry that monitors pregnancy outcomes in women exposed to TREMFYA during pregnancy. Patients should be encouraged to enroll by calling 1-877-311- 8972.. Risk SummaryThere are no available data on TREMFYA use in pregnant women to inform drug associated risk of adverse developmental outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, TREMFYA may be transmitted from the mother to the developing fetus. In combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD). Neonatal deaths were observed at 6- to 30-times the MRHD (see Data). The clinical significance of these nonclinical findings is unknown.All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 DataIn combined embryofetal development and pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of guselkumab up to 50 mg/kg (30 times the MRHD based on mg/kg comparison) from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of one control monkey, three monkeys administered guselkumab at 10 mg/kg/week (6 times the MRHD based on mg/kg comparison) and three monkeys administered guselkumab at 50 mg/kg/week (30 times the MRHD based on mg/kg comparison). The clinical significance of these findings is unknown. No guselkumab-related effects on functional or immunological development were observed in the infants from birth through months of age.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.2)07/2020Dosage and Administration (2.2)07/2020Warnings and Precautions, Hypersensitivity (5.1)06/2020Warnings and Precautions, Infections (5.2)07/2020Warnings and Precautions, Pre-treatment Evaluation for TB (5.3)07/2020.

SPL MEDGUIDE SECTION.

Medication Guide TREMFYA(R) (trem fye ah) (guselkumab) injection, for subcutaneous useThis Medication Guide had been approved by the U.S. Food and Drug Administration.Revised: 07/2020What is the most important information should know about TREMFYATREMFYA may cause serious side effects, including:Serious allergic reactions. Stop using TREMFYA and get emergency medical help right away if you develop any of the following symptoms of serious allergic reaction:fainting, dizziness, feeling lightheaded (low blood pressure)swelling of your face, eyelids, lips, mouth, tongue or throattrouble breathing or throat tightnesschest tightnessskin rash, hivesitchingInfections. TREMFYA is medicine that may lower the ability of your immune system to fight infections and may increase your risk of infections. Your healthcare provider should check you for infections and tuberculosis (TB) before starting treatment with TREMFYA and may treat you for TB before you begin treatment with TREMFYA if you have history of TB or have active TB. Your healthcare provider should watch you closely for signs and symptoms of TB during and after treatment with TREMFYA. Tell your healthcare provider right away if you have an infection or have symptoms of an infection, including:fever, sweats, or chillscoughshortness of breathblood in your phlegm (mucus)muscle acheswarm, red, or painful skin or sores on your body different from your psoriasisweight lossdiarrhea or stomach painburning when you urinate or urinating more often than normalSee What are the possible side effects of TREMFYA for more information about side effects.What is TREMFYATREMFYA is prescription medicine used to treat adults:with moderate to severe plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet or UV light)with active psoriatic arthritis (PsA).It is not known if TREMFYA is safe and effective in children under 18 years of age.Do not use TREMFYA if you have had serious allergic reaction to guselkumab or any of the other ingredients in TREMFYA. See the end of this Medication Guide for complete list of ingredients in TREMFYA.Before using TREMFYA, tell your healthcare provider about all of your medical conditions, including if you:have any of the conditions or symptoms listed in the section What is the most important information should know about TREMFYA have an infection that does not go away or that keeps coming back.have TB or have been in close contact with someone with TB.have recently received or are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with TREMFYA.are pregnant or plan to become pregnant. It is not known if TREMFYA can harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if TREMFYA passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use TREMFYASee the detailed Instructions for Use that comes with TREMFYA for information on how to prepare and inject dose of TREMFYA, and how to properly throw away (dispose of) used TREMFYA prefilled syringes or One-Press injectors.Use TREMFYA exactly as your healthcare provider tells you to use it.If you miss your TREMFYA dose, inject dose as soon as you remember. Then, take your next dose at your regular scheduled time. Call your healthcare provider if you are not sure what to do.If you inject more TREMFYA than prescribed, call your healthcare provider right away.What are the possible side effects of TREMFYATREMFYA may cause serious side effects including:See What is the most important information should know about TREMFYAThe most common side effects of TREMFYA include:upper respiratory infectionsjoint pain (arthralgia)fungal skin infectionsheadachediarrheaherpes simplex infectionsinjection site reactionsstomach flu (gastroenteritis)bronchitisThese are not all the possible side effects of TREMFYA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of TREMFYAMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TREMFYA for condition for which it was not prescribed. Do not give TREMFYA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TREMFYA that is written for health professionals.What are the ingredients in TREMFYAActive ingredient: guselkumabInactive ingredients: L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose and water for injectionNot made with natural rubber latex.Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, U.S. License Number 1864 For more information, call 1-800-526-7736 or go to www.tremfya.com.. Serious allergic reactions. Stop using TREMFYA and get emergency medical help right away if you develop any of the following symptoms of serious allergic reaction:. fainting, dizziness, feeling lightheaded (low blood pressure). swelling of your face, eyelids, lips, mouth, tongue or throat. trouble breathing or throat tightness. chest tightness. skin rash, hives. itching. Infections. TREMFYA is medicine that may lower the ability of your immune system to fight infections and may increase your risk of infections. Your healthcare provider should check you for infections and tuberculosis (TB) before starting treatment with TREMFYA and may treat you for TB before you begin treatment with TREMFYA if you have history of TB or have active TB. Your healthcare provider should watch you closely for signs and symptoms of TB during and after treatment with TREMFYA. Tell your healthcare provider right away if you have an infection or have symptoms of an infection, including:. fever, sweats, or chills. cough. shortness of breath. blood in your phlegm (mucus). muscle aches. warm, red, or painful skin or sores on your body different from your psoriasis. weight loss. diarrhea or stomach pain. burning when you urinate or urinating more often than normal. with moderate to severe plaque psoriasis who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet or UV light). with active psoriatic arthritis (PsA).. have any of the conditions or symptoms listed in the section What is the most important information should know about TREMFYA have an infection that does not go away or that keeps coming back.. have TB or have been in close contact with someone with TB.. have recently received or are scheduled to receive an immunization (vaccine). You should avoid receiving live vaccines during treatment with TREMFYA.. are pregnant or plan to become pregnant. It is not known if TREMFYA can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if TREMFYA passes into your breast milk.. Use TREMFYA exactly as your healthcare provider tells you to use it.. If you miss your TREMFYA dose, inject dose as soon as you remember. Then, take your next dose at your regular scheduled time. Call your healthcare provider if you are not sure what to do.. See What is the most important information should know about TREMFYA. upper respiratory infections. joint pain (arthralgia). fungal skin infections. headache. diarrhea. herpes simplex infections. injection site reactions. stomach flu (gastroenteritis). bronchitis.

SPL UNCLASSIFIED SECTION.

1.1Plaque Psoriasis. TREMFYA(R) is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

STORAGE AND HANDLING SECTION.

16.2Storage and Handling. TREMFYA is sterile and preservative-free. Discard any unused portion.Store in refrigerator at 2oC to 8oC (36oF to 46oF).Store in original carton until time of use.Protect from light until use.Do not freeze.Do not shake.Not made with natural rubber latex.Keep out of reach of children.. Store in refrigerator at 2oC to 8oC (36oF to 46oF).. Store in original carton until time of use.. Protect from light until use.. Do not freeze.. Do not shake.. Not made with natural rubber latex.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy registry that monitors pregnancy outcomes in women exposed to TREMFYA during pregnancy. Patients should be encouraged to enroll by calling 1-877-311- 8972.. Risk SummaryThere are no available data on TREMFYA use in pregnant women to inform drug associated risk of adverse developmental outcomes. Human IgG antibodies are known to cross the placental barrier; therefore, TREMFYA may be transmitted from the mother to the developing fetus. In combined embryofetal development and pre- and post-natal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of guselkumab during organogenesis through parturition at doses up to 30 times the maximum recommended human dose (MRHD). Neonatal deaths were observed at 6- to 30-times the MRHD (see Data). The clinical significance of these nonclinical findings is unknown.All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 DataIn combined embryofetal development and pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of guselkumab up to 50 mg/kg (30 times the MRHD based on mg/kg comparison) from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of one control monkey, three monkeys administered guselkumab at 10 mg/kg/week (6 times the MRHD based on mg/kg comparison) and three monkeys administered guselkumab at 50 mg/kg/week (30 times the MRHD based on mg/kg comparison). The clinical significance of these findings is unknown. No guselkumab-related effects on functional or immunological development were observed in the infants from birth through months of age.. 8.2 Lactation. Risk SummaryThere are no data on the presence of guselkumab in human milk, the effects on the breastfed infant, or the effects on milk production. Guselkumab was not detected in the milk of lactating cynomolgus monkeys. Maternal IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TREMFYA and any potential adverse effects on the breastfed infant from TREMFYA or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and efficacy of TREMFYA in pediatric patients (less than 18 years of age) have not been established.. 8.5 Geriatric Use. Of the 3406 subjects with plaque psoriasis or psoriatic arthritis exposed to TREMFYA, total of 185 subjects were 65 years or older, and 13 subjects were 75 years or older. No overall differences in safety or effectiveness were observed between older and younger subjects who received TREMFYA. However, the number of subjects aged 65 years and older was not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur. (5.1)Infections: TREMFYA may increase the risk of infection. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If serious infection develops, discontinue TREMFYA until the infection resolves. (5.2)Tuberculosis (TB): Evaluate for TB prior to initiating treatment with TREMFYA. (5.3). Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur. (5.1). Infections: TREMFYA may increase the risk of infection. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If serious infection develops, discontinue TREMFYA until the infection resolves. (5.2). Tuberculosis (TB): Evaluate for TB prior to initiating treatment with TREMFYA. (5.3). 5.1Hypersensitivity Reactions. Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarket use of TREMFYA. Some cases required hospitalization. If serious hypersensitivity reaction occurs, discontinue TREMFYA and initiate appropriate therapy.. 5.2Infections. TREMFYA may increase the risk of infection. In clinical trials in subjects with plaque psoriasis, infections occurred in 23% of subjects in the TREMFYA group versus 21% of subjects in the placebo group through 16 weeks of treatment. Upper respiratory tract infections, gastroenteritis, tinea infections, and herpes simplex infections occurred more frequently in the TREMFYA group than in the placebo group [see Adverse Reactions (6.1)]. The rate of serious infections for the TREMFYA group and the placebo group was <= 0.2%. similar risk of infection was seen in placebo-controlled trials in subjects with psoriatic arthritis. Treatment with TREMFYA should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.In patients with chronic infection or history of recurrent infection, consider the risks and benefits prior to prescribing TREMFYA. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If patient develops clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and discontinue TREMFYA until the infection resolves.. 5.3Pre-treatment Evaluation for Tuberculosis. Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TREMFYA. Initiate treatment of latent TB prior to administering TREMFYA. In clinical trials, 105 subjects with plaque psoriasis and 71 subjects with psoriatic arthritis with latent TB who were concurrently treated with TREMFYA and appropriate TB prophylaxis did not develop active TB. Monitor patients for signs and symptoms of active TB during and after TREMFYA treatment. Consider anti-TB therapy prior to initiating TREMFYA in patients with past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer TREMFYA to patients with active TB infection.. 5.4Immunizations. Prior to initiating therapy with TREMFYA, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with TREMFYA. No data are available on the response to live or inactive vaccines.