Tremfya

Tremfya

guselkumab

Manufacturer:

Janssen-Cilag

Distributor:

DKSH
Full Prescribing Info
Contents
Guselkumab.
Description
Tremfya 100 mg solution for injection in pre-filled syringe: Each pre-filled syringe contains 100 mg of guselkumab in 1 mL solution.
Tremfya 100 mg solution for injection in pre-filled pen: Each pre-filled pen contains 100 mg of guselkumab in 1 mL solution.
Guselkumab is a fully human immunoglobulin G1 lamda (IgG1λ) monoclonal antibody (mAb) to the interleukin (IL)-23 protein, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.
Excipients/Inactive Ingredients: Histidine, Histidine monohydrochloride monohydrate, Polysorbate 80, Sucrose, Water for injections.
Action
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors. ATC code: L04AC16.
Pharmacology: Pharmacodynamics: Mechanism of action: Guselkumab is a human IgG1λ monoclonal antibody (mAb) that binds selectively to the interleukin 23 (IL-23) protein with high specificity and affinity. IL-23, a regulatory cytokine, affects the differentiation, expansion, and survival of T cell subsets, (e.g., Th17 cells and Tc17 cells) and innate immune cell subsets, which represent sources of effector cytokines, including IL-17A, IL-17F and IL-22 that drive inflammatory disease. In humans, selective blockade of IL-23 was shown to normalize production of these cytokines.
Levels of IL-23 are elevated in the skin of patients with plaque psoriasis. In in vitro models, guselkumab was shown to inhibit the bioactivity of IL-23 by blocking its interaction with cell surface IL-23 receptor, disrupting IL-23-mediated signaling, activation and cytokine cascades. Guselkumab exerts clinical effects in plaque psoriasis and psoriatic arthritis through blockade of the IL-23 cytokine pathway.
Pharmacodynamic effects: In a phase I study, treatment with guselkumab resulted in reduced expression of IL-23/Th17 pathway genes and psoriasis-associated gene expression profiles, as shown by analyses of mRNA obtained from lesional skin biopsies of patients with plaque psoriasis at Week 12 compared to baseline. In the same phase I study, treatment with guselkumab resulted in improvement of histological measures of psoriasis at Week 12, including reductions in epidermal thickness and T-cell density. In addition, reduced serum IL-17A, IL-17F and IL-22 levels compared to placebo were observed in guselkumab treated patients in phase II and phase III plaque psoriasis studies. These results are consistent with the clinical benefit observed with guselkumab treatment in plaque psoriasis.
In psoriatic arthritis patients in phase III studies, serum levels of acute phase proteins C-reactive protein, serum amyloid A, and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 were elevated at baseline. Guselkumab decreased the levels of these proteins within 4 weeks of initiation of treatment. Guselkumab further reduced the levels of these proteins by Week 24 compared to baseline and also to placebo.
Clinical efficacy and safety: Plaque psoriasis: The efficacy and safety of guselkumab was assessed in three randomised, double-blind, active controlled phase III studies in adult patients with moderate to severe plaque psoriasis, who were candidates for phototherapy or systemic therapy.
VOYAGE 1 and VOYAGE 2: Two studies (VOYAGE 1 and VOYAGE 2) evaluated the efficacy and safety of guselkumab versus placebo and adalimumab in 1829 adult patients. Patients randomised to guselkumab (N=825) received 100 mg at Weeks 0 and 4, and every 8 weeks (q8w) thereafter through Week 48 (VOYAGE 1) and Week 20 (VOYAGE 2). Patients randomised to adalimumab (N=582) received 80 mg at Week 0 and 40 mg at Week 1, followed by 40 mg every other week (q2w) through Week 48 (VOYAGE 1) and Week 23 (VOYAGE 2). In both studies, patients randomised to placebo (N=422) received guselkumab 100 mg at Weeks 16, 20 and q8w thereafter. In VOYAGE 1, all patients, including those randomised to adalimumab at Week 0, started to receive open-label guselkumab q8w at Week 52. In VOYAGE 2, patients randomised to guselkumab at Week 0 who were Psoriasis Area and Severity Index (PASI) 90 responders at Week 28 were re-randomised to either continue treatment with guselkumab q8w (maintenance treatment) or receive placebo (withdrawal treatment). Withdrawal patients re-initiated guselkumab (dosed at time of retreatment, 4 weeks later and q8w thereafter) when they experienced at least a 50% loss of their Week 28 PASI improvement. Patients randomised to adalimumab at Week 0 who were PASI 90 non responders received guselkumab at Weeks 28, 32 and q8w thereafter. In VOYAGE 2, all patients started to receive open-label guselkumab q8w at Week 76.
Baseline disease characteristics were consistent for the study populations in VOYAGE 1 and 2 with a median body surface area (BSA) of 22% and 24%, a median baseline PASI score of 19 for both studies, a median baseline dermatology quality of life index (DLQI) score of 14 and 14.5, a baseline investigator global assessment (IGA) score of severe for 25% and 23% of patients, and a history of psoriatic arthritis for 19% and 18% of patients, respectively.
Of all patients included in VOYAGE 1 and 2, 32% and 29% were naïve to both conventional systemic and biologic therapy, 54% and 57% had received prior phototherapy, and 62% and 64% had received prior conventional systemic therapy, respectively. In both studies, 21% had received prior biologic therapy, including 11% who had received at least one anti-tumour necrosis factor alpha (TNFα) agent, and approximately 10% who had received an anti IL-12/IL-23 agent.
The efficacy of guselkumab was evaluated with respect to overall skin disease, regional disease (scalp, hand and foot and nails) and quality of life and patient reported outcomes. The co-primary endpoints in VOYAGE 1 and 2 were the proportion of patients who achieved an IGA score of cleared or minimal (IGA 0/1) and a PASI 90 response at Week 16 versus placebo (see Table 1).
Overall skin disease: Treatment with guselkumab resulted in significant improvements in the measures of disease activity compared to placebo and adalimumab at Week 16 and compared to adalimumab at Weeks 24 and 48. The key efficacy results for the primary and major secondary study endpoints are shown in Table 1 as follows. (See Table 1.)

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Response over time: Guselkumab demonstrated rapid onset of efficacy, with a significantly higher percent improvement in PASI as compared with placebo as early as Week 2 (p < 0.001). The percentage of patients achieving a PASI 90 response was numerically higher for guselkumab than adalimumab starting at Week 8 with the difference reaching a maximum around Week 20 (VOYAGE 1 and 2) and maintained through Week 48 (VOYAGE 1) (see Figure 1.)

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In VOYAGE 1, for patients receiving continuous guselkumab treatment, the PASI 90 response rate was maintained from Week 52 through Week 156. For patients randomised to adalimumab at Week 0 who crossed over to guselkumab at Week 52, the PASI 90 response rate increased from Week 52 through Week 76 and was then maintained through Week 156 (see Figure 2).

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The efficacy and safety of guselkumab was demonstrated regardless of age, gender, race, body weight, plaques location, PASI baseline severity, concurrent psoriatic arthritis, and previous treatment with a biologic therapy. Guselkumab was efficacious in conventional systemic-naive, biologic-naive, and biologic-exposed patients.
In VOYAGE 2, 88.6% of patients receiving guselkumab maintenance treatment at Week 48 were PASI 90 responders compared to 36.8% of patients who were withdrawn from treatment at Week 28 (p < 0.001). Loss of PASI 90 response was noted as early as 4 weeks after withdrawal of guselkumab treatment with a median time to loss of PASI 90 response of approximately 15 weeks. Among patients who were withdrawn from treatment and subsequently re-initiated guselkumab, 80% regained a PASI 90 response when assessed 20 weeks after initiation of retreatment.
In VOYAGE 2, among 112 patients randomised to adalimumab who failed to achieve a PASI 90 response at Week 28, 66% and 76% achieved a PASI 90 response after 20 and 44 weeks of treatment with guselkumab, respectively. In addition, among 95 patients randomised to guselkumab who failed to achieve a PASI 90 response at Week 28, 36% and 41% achieved a PASI 90 response with an additional 20 and 44 weeks of continued treatment with guselkumab, respectively. No new safety findings were observed in patients who switched from adalimumab to guselkumab.
Regional disease: In VOYAGE 1 and 2, significant improvements were seen in scalp, hand and foot, and nail psoriasis (as measured by the Scalp-specific Investigator Global Assessment [ss-IGA], Physician's Global Assessment of Hands and/or Feet [hf-PGA], Fingernail Physician's Global Assessment [f-PGA] and Nail Psoriasis Severity Index [NAPSI], respectively) in guselkumab treated patients compared to placebo treated patients at Week 16 (p < 0.001, Table 2). Guselkumab demonstrated superiority compared to adalimumab for scalp and hand and foot psoriasis at Week 24 (VOYAGE 1 and 2) and Week 48 (VOYAGE 1) (p ≤ 0.001, except for hand and foot psoriasis at Week 24 [VOYAGE 2] and Week 48 [VOYAGE 1], p < 0.05). (See Table 2.)

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Health-related quality of life/Patient reported outcomes: Across VOYAGE 1 and 2 significantly greater improvements in health-related quality of life as measured by Dermatology Life Quality Index (DLQI) and in patient-reported psoriasis symptoms (itching, pain, burning, stinging and skin tightness) and signs (skin dryness, cracking, scaling, shedding or flaking, redness and bleeding) as measured by the Psoriasis Symptoms and Signs Diary (PSSD) were observed in guselkumab patients compared to placebo patients at Week 16 (Table 3). Signs of improvement on patient-reported outcomes were maintained through Week 24 (VOYAGE 1 and 2) and Week 48 (VOYAGE 1). In VOYAGE 1, for patients receiving continuous guselkumab treatment, these improvements were maintained in the open-label phase through Week 156 (Table 4). (See Tables 3 and 4.)

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In VOYAGE 2, guselkumab patients had significantly greater improvement from baseline compared to placebo in health-related quality of life, anxiety and depression, and work limitation measures at Week 16, as measured by the 36-item Short Form (SF-36) health survey questionnaire, Hospital Anxiety and Depression Scale (HADS), and Work Limitations Questionnaire (WLQ), respectively. The improvements in SF-36, HADS and WLQ were all maintained through Week 48 and in the open-label phase through Week 156 among patients randomised to maintenance therapy at Week 28.
NAVIGATE: The NAVIGATE study examined the efficacy of guselkumab in patients who had an inadequate response (ie, who had not achieved a 'cleared' or 'minimal' response defined as IGA ≥ 2) to ustekinumab at Week 16. All patients (N=871) received open-label ustekinumab (45 mg ≤100 kg and 90 mg >100 kg) at Weeks 0 and 4. At Week 16, 268 patients with an IGA ≥ 2 score were randomised to either continue ustekinumab treatment (N=133) q12w, or to initiate guselkumab treatment (N=135) at Weeks 16, 20, and q8w thereafter. Baseline characteristics for randomised patients were similar to those observed in VOYAGE 1 and 2.
After randomisation, the primary endpoint was the number of post-randomisation visits between Weeks 12 and 24 at which patients achieved an IGA score 0/1 and had ≥ 2 grade improvement. Patients were examined at four week intervals for a total of four visits. Among patients who inadequately responded to ustekinumab at the time of randomisation, significantly greater improvement of efficacy was observed in patients who switched to guselkumab treatment compared to patients who continued ustekinumab treatment. Between 12 and 24 weeks after randomisation, guselkumab patients achieved an IGA score 0/1 with ≥ 2 grade improvement twice as often as ustekinumab patients (mean 1.5 vs 0.7 visits, respectively, p < 0.001). Additionally, at 12 weeks after randomisation a higher proportion of guselkumab patients compared to ustekinumab patients achieved an IGA score 0/1 and ≥ 2 grade improvement (31.1% vs. 14.3%, respectively; p = 0.001) and a PASI 90 response (48% vs 23%, respectively, p < 0.001). Differences in response rates between guselkumab and ustekinumab treated patients were noted as early as 4 weeks after randomisation (11.1% and 9.0%, respectively) and reached a maximum 24 weeks after randomisation (see Figure 3). No new safety findings were observed in patients who switched from ustekinumab to guselkumab. (See Figure 3.)

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ECLIPSE: Efficacy and safety of guselkumab were also investigated in a double-blind study compared to secukinumab. Patients were randomised to receive guselkumab (N=534; 100 mg at Week 0, 4 and q8w thereafter), or secukinumab (N=514; 300 mg at Week 0, 1, 2, 3, 4, and q4w thereafter). The last dose was at week 44 for both treatment groups.
Baseline disease characteristics were consistent with a population of moderate to severe plaque psoriasis with a median BSA of 20%, a median PASI score of 18, and an IGA score of severe for 24% of patients.
Guselkumab was superior to secukinumab as measured by the primary endpoint of PASI 90 response at Week 48 (84.5% versus 70.0%, p < 0.001). Comparative PASI response rates are presented in Table 5. (See Table 5.)

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Guselkumab and secukinumab PASI 90 response rates through Week 48 are presented in Figure 4. (See Figure 4.)

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Psoriatic arthritis (PsA): Guselkumab has been shown to improve signs and symptoms, physical function and health-related quality of life, and reduce the rate of progression of peripheral joint damage in adult patients with active PsA.
DISCOVER 1 and DISCOVER 2: Two randomised, double-blind, placebo-controlled phase III studies (DISCOVER 1 and DISCOVER 2) evaluated the efficacy and safety of guselkumab versus placebo in adult patients with active PsA (≥3 swollen and ≥3 tender joints, and a C-reactive protein (CRP) level of ≥0.3 mg/dL in DISCOVER 1, and ≥5 swollen and ≥5 tender joints, and a CRP level of ≥0.6 mg/dL in DISCOVER 2), despite conventional synthetic (cs)DMARD, apremilast, or nonsteroidal anti-inflammatory drug (NSAID) therapy. Patients in these studies had a diagnosis of PsA based on the Classification criteria for Psoriatic Arthritis [CASPAR]) for a median duration of 4 years. Patients with different subtypes of PsA were enrolled in both studies, 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%). Over 65% and 42% of the patients had enthesitis and dactylitis at baseline, respectively, and over 75% of patients had ≥3% BSA psoriasis skin involvement. DISCOVER 1 and DISCOVER 2 evaluated 381 and 739 patients, respectively, who received treatment with guselkumab 100 mg administered at Weeks 0 and 4 followed by every 8 weeks (q8w) or guselkumab 100 mg q4w, or placebo. Approximately 58% of patients in both studies continued on stable doses of MTX (≤ 25 mg/week).
In both studies over 90% of patients had prior csDMARD use. In DISCOVER 1, 31% of patients had previously received anti-TNFα treatment. In DISCOVER 2, all patients were naive to biologic therapy.
Signs and symptoms: Treatment with guselkumab resulted in significant improvements in the measures of disease activity compared to placebo at Week 24. The primary endpoint in both studies was the percentage of patients who achieved American College of Rheumatology (ACR) 20 response at Week 24. The key efficacy results are shown in Table 6. (See Table 6.)

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Response over time: In DISCOVER 2, a greater ACR 20 response was observed in both guselkumab groups compared to placebo as early as Week 4 and the treatment difference continued to increase over time through Week 24 (Figure 5). (See Figure 5.)

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Responses observed in the guselkumab groups were similar regardless of concomitant csDMARD use, including MTX (DISCOVER 1 and 2). Additionally, examination of age, gender, race, body weight, and previous csDMARD use (DISCOVER 1 and 2) and previous anti-TNFα use (DISCOVER 1), did not identify differences in response to guselkumab among these subgroups.
In DISCOVER 1 and 2, improvements were shown in all components of the ACR scores including patient assessment of pain. At Week 24 in both studies, the proportion of patients achieving a modified PsA response criteria (PsARC) response was greater in the guselkumab groups compared to placebo.
Dactylitis and enthesitis were assessed based on pooled data from DISCOVER 1 and 2. At Week 24, among patients with dactylitis at baseline, the proportion of subjects with dactylitis resolution was greater in the guselkumab q8w group (59.4%, nominal p<0.001) and q4w group (63.5%, p=0.006) compared to placebo (42.2%). At Week 24, among patients with enthesitis at baseline, the proportion of subjects with enthesitis resolution was greater in the guselkumab q8w group (49.6%, nominal p<0.001) and q4w group (44.9%, p=0.006) compared to placebo (29.4%).
In DISCOVER 1 and 2, patients treated with guselkumab who had spondylitis with peripheral arthritis as their primary presentation, demonstrated greater improvement from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) compared to placebo at Week 24.
Radiographic response: In DISCOVER 2, inhibition of structural damage progression was measured radiographically and expressed as the mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score. At Week 24, the guselkumab q4w group demonstrated statistically significantly less radiographic progression and the guselkumab q8w group showed numerically less progression than placebo (Table 7). The observed benefit with the guselkumab q4w dosing regimen on inhibition of radiographic progression (ie, smaller mean change from baseline in total modified vdH-S score in the q4w group versus placebo) was most pronounced in subjects with both a high C-reactive protein value and high number of joints with erosions at baseline. (See Table 7.)

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At Week 52, the mean change from baseline in total modified vdH-S was similar in the guselkumab q8w and q4w groups (Table 8). (See Table 8.)

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Physical function and health-related quality of life: In DISCOVER 1 and 2, guselkumab treated patients showed significant improvement (p<0.001) in physical function compared to placebo as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24.
A significantly greater improvement from baseline in the SF-36 Physical Component Summary score was observed in guselkumab treated patients compared to placebo at Week 24 in DISCOVER 1 (p<0.001 for both dose groups) and DISCOVER 2 (p=0.006 for q4w group). At Week 24, a greater increase from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score was observed in guselkumab treated patients compared to placebo in both studies. In DISCOVER 2, greater improvements in health-related quality of life as measured by the Dermatology Life Quality Index (DLQI) were observed in guselkumab treated patients compared to placebo at Week 24.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies with Tremfya in plaque psoriasis and psoriatic arthritis in one or more subsets of the paediatric population (see Dosage & Administration for information on paediatric use).
Palmoplantar Pustulosis: A double-blind, placebo-controlled study was conducted in 159 patients with moderate to severe plaque-type psoriasis (Palmo-Plantar Pustulosis Area and Severity Index; PPPASI) score ≥ 12, and PPPASI severity score ≥ 2 pustules/vesicles on the palms or soles). Placebo, TREMFYA 100mg or 200mg was administered at Week 0 and 4, and then every 8 weeks thereafter. Change from baseline in PPPASI total score at Week 16, the proportion of subjects who achieved a PPPASI-50 at Week 16, and change from baseline in PPSI (Palmoplantar Pustulosis Severity Index) at Week 16 are shown the table as follows.
The PPPASI score at Week 16 were statistically significantly higher in the TREMFYA group compared to the placebo group. PPPASI-50 in the TREMFYA 100 mg group was 57.4% (31/54 patients) at Week 16 and 83.3% (45/54 patients) at Week 52, respectively. (See Table 9.)

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The frequency (100mg cases) of adverse drug reactions was 31.6% (25/79), and common adverse drug reactions were injection site erythema (7.6%: 6 cases), tinea infection (5.1%: 4 cases) and upper respiratory tract infection (2.5%: 2 cases).
Pharmacokinetics: Absorption: Following a single 100 mg subcutaneous injection in healthy subjects, guselkumab reached a mean (± SD) maximum serum concentration (Cmax) of 8.09 ± 3.68 mcg/mL by approximately 5.5 days post dose.
Steady-state serum guselkumab concentrations were achieved by Week 20 following subcutaneous administrations of 100 mg guselkumab at Weeks 0 and 4, and every 8 weeks thereafter. The mean (± SD) steady-state trough serum guselkumab concentrations in two phase III studies in patients with plaque psoriasis were 1.15 ± 0.73 mcg/mL and 1.23 ± 0.84 mcg/mL.
The pharmacokinetics of guselkumab in subjects with psoriatic arthritis was similar to that in subjects with psoriasis. Following subcutaneous administration of 100 mg of Tremfya at Weeks 0, 4, and every 8 weeks thereafter, mean steady-state trough serum guselkumab concentration was also approximately 1.2 mcg/mL. Following subcutaneous administration of 100 mg of Tremfya every 4 weeks, mean steady-state trough serum guselkumab concentration was approximately 3.8 mcg/mL.
The absolute bioavailability of guselkumab following a single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects.
Distribution: Mean volume of distribution during the terminal phase (Vz) following a single intravenous administration to healthy subjects ranged from approximately 7 to 10 L across studies.
Biotransformation: The exact pathway through which guselkumab is metabolized has not been characterized. As a human IgG mAb, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Elimination: Mean systemic clearance (CL) following a single intravenous administration to healthy subjects ranged from 0.288 to 0.479 L/day across studies. Mean half-life (T½) of guselkumab was approximately 17 days in healthy subjects and approximately 15 to 18 days in patients with plaque psoriasis across studies.
Population pharmacokinetic analyses indicated that concomitant use of NSAIDs, oral corticosteroids and csDMARDs such as methotrexate, did not affect the clearance of guselkumab.
Linearity/non-linearity: The systemic exposure of guselkumab (Cmax and AUC) increased in an approximately dose-proportional manner following a single subcutaneous injection at doses ranging from 10 mg to 300 mg in healthy subjects or patients with plaque psoriasis.
Elderly patients: No specific studies have been conducted in elderly patients. Of the 1384 plaque psoriasis patients exposed to guselkumab in phase III clinical studies and included in the population pharmacokinetic analysis, 70 patients were 65 years of age or older, including 4 patients who were 75 years of age or older. Of the 746 psoriatic arthritis patients exposed to guselkumab in phase III clinical studies, a total of 38 patients were 65 years of age or older, and no patients were 75 years of age or older.
Population pharmacokinetic analyses in plaque psoriasis and psoriatic arthritis patients indicated no apparent changes in CL/F estimate in patients ≥ 65 years of age compared to patients < 65 years of age, suggesting no dose adjustment is needed for elderly patients.
Patients with renal or hepatic impairment: No specific study has been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab. Renal elimination of intact guselkumab, an IgG mAb, is expected to be low and of minor importance; similarly, hepatic impairment is not expected to influence clearance of guselkumab as IgG mAbs are mainly eliminated via intracellular catabolism.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, toxicity to reproduction and pre- and post-natal development.
In repeat-dose toxicity studies in cynomolgus monkeys, guselkumab was well tolerated via intravenous and subcutaneous routes of administration. A weekly subcutaneous dose of 50 mg/kg to monkeys resulted in exposure (AUC) and Cmax values that were at least 49-fold and >200-fold higher, respectively, than those measured in the human clinical PK study.
Additionally, there were no adverse immunotoxicity or cardiovascular safety pharmacology effects noted during the conduct of the repeat-dose toxicity studies or in a targeted cardiovascular safety pharmacology study in cynomolgus monkeys.
There were no preneoplastic changes observed in histopathology evaluations of animals treated up to 24-weeks, or following the 12-week recovery period during which drug was detectable in the serum.
No mutagenicity or carcinogenicity studies were conducted with guselkumab.
Guselkumab could not be detected in breast milk from cynomolgus monkeys as measured at post-natal day 28.
Indications/Uses
Plaque psoriasis: Tremfya is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy.
Psoriatic arthritis: Tremfya, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy (see Pharmacology: Pharmacodynamics under Actions).
Palmoplantar pustulosis: Tremfya is indicated for the treatment of adults with moderate to severe palmoplantar pustulosis who do not adequately response to conventional treatments.
Dosage/Direction for Use
Tremfya is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which Tremfya is indicated.
Posology: The recommended dose of Tremfya is 100 mg by subcutaneous injection at weeks 0 and 4, followed by a maintenance dose every 8 weeks.
Plaque psoriasis: Consideration should be given to discontinuing treatment in patients who have shown no response after 16 weeks of treatment.
Psoriatic arthritis: The recommended dose of Tremfya is 100 mg by subcutaneous injection at weeks 0 and 4, followed by a maintenance dose every 8 weeks. For patients at high risk for joint damage according to clinical judgement, a dose of 100 mg every 4 weeks may be considered (see Pharmacology: Pharmacodynamics under Actions).
Consideration should be given to discontinuing treatment in patients who have shown no response after 24 weeks of treatment.
Palmoplantar pustulosis: Clinical response is usually achieved within 24 weeks of initiation of treatment with TREMFYA. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within 24 weeks of treatment.
Special Populations: Elderly (≥ 65 years): No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
There is limited information in subjects aged ≥ 65 years and very limited information in subjects aged ≥ 75 years (see Pharmacology: Pharmacokinetics under Actions).
Renal or hepatic impairment: Tremfya has not been studied in these patient populations. No dose recommendations can be made. For further information on elimination of guselkumab, see Pharmacology: Pharmacokinetics under Actions.
Paediatric population: The safety and efficacy of Tremfya in children and adolescents below the age of 18 years have not been established. No data are available.
Method of administration: Subcutaneous use. If possible, areas of the skin that show psoriasis should be avoided as injection sites.
After proper training in subcutaneous injection technique, patients may inject Tremfya if a physician determines that this is appropriate. However, the physician should ensure appropriate medical follow-up of patients. Patients should be instructed to inject the full amount of Tremfya according to the Instructions for use under Patient Counselling Information.
For further instructions on preparation and special precautions for handling, see Special precautions for disposal and other handling under Cautions for Usage and Instructions for use under Patient Counselling Information.
Overdosage
Single intravenous doses of guselkumab up to 987 mg (10 mg/kg) have been administered in healthy volunteers and single subcutaneous doses of guselkumab up to 300 mg have been administered in patients with plaque psoriasis in clinical studies without dose-limiting toxicity. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.
Contraindications
Serious hypersensitivity to the active substance or to any of the excipients listed in Description.
Clinically important active infections (e.g., active tuberculosis, see Precautions).
Warnings
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See Adverse Reactions for how to report adverse reactions.
Special Precautions
Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Infections: Tremfya may increase the risk of infection. Treatment with Tremfya should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.
Patients treated with Tremfya should be instructed to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, the patient should be monitored closely and Tremfya should be discontinued until the infection resolves.
Pre-treatment evaluation for tuberculosis: Prior to initiating treatment with Tremfya, patients should be evaluated for tuberculosis (TB) infection. Patients receiving Tremfya should be monitored for signs and symptoms of active TB during and after treatment. Anti-TB therapy should be considered prior to initiating Tremfya in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed.
Hypersensitivity: Serious hypersensitivity reactions, including anaphylaxis, have been reported in the post-marketing setting. Some serious hypersensitivity reactions occurred several days after treatment with guselkumab, including cases with urticaria and dyspnoea. If a serious hypersensitivity reaction occurs, administration of Tremfya should be discontinued immediately and appropriate therapy initiated.
Hepatic Transaminase Elevations: In psoriatic arthritis clinical studies, an increased incidence of liver enzyme elevations was observed in patients treated with Tremfya q4w compared to patients treated with Tremfya q8w or placebo (see Table 11 under Adverse Reactions).
When prescribing Tremfya q4w in psoriatic arthritis, it is recommended to evaluate liver enzymes at baseline and thereafter according to routine patient management. If increases in ALT or AST are observed and drug-induced liver injury is suspected, Tremfya should be temporarily interrupted until this diagnosis is excluded.
Immunisations: Prior to initiating therapy with Tremfya, completion of all appropriate immunisations should be considered according to current immunisation guidelines. Live vaccines should not be used concurrently in patients treated with Tremfya. No data are available on the response to live or inactive vaccines.
Before live viral or live bacterial vaccination, treatment with Tremfya should be withheld for at least 12 weeks after the last dose and can be resumed at least 2 weeks after vaccination. Prescribers should consult the Summary of Product Characteristics of the specific vaccine for additional information and guidance on concomitant use of immunosuppressive agents post-vaccination.
Palmoplantar pustulosis: Fully consider using existing therapy including phototherapy before starting treatment with TREMFYA.
Effects on ability to drive and use machines: Tremfya has no or negligible influence on the ability to drive and use machines.
Use In Pregnancy & Lactation
Women of childbearing potential: Women of childbearing potential should use effective methods of contraception during treatment and for at least 12 weeks after treatment.
Pregnancy: There are no data from the use of guselkumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). As a precautionary measure, it is preferable to avoid the use of Tremfya in pregnancy.
Breast-feeding: It is unknown whether guselkumab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, and decrease to low concentrations soon afterwards; consequently, a risk to the breast-fed infant during this period cannot be excluded. A decision should be made whether to discontinue, or abstain from initiating treatment with Tremfya, taking into account the benefit of breast-feeding to the child and the benefit of Tremfya therapy to the woman. See Pharmacology: Toxicology: Preclinical Safety Data under Actions for information on the excretion of guselkumab in animal (cynomolgus monkey) milk.
Fertility: The effect of guselkumab on human fertility has not been evaluated. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Adverse Reactions
Summary of the safety profile: The most common adverse drug reaction (ADR) was upper respiratory infection.
Tabulated list of adverse reactions: Table 10 provides a list of adverse reactions from psoriasis and psoriatic arthritis clinical studies as well as from post-marketing experience. The adverse reactions are classified by MedDRA System Organ Class and frequency, using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data). (See Table 10.)

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Description of selected adverse reactions: Transaminases Increased: In two phase III psoriatic arthritis clinical studies, through the placebo-controlled period, increased transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) were reported more frequently as adverse events in the Tremfya-treated groups (8.6% in the q4w group and 8.3% in the q8w group) than in the placebo group (4.6%).
Based on laboratory assessments, most transaminase increases were ≤3 x upper limit of normal (ULN). Transaminase increases from >3 to ≤ 5 x ULN and >5 x ULN were low in frequency, occurring more often in the Tremfya q4w group compared with the Tremfya q8w group (Table 11). Through 1 year, in most cases, the increase in transaminases was transient and did not lead to discontinuation of treatment. (See Table 11.)

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Neutrophil count decreased: In two phase III psoriatic arthritis clinical studies, through the placebo-controlled period, decreased neutrophil count was reported more frequently as an adverse event in the Tremfya-treated group (0.9%) than in the placebo group (0%). In most cases, the decrease in blood neutrophil count was mild, transient, not associated with infection and did not lead to discontinuation of treatment.
Gastroenteritis: In two phase III psoriasis clinical studies through the placebo-controlled period, gastroenteritis occurred more frequently in the Tremfya-treated group (1.1%) than in the placebo group (0.7%). Through Week 156, 4.9% of all Tremfya-treated patients reported gastroenteritis. Adverse reactions of gastroenteritis were non-serious and did not lead to discontinuation of Tremfya through Week 156.
Gastroenteritis rates observed in psoriatic arthritis clinical studies through the placebo-controlled period were similar to those observed in the psoriasis clinical studies.
Injection site reactions: In two phase III psoriasis clinical studies through Week 48, 0.7% of Tremfya injections and 0.3% of placebo injections were associated with injection site reactions. Through Week 156, 0.5% of Tremfya injections were associated with injection site reactions. Adverse reactions of injection site erythema and injection site pain were the most commonly reported events of injection site reaction and were generally mild to moderate in severity, none were serious, and none led to discontinuation of Tremfya.
In two phase III psoriatic arthritis clinical studies through Week 24, the number of subjects that reported 1 or more injection site reactions was low and slightly higher in the Tremfya groups than in the placebo group; 5 (1.3%) subjects in the Tremfya q8w group, 4 (1.1%) subjects in the Tremfya q4w group, and 1 (0.3%) subject in the placebo group. One subject discontinued Tremfya due to an injection site reaction during the placebo-controlled period of the psoriatic arthritis clinical studies. Overall, the rate of injections associated with injection site reactions observed in psoriatic arthritis clinical studies through the placebo-controlled period similar to rates observed in the psoriasis clinical studies.
Immunogenicity: The immunogenicity of Tremfya was evaluated using a sensitive and drug-tolerant immunoassay.
Plaque psoriasis: In pooled phase II and phase III analyses in patients with psoriasis, fewer than 6% of patients treated with Tremfya developed antidrug antibodies in up to 52 weeks of treatment. Of the patients who developed antidrug antibodies, approximately 7% had antibodies that were classified as neutralizing, which equates to 0.4% of all patients treated with Tremfya. In pooled phase III analyses, approximately 9% of patients treated with Tremfya developed antidrug antibodies in up to 156 weeks of treatment. Antidrug antibodies were not associated with lower efficacy or development of injection-site reactions.
Psoriatic arthritis: In pooled phase III analyses in patients with psoriatic arthritis, 2% (n=15) of patients treated with Tremfya developed antidrug antibodies in up to 24 weeks of treatment. Of these patients, 1 patient had antibodies that were classified as neutralizing. None of these patients developed injection site reactions. Overall, the small number of patients with antidrug antibodies limits definitive conclusion of the effect of immunogenicity on the pharmacokinetics, efficacy or safety of guselkumab in patients with psoriatic arthritis.
In a phase III study in Japanese patients with Palmoplantar pustulosis, antidrug antibodies were detected in 2.6% of patients through Week 52. Of the patients who developed antidrug antibodies, no neutralizing antibodies were detected.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Interactions with CYP450 substrates: In a Phase 1 study in subjects with moderate to severe plaque psoriasis, changes in systemic exposures (Cmax and AUCinf) of midazolam, S-warfarin, omeprazole, dextromethorphan, and caffeine after a single dose of guselkumab were not clinically relevant, indicating that drug interactions between guselkumab and substrates of various CYP enzymes (CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2) are unlikely. There is no need for dose adjustment when co-administering guselkumab and CYP450 substrates.
Concomitant immunosuppressive therapy or phototherapy: In psoriasis studies, the safety and efficacy of Tremfya in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated.
Caution For Usage
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: After removing the pre-filled syringe or pre-filled pen from the refrigerator, keep the pre-filled syringe or pre-filled pen inside the carton and allow to reach room temperature by waiting for 30 minutes before injecting Tremfya. The pre-filled syringe or pre-filled pen should not be shaken.
Prior to use, a visual inspection of the pre-filled syringe or pre-filled pen is recommended. The solution should be clear, colourless to light yellow, and may contain a few small white or clear particles. Tremfya should not be used if the solution is cloudy or discoloured, or contains large particles.
Each Tremfya pack is provided with an 'Instructions for use' leaflet that fully describes the preparation and administration of the pre-filled syringe or pre-filled pen.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Store in a refrigerator (2°C - 8°C). Do not freeze.
Keep the pre-filled syringe or pre-filled pen in the outer carton in order to protect from light.
Shelf-life: 2 years.
Patient Counseling Information
Instructions for use: Tremfya Pre-filled syringe: Important: If your doctor decides that you or a 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 pre-filled syringe before attempting to inject.
Please read these Instructions for use before using the Tremfya pre-filled syringe and each time you get a refill. There may be new information. This instruction guide does not take the place of talking with your doctor about your medical condition or your treatment. Please also read the Package Leaflet carefully before starting your injection and discuss any questions you may have with your doctor or nurse.
The Tremfya pre-filled 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 information: Store in refrigerator at 2° to 8°C. Do not freeze.
Do not shake the pre-filled syringe at any time.
Pre-filled syringe at-a-glance: Before injection: Plunger: Do not hold or pull plunger at any time.
Safety guard.
Finger flange.
Body: Hold syringe body below finger flange.
Viewing window.
Needle cover: Do not remove until you are ready to inject Tremfya (See Step 2).
After injection: Plunger locks.
Safety guard activates.
Needle retracts into the body.
You will need these supplies: 1 Alcohol swab, 1 Cotton ball or gauze pad, 1 Adhesive bandage, 1 Sharps container (See Step 3).
1. Prepare for your injection: Inspect carton: Remove carton with the pre-filled syringe from the refrigerator.
Keep the pre-filled syringe in the carton and let it sit on a flat surface at room temperature for at least 30 minutes before use.
Do not warm any other way.
Check the expiration date ('EXP') on the back panel of the carton.
Do not use if the expiration date has passed.
Do not inject if the perforations on the carton are broken.
Call your doctor or pharmacist for a refill.
Choose injection site: Select from the following areas for your injection: Front of thighs (recommended).
Lower abdomen: Do not use the 5-centimetre area around your belly button.
Back of upper arms (if a caregiver is giving you the injection).
Do not inject into skin that is tender, bruised, red, scaly or hard.
Do not inject into areas with scars or stretch marks.
Clean injection site: Wash 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 liquid: Take the pre-filled syringe out of the carton.
Check the 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 discoloured, or has large particles. If you are uncertain, call your doctor or pharmacist for a refill.
2. Inject Tremfya using the pre-filled syringe: Remove needle cover: Hold syringe by the body and pull needle cover straight off.
It is normal to see a drop of liquid.
Inject within 5 minutes of removing the needle cover.
Do not put needle cover back on, as this may damage the needle.
Do not touch needle or let it touch any surface.
Do not use the Tremfya pre-filled syringe if it is dropped. Call your doctor or pharmacist for a refill.
Position fingers and insert needle: Place your thumb, index and middle fingers directly under the finger flange.
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 a 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 a quick, dart like motion.
Release pinch and reposition hand: Use your free hand to grasp the body of the syringe.
Press plunger: Place thumb from the opposite hand on the plunger and press the plunger all the way down until it stops.
Release pressure from plunger: The safety guard will cover the needle and lock into place, removing the needle from your skin.
3. After your injection: Throw the used pre-filled syringe away: Put your used syringe in a sharps disposal container right away after use.
Make sure you dispose of the bin as instructed by your doctor or nurse when the container is full.
Check injection site: There may be a small amount of blood or liquid at the injection site. Hold pressure over your skin with a cotton ball or gauze pad until any bleeding stops.
Do not rub the injection site.
If needed, cover injection site with a bandage.
Your injection is now complete.
Need help: Call your doctor to talk about any questions you may have. For additional assistance or to share your feedback refer to the Package Leaflet for your local representative contact information.
Instructions for use: Tremfya Pre-filled pen: Important: If your doctor decides that you or a 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 pre-filled pen.
Please read these Instructions for use before using the Tremfya pre-filled pen and each time you get a new pre-filled pen. There may be new information. This instruction guide does not take the place of talking with your doctor about your medical condition or your treatment.
Please also read the Package Leaflet carefully before starting your injection and discuss any questions you may have with your doctor or nurse.
Storage information: Store in refrigerator at 2° to 8°C.
Do not freeze.
Do not shake your pre-filled pen at any time.
Need help: Call your doctor to talk about any questions you may have. For additional assistance or to share your feedback refer to the Package Leaflet for your local representative contact information.
You will need these supplies: 1 Alcohol swab, 1 Cotton ball or gauze pad, 1 Adhesive bandage, 1 Sharps container (See Step 3).
1. Prepare for your injection: Inspect carton: Remove carton with the pre-filled pen from the refrigerator.
Keep pre-filled pen in the carton and let it sit on a flat surface at room temperature for at least 30 minutes before use.
Do not warm any other way.
Check the expiration date ('EXP') on the back panel of the carton.
Do not use if the expiration date has passed.
Do not inject if perforations on the carton are broken.
Call your doctor or pharmacist for a new pre-filled pen.
Choose injection site: Select from the following areas for your injection: Front of thighs (recommended).
Lower abdomen: Do not use the 5-centimetre area around your belly button.
Back of upper arms (if a caregiver is giving you the injection).
Do not inject into skin that is tender, bruised, red, scaly, hard or has scars or stretch marks.
Wash hands: Wash your hands well with soap and warm water.
Clean injection site: 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 liquid in window: Take the pre-filled pen out of the carton.
Check the liquid in the 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 discoloured, or has large particles. If you are uncertain, call your doctor or pharmacist for a new pre-filled pen.
2. Inject Tremfya using the pre-filled pen: Twist and pull off bottom cap: Keep hands away from the needle guard after the cap is removed.
Inject within 5 minutes of removing the cap.
Do not put the cap back on, this could damage the needle.
Do not use the pre-filled pen if it is dropped after removing the cap.
Call your doctor or pharmacist for a new pre-filled pen.
Place on skin: Position the pre-filled pen straight onto the skin (about 90 degrees relative to injection site).
Push handle straight down: Medication injects as you push. Do this at a speed that is comfortable for you.
Do not lift the pre-filled pen during the injection. The needle guard will lock and the full dose will not be delivered.
Complete injection: Injection is complete when the handle is pushed all the way down, you hear a click, and the green body is no longer visible.
Lift straight up: The yellow band indicates that the needle guard is locked.
3. After your injection: Throw the used pre-filled pen away: Put your used pre-filled pen in a sharps disposal container right away after use.
Make sure you dispose of the bin as instructed by your doctor or nurse when the container is full.
Check injection site: There may be a small amount of blood or liquid at the injection site. Hold pressure over your skin with a cotton ball or gauze pad until any bleeding stops.
Do not rub the injection site.
If needed, cover injection site with a bandage.
Your injection is now complete.
ATC Classification
L04AC16 - guselkumab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.
Presentation/Packing
Soln for inj (pre-filled syringe) (clear and colourless to light yellow) 100 mg/mL x 1's, (pre-filled pen, One-Press) 100 mg/mL x 1's.
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