The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC please click here: https://www.medicines.org.uk/emc/product/100877/smpc

Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11

Introduction and 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 through the antigen binding site. IL-23 is a cytokine that is involved in inflammatory and immune responses. By blocking IL-23 from binding to its receptor, guselkumab inhibits IL-23-dependent cell signalling and release of proinflammatory cytokines.

In patients with Crohn's disease or ulcerative colitis, levels of IL-23 are elevated in the colon tissue. 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 signalling, activation and cytokine cascades. Guselkumab exerts clinical effects in Crohn's disease and ulcerative colitis through blockade of the IL-23 cytokine pathway.

Myeloid cells expressing Fc-gamma receptor 1 (CD64) have been shown to be a predominant source of IL-23 in inflamed tissue in Crohn's disease and ulcerative colitis. Guselkumab has demonstrated in vitro blocking of IL-23 and binding to CD64. These results indicate that guselkumab is able to neutralise IL-23 at the cellular source of inflammation.

Therapeutic indications

Crohn's disease: guselkumab is indicated for the treatment of adult patients with moderately to severely active Crohn's disease who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic treatment.

Ulcerative colitis: guselkumab is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy, a biologic treatment, or a Janus kinase (JAK) inhibitor.

Dosing, administration

The recommended induction dose is either 200 mg administered by intravenous infusion (of at least 1 hour) at Week 0, Week 4, and Week 8 OR 400 mg administered by subcutaneous injection (given as two consecutive injections of 200 mg each) at Week 0, Week 4 and Week 8. 

After completion of the induction dose regimen, the recommended maintenance dose starting at Week 16 is 100 mg administered by subcutaneous injection every 8 weeks (q8w). Alternatively, for patients who do not show adequate therapeutic benefit to induction treatment according to clinical judgement, a maintenance dose of 200 mg administered by subcutaneous injection starting at Week 12 and every 4 weeks (q4w) thereafter, may be considered.

Immunomodulators and/or corticosteroids may be continued during treatment with guselkumab.
Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit after 24 weeks of treatment.

If a dose is missed, the dose should be administered as soon as possible. Thereafter, dosing should be resumed at the regular scheduled time.

Special populations

- Elderly: No dose adjustment is required. There is limited information in patients aged ≥ 65 years and very limited information in patients aged ≥ 75 years.

- Renal or hepatic impairment: Tremfya has not been studied in these patient populations. These conditions are generally not expected to have any significant impact on the pharmacokinetics of monoclonal antibodies, and no dose adjustments are considered necessary.

- 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.

Contraindications

- Serious hypersensitivity to the active substance or to any of the excipients.

- Clinically important active infections (e.g. active tuberculosis, see below for details).

Adverse effects

The most common adverse reaction was respiratory tract infections (approximately 8% of patients in ulcerative colitis, 11% of patients in the Crohn's disease studies).

The overall safety profile in patients treated with guselkumab is similar for patients with Crohn's disease and ulcerative colitis.

Tabulated list of adverse reactions

Table 1 provides a list of adverse reactions from psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis clinical studies as well as adverse reactions reported 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

For additional informations, see the SmPC of the reference drug. 

Interactions with other Drugs

Interactions with CYP450 substrates

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 Crohn's disease and ulcerative colitis studies, concomitant use of immunomodulators (eg, azathioprine [AZA], 6-mercaptopurine [6-MP]) or corticosteroids did not appear to influence the safety or efficacy of guselkumab.

In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of guselkumab.

Special warnings and precautions

Infections

Guselkumab may increase the risk of infection. Treatment should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.
If a patient develops a clinically important or serious infection or is not responding to standard therapy, the patient should be monitored closely and treatment should be discontinued until the infection resolves.

Pre-treatment evaluation for tuberculosis

Prior to initiating treatment, patients should be evaluated for tuberculosis (TB) infection. Patients receiving guselkumab should be monitored for signs and symptoms of active TB during and after treatment. Anti-TB therapy should be considered prior to initiating treatment 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, including cases with urticaria and dyspnoea. If a serious hypersensitivity reaction occurs, administration of guselkumab 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 with guselkumab q4w compared to patients treated with guselkumab q8w or placebo.

When prescribing guselkumab q4w in psoriatic arthritis, it is recommended to evaluate liver enzymes at baseline and thereafter according to routine patient management. If increases in alanine aminotransferase [ALT] or aspartate aminotransferase [AST] are observed and drug-induced liver injury is suspected, treatment should be temporarily interrupted until this diagnosis is excluded.

Immunisations

Prior to initiating therapy, completion of all appropriate immunisations should be considered according to current immunisation guidelines. Live vaccines should not be used concurrently in patients treated with guselkumab. No data are available on the response to live or inactive vaccines.
Before live viral or live bacterial vaccination, treatment should be withheld for at least 12 weeks after the last dose and can be resumed at least 2 weeks after vaccination.

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 limited 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. As a precautionary measure, it is preferable to avoid the use of guselkumab during 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 breast-feeding or to abstain from guselkumab therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.