4.1. Therapeutic indications

Crohn's disease

Tremfya 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

Tremfya 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.

4.2. Posology and method of administration

This medicinal product is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of conditions for which it is indicated.

Guselkumab 200 mg concentrate for solution for infusion should only be used for induction dose.

Posology

Crohn's disease

The recommended induction dose is:

• 200 mg administered by intravenous infusion 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. See SmPC for Tremfya 200 mg solution for injection

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 (see section 5.1). See SmPC for Tremfya 100 mg solution for injection and 200 mg solution for injection.

Immunomodulators and/or corticosteroids may be continued during treatment with guselkumab. In patients who have responded to treatment with guselkumab, corticosteroids may be reduced or discontinued in accordance with standard of care.

Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit after 24 weeks of treatment.

Ulcerative colitis

The recommended induction dose is:

• 200 mg administered by intravenous infusion 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. See SmPC for Tremfya 200 mg solution for injection.

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 (see section 5.1). See SmPC for Tremfya 100 mg solution for injection and 200 mg solution for injection.

Immunomodulators and/or corticosteroids may be continued during treatment with guselkumab. In patients who have responded to treatment with guselkumab, corticosteroids may be reduced or discontinued in accordance with standard of care.

Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit after 24 weeks of treatment.

Missed dose

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 (see section 5.2).

There is limited information in patients aged ≥ 65 years and very limited information in patients aged ≥ 75 years (see section 5.2).

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. For further information on elimination of guselkumab, see section 5.2.

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

Tremfya 200 mg concentrate for solution for infusion is for intravenous use only. It should be administered over a period of at least one hour. Each vial is for single use only. For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Serious hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Clinically important active infections (e.g. active tuberculosis, see section 4.4).

4.4. Special warnings and precautions for use

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

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.

Patients treated with guselkumab 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 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 (see section 4.8). 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 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 in patients treated with guselkumab q4w compared to patients treated with guselkumab q8w or placebo (see section 4.8).

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. 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.

Excipients

Polysorbate 80 content

This medicinal product contains 10 mg of polysorbate 80 (E433) in each dosage unit which is equivalent to 0.5 mg/mL. Polysorbates may cause allergic reactions.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Interactions with CYP450 substrates

In a Phase I study in patients 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 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 guselkumab in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of guselkumab.

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.

4.6. Fertility, pregnancy and 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 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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Tremfya 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 Tremfya therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. See section 5.3 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 section 5.3).

4.7. Effects on ability to drive and use machines

Tremfya has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

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, and 15% of patients in the psoriasis and psoriatic arthritis clinical studies).

The overall safety profile in patients treated with Tremfya is similar for patients with psoriasis, psoriatic arthritis, 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.

Table 1: List of adverse reactions

System Organ Class

Frequency

Adverse reactions

Infections and infestations

Very common

Respiratory tract infections

Uncommon

Herpes simplex infections

Uncommon

Tinea infections

Uncommon

Gastroenteritis

Immune system disorders

Rare

Hypersensitivity

Rare

Anaphylaxis

Nervous system disorders

Common

Headache

Gastrointestinal disorders

Common

Diarrhoea

Skin and subcutaneous tissue disorders

Common

Rash

Uncommon

Urticaria

Musculoskeletal and connective tissue disorders

Common

Arthralgia

General disorders and administration site conditions

Common

Injection site reactions

Investigations

Common

Transaminases increased

Uncommon

Neutrophil count decreased

Description of selected adverse reactions

Transaminases increased

In two Phase III psoriatic arthritis clinical studies, through the placebo-controlled period, adverse events of increased transaminases (includes ALT increased, AST increased, hepatic enzyme increased, transaminases increased, liver function test abnormal, hypertransaminasaemia) were reported more frequently in the guselkumab-treated groups (8.6% in the 100 mg subcutaneous q4w group and 8.3% in the 100 mg subcutaneous q8w group) than in the placebo group (4.6%). Through 1 year, adverse events of increased transaminases (as above) were reported in 12.9% of patients in the q4w group and 11.7% of patients in the q8w group.

Based on laboratory assessments, most transaminase increases (ALT and AST) 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 guselkumab q4w group compared with the guselkumab q8w group (Table 2). A similar pattern of frequency by severity and by treatment group was observed through the end of the 2-year Phase III psoriatic arthritis clinical study.

Table 2: Frequency of patients with transaminase increases post-baseline in two Phase III psoriatic arthritis clinical studies

Through week 24a

Through 1 yearb

Placebo

N=370c

guselkumab

100 mg q8w

N=373c

guselkumab

100 mg q4w

N=371c

guselkumab

100 mg q8w

N=373c

guselkumab

100 mg q4w

N=371c

ALT

>1 to ≤3 x ULN

30.0%

28.2%

35.0%

33.5%

41.2%

>3 to ≤ 5 x ULN

1.4%

1.1%

2.7%

1.6%

4.6%

>5 x ULN

0.8%

0.8%

1.1%

1.1%

1.1%

AST

>1 to ≤3 x ULN

20.0%

18.8%

21.6%

22.8%

27.8%

>3 to ≤ 5 x ULN

0.5%

1.6%

1.6%

2.9%

3.8%

>5 x ULN

1.1%

0.5%

1.6%

0.5%

1.6%

a placebo-controlled period.

b patients randomised to placebo at baseline and crossed over to guselkumab are not included.

c number of patients with at least one post-baseline assessment for the specific laboratory test within the time period.

In the psoriasis clinical studies, through 1 year, the frequency of transaminase increases (ALT and AST) for the guselkumab q8w dose was similar to that observed for the guselkumab q8w dose in the psoriatic arthritis clinical studies. Through 5 years, the incidence of transaminase elevation did not increase by year of guselkumab treatment. Most transaminase increases were ≤ 3 x ULN.

In most cases, the increase in transaminases was transient and did not lead to discontinuation of treatment.

In pooled Phase II and Phase III Crohn's disease clinical studies, through the placebo-controlled period (week 0-12), adverse events of increased transaminases (includes ALT increased, AST increased, hepatic enzyme increased, transaminases increased, and liver function test increased) were reported more frequently in the guselkumab treated groups (1.7% of patients) than in the placebo group (0.6% of patients). In pooled Phase II and Phase III Crohn's disease clinical studies, through the reporting period of approximately one year, adverse events of increased transaminases (includes ALT increased, AST increased, hepatic enzyme increased, transaminases increased, hepatic function abnormal, and liver function test increased) were reported in 3.4% of patients in the guselkumab 200 mg subcutaneous q4w treatment group and 4.1% of patients in the guselkumab 100 mg subcutaneous q8w treatment group compared to 2.4% in the placebo group.

Based on laboratory assessments in pooled Phase II and Phase III Crohn's disease clinical studies, the frequency of ALT or AST elevations were lower than those observed in psoriatic arthritis Phase III clinical studies. In pooled Phase II and Phase III Crohn's disease clinical studies, through the placebo-controlled period (Week 12), ALT (<1% of patients) and AST (<1% of patients) elevations ≥3x ULN were reported in guselkumab treated patients. In pooled Phase II and Phase III Crohn's disease clinical studies, through the reporting period of approximately one year, ALT and/or AST elevations ≥ 3x ULN were reported in 2.7% of patients in the guselkumab 200 mg subcutaneous q4w treatment group and 2.6% of patients in the guselkumab 100 mg subcutaneous q8w treatment group compared to 1.9% in the placebo group.In most cases, the increase in transaminases was transient and did not lead to discontinuation of treatment.

Neutrophil count decreased

In two Phase III psoriatic arthritis clinical studies, through the placebo-controlled period, the adverse event of decreased neutrophil count was reported more frequently in the guselkumab-treated group (0.9%) than in the placebo group (0%). Through 1 year, the adverse event of decreased neutrophil count was reported in 0.9% of patients treated with guselkumab. 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 guselkumab‑treated group (1.1%) than in the placebo group (0.7%). Through Week 264, 5.8% of all guselkumab‑treated patients reported gastroenteritis. Adverse reactions of gastroenteritis were non‑serious and did not lead to discontinuation of guselkumab through Week 264. 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 guselkumab injections and 0.3% of placebo injections were associated with injection site reactions. Through Week 264, 0.4% of guselkumab injections were associated with injection site reactions. Injection site reactions were generally mild to moderate in severity; none were serious, and one led to discontinuation of guselkumab.

In two Phase III psoriatic arthritis clinical studies through Week 24, the number of patients that reported 1 or more injection site reactions was low and slightly higher in the guselkumab groups than in the placebo group; 5 (1.3%) patients in the guselkumab q8w group, 4 (1.1%) patients in the guselkumab q4w group, and 1 (0.3%) patient in the placebo group. One patient discontinued guselkumab due to an injection site reaction during the placebo-controlled period of the psoriatic arthritis clinical studies. Through 1 year, the proportion of patients reporting 1 or more injection site reactions was 1.6% and 2.4% in the guselkumab q8w and q4w groups respectively. Overall, the rate of injections associated with injection site reactions observed in psoriatic arthritis clinical studies through the placebo-controlled period was similar to rates observed in the psoriasis clinical studies.

In Phase II and Phase III Crohn's disease clinical studies through Week 48, the proportion of patients that reported 1 or more injection site reactions to guselkumab was 4.1% (0.8% of injections) in the treatment group which received guselkumab 200 mg intravenous induction followed by 200 mg subcutaneous q4w, and 1.4% (0.6% of injections) of patients in the guselkumab 200 mg intravenous induction followed by 100 mg subcutaneous q8w group. Overall injection site reactions were mild; none were serious.

In a Phase III Crohn's disease clinical study through Week 48, the proportion of patients that reported 1 or more injection site reactions to guselkumab was 7% (1.3% of injections) in the treatment group which received 400 mg subcutaneous induction followed by 200 mg subcutaneous q4w and 4.3% (0.7% of injections) of patients in the 400 mg guselkumab subcutaneous induction followed by 100 mg subcutaneous q8w group. Most injection site reactions were mild; none were serious.

In the Phase III ulcerative colitis maintenance clinical study through Week 44, the proportion of patients that reported 1 or more subcutaneous injection site reactions to guselkumab was 7.9% (2.5% of injections) in the guselkumab 200 mg subcutaneous q4w group and no injections in the guselkumab 100 mg subcutaneous q8w group. Most injection site reactions were mild and none were serious.

Immunogenicity

The immunogenicity of guselkumab was evaluated using a sensitive and drug‑tolerant immunoassay.

In pooled Phase II and Phase III analyses in patients with psoriasis and psoriatic arthritis, 5% (n=145) of patients treated with guselkumab developed antidrug antibodies in up to 52 weeks of treatment. Of the patients who developed antidrug antibodies, approximately 8% (n=12) had antibodies that were classified as neutralizing, which equates to 0.4% of all patients treated with guselkumab. In pooled Phase III analyses in patients with psoriasis, approximately 15% of patients treated with guselkumab developed antidrug antibodies in up to 264 weeks of treatment. Of the patients who developed antidrug antibodies, approximately 5% had antibodies that were classified as neutralising, which equates to 0.76% of all patients treated with guselkumab. Antidrug antibodies were not associated with lower efficacy or development of injection‑site reactions.

In pooled Phase II and Phase III analyses up to Week 48 in patients with Crohn's disease who were treated with intravenous induction followed by subcutaneous maintenance dose regimen, approximately 5% (n=30) of patients treated with guselkumab developed antidrug antibodies. Of the patients who developed antidrug antibodies, approximately 7% (n=2) had antibodies that were classified as neutralising antibodies, which equates to 0.3% of guselkumab treated patients.

In a Phase III analysis up to Week 48 in patients with Crohn's disease who were treated with subcutaneous induction followed by subcutaneous maintenance dose regimen, approximately 9% (n=24) of patients treated with guselkumab developed antidrug antibodies. Of these patients, 13% (n=3) had antibodies that were classified as neutralising antibodies, which equates to 1% of guselkumab treated patients. Antidrug antibodies were not associated with lower efficacy or development of injection site reactions

In pooled Phase II and Phase III analyses in patients with ulcerative colitis who were treated with intravenous induction followed by subcutaneous maintenance, approximately 12% (n=58) of patients treated with guselkumab for up to 56 weeks developed antidrug antibodies. Of the patients who developed antidrug antibodies, approximately 16% (n=9) had antibodies that were classified as neutralising, which equates to 2% of all patients treated with guselkumab. In a Phase III analysis up to Week 24 in patients with ulcerative colitis who were treated with subcutaneous induction followed by subcutaneous maintenance, approximately 9% (n=24) of patients treated with guselkumab developed antidrug antibodies. Of the patients who developed antidrug antibodies, 12% (n=3) had antibodies that were classified as neutralising antibodies, which equates to 1% of guselkumab-treated patients. Antidrug antibodies were not associated with lower efficacy or the development of injection-site reactions.

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 Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Guselkumab intravenous doses up to 1200 mg as well as subcutaneous doses up to 400 mg at a single dosing visit have been administered in clinical studies without dose-limiting toxicity. In the event of overdose, the patient must be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment must be administered immediately.