TREMFYA 100 MG SOLUTION FOR INJECTION IN PRE-FILLED PEN - summary of medicine characteristics

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 section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Tremfya 100 mg solution for injection in pre-filled pen.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled pen contains 100 mg of guselkumab in 1 mL solution.

Guselkumab is a fully human immunoglobulin G1 lamda (IgG1X) monoclonal antibody (mAb) to the interleukin (IL)-23 protein, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection (injection)

The solution is clear and colourless to light yellow.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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 section 5.1).

4.2 Posology and method of administration

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

Plaque psoriasis

he recommended dose of Tremfya is 100 mg by subcutaneous injection at weeks 0 and 4, followed by a maintenance dose every 8 weeks.

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 section 5.1).

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

Special Populations

Elderly (> 65 years)

No dose adjustment is required (see section 5.2).

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

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 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

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’ provided in the carton.

For further instructions on preparation and special precautions for handling, see section 6.6 and the ‘Instructions for use’ leaflet.

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

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 section 4.8, Table 2).

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 alanine aminotransferase [ALT] or aspartate aminotransferase [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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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 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 section 5.3). 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 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 drug reaction (ADR) was respiratory tract infections.

Tabulated list of adverse reactions

Table 1 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).

Table 1:       List of adverse reactions

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 and AST Increased) were reported more frequently 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%). 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 Tremfya q4w group compared with the Tremfya q8w group (Table 2). Through 1 year, in most cases, the increase in transaminases was transient and did not lead to discontinuation of treatment.

Table 2:    Frequency of patients with transaminase increases post-baseline in two

Phase III psoriatic arthritis clinical studies

a placebo-controlled period

b patients randomised to Tremfya at baseline

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 Tremfya-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 Tremfya. 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. Through 1 year, the proportion of subjects reporting 1 or more injection site reactions was 1.6% and 2.4% in the Tremfya 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.

Immunogenicity

The immunogenicity of Tremfya was evaluated using a sensitive and drug-tolerant immunoassay.

In pooled phase II and phase III analyses in patients with psoriasis and psoriatic arthritis, fewer than 5% (n=145) of patients treated with Tremfya 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 Tremfya. In pooled phase III analyses in patients with psoriasis, 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.

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

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

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 metabolised has not been characterised. 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 (T1/2) 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.

5.3 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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Histidine

Histidine monohydrochloride monohydrate

Polysorbate 80

Sucrose

Water for injections

6.2 Incompati­bilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store in a refrigerator (2°C-8°C). Do not freeze.

Keep the pre-filled pen in the outer carton in order to protect from light.

6.5 Nature and contents of container

1 mL solution in a pre-filled glass syringe assembled in a pre-filled pen with an automatic needle guard.

Tremfya is available in a pack containing one pre-filled pen and in a multipack containing 2 (2 packs of 1) pre-filled pens.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

After removing the pre-filled pen from the refrigerator, keep the pre-filled pen inside the carton and allow to reach room temperature by waiting for 30 minutes before injecting Tremfya. The pre-filled pen should not be shaken.

Prior to use, a visual inspection of the 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 pen.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Janssen-Cilag Limited

50–100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 00242/0665

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021