4.1. Therapeutic indications

Ulcerative colitis

Omvoh is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic treatment.

Crohn's disease

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

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 ulcerative colitis or Crohn' disease.

Omvoh 300 mg concentrate for solution for infusion should only be used for the induction dose.

Posology

Ulcerative colitis

The recommended mirikizumab dose regimen has 2 parts.

Induction dose

The induction dose is 300 mg by intravenous infusion for at least 30 minutes at weeks 0, 4 and 8.

Maintenance dose

The maintenance dose is 200 mg by subcutaneous injection every 4 weeks after completion of induction dosing. It can be administered either as two pre‑filled syringes or pre-filled pens of 100 mg each, or as one pre‑filled syringe or pre-filled pen of 200 mg.

For the posology of the subcutaneous dosing regimen, see section 4.2 of the Summary of Product Characteristics for Omvoh 100 mg and Omvoh 200 mg solution for injection in pre‑filled syringe and Omvoh 100 mg and Omvoh 200 mg solution for injection in pre‑filled pen.

Patients should be evaluated after the 12‑week induction dosing and if there is adequate therapeutic response, transition to maintenance dosing. For patients who do not achieve adequate therapeutic benefit at week 12 of induction dosing, mirikizumab 300 mg by intravenous infusion may be continued at weeks 12, 16 and 20 (extended induction therapy). If therapeutic benefit is achieved with the additional intravenous therapy, patients may initiate mirikizumab subcutaneous maintenance dosing (200 mg) every 4 weeks, starting at week 24. Mirikizumab should be discontinued in patients who do not show evidence of therapeutic benefit to extended induction therapy by week 24.

Patients with loss of therapeutic response during maintenance treatment may receive 300 mg mirikizumab by intravenous infusion every 4 weeks, for a total of 3 doses (re-induction). If clinical benefit is achieved from this additional intravenous therapy, patients may resume mirikizumab subcutaneous dosing every 4 weeks. The efficacy and safety of repeated re-induction therapy have not been evaluated.

Crohn's disease

The recommended mirikizumab dose regimen has 2 parts.

Induction dose

The induction dose is 900 mg (3 vials of 300 mg each) by intravenous infusion for at least 90 minutes at weeks 0, 4 and 8.

Maintenance dose

The maintenance dose is 300 mg (i.e. one pre‑filled syringe or pre‑filled pen of 100 mg and one pre‑filled syringe or pre-filled pen of 200 mg) by subcutaneous injection every 4 weeks after completion of induction dosing.

The injections may be administered in any order.

For the posology of the subcutaneous dosing regimen, see section 4.2 of the Summary of Product Characteristics for Omvoh solutions for injection in pre‑filled syringe and pre‑filled pen.

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

Special populations

Elderly

No dose adjustment is required (see section 5.2). There is limited information in subjects aged ≥ 75 years.

Renal or hepatic impairment

Omvoh 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 (see section 5.2).

Paediatric population

The safety and efficacy of Omvoh in children and adolescents aged 2 to less than 18 years have not yet been established. No data are available.

There is no relevant use of Omvoh in children below 2 years for the indication of ulcerative colitis or Crohn's disease.

Method of administration

Omvoh 300 mg concentrate for solution for infusion is for intravenous use only. Each vial is for single use only.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Administration of the diluted solution

• The intravenous administration set (infusion line) should be connected to the prepared intravenous bag and the line should be primed.

o For ulcerative colitis the infusion should be administered for at least 30 minutes.

o For Crohn's disease the infusion should be administered for at least 90 minutes.

• At the end of the infusion, to ensure a full dose is administered, the infusion line should be flushed with sodium chloride 9 mg/mL (0.9 %) solution or 5 % glucose solution for injection. The flush should be administered at the same rate as used for Omvoh administration. The time required to flush Omvoh solution from the infusion line is in addition to the minimum 30 minutes (ulcerative colitis) or 90 minutes (Crohn's disease) infusion time.

4.3. Contraindications

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

Clinically important active infections (active tuberculosis).

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.

Hypersensitivity reactions

In clinical studies, hypersensitivity reactions have been reported. Most were mild or moderate, severe reactions were uncommon (see section 4.8). If a serious hypersensitivity reaction, including anaphylaxis, occurs, mirikizumab must be discontinued immediately and appropriate therapy must be initiated.

Infections

Mirikizumab may increase the risk of severe infection (see section 4.8). Treatment with mirikizumab should not be initiated in patients with a clinically important active infection until the infection resolves or is adequately treated (see section 4.3). The risks and benefits of treatment should be considered prior to initiating use of mirikizumab in patients with a chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms of clinically important acute or chronic infection occur. If a serious infection develops, discontinuation of mirikizumab should be considered until the infection resolves.

Pre-treatment evaluation for tuberculosis

Prior to initiating treatment, patients should be evaluated for tuberculosis (TB) infection. Patients receiving mirikizumab 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.

Hepatic enzyme elevations

Cases of drug-induced liver injury (including one case meeting Hy's Law criteria) occurred in patients receiving mirikizumab in clinical trials. Liver enzymes and bilirubin should be evaluated at baseline and monthly during induction (including extended induction period, if applicable). Thereafter, liver enzymes and bilirubin should be monitored (every 1 ‑ 4 months) according to standard practice for patient management and as clinically indicated. If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are observed and drug‑induced liver injury is suspected, mirikizumab must be discontinued until this diagnosis is excluded.

Immunisations

Prior to initiating therapy with mirikizumab, completion of all appropriate immunisations should be considered according to current immunisation guidelines. Avoid use of live vaccines in patients treated with mirikizumab. No data are available on the response to live or non‑live vaccines.

Excipients with known effect

Sodium

Ulcerative colitis

This medicinal product contains approximately 18 mg sodium (less than 1 mmol sodium) per 300 mg dose, that is to say essentially 'sodium-free'.

If prepared with sodium chloride 9 mg/mL (0.9 %) solution for injection, the amount of sodium contributed by the sodium chloride diluent will range from 177 mg (for a 50 mL bag) to 885 mg (for a 250 mL bag), equivalent to 9‑44 % of the WHO recommended maximum daily intake. This is in addition to the amount contributed by the medicinal product.

Crohn's disease

This medicinal product contains approximately 54 mg sodium (less than 3 mmol sodium) per 900 mg dose, equivalent to 2.7% of the WHO recommended maximum daily intake of 2 g sodium (main component of cooking/table salt) for an adult.

If prepared with sodium chloride 9 mg/mL (0.9 %) solution for injection, the amount of sodium contributed by the sodium chloride diluent will range from 195 mg (for a 100 mL bag) to 726 mg (for a 250 mL bag), equivalent to 10‑36 % of the WHO recommended maximum daily intake. This is in addition to the amount contributed by the medicinal product.

Polysorbate

This medicinal product contains 0.5 mg/mL of polysorbate 80 in each vial which is equivalent to 7.5 mg for the induction dose to treat ulcerative colitis and equivalent to 22.5 mg for the induction dose to treat Crohn's disease. Polysorbates may cause allergic reactions.

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

No interaction studies have been performed.

In clinical studies, concomitant use of corticosteroids or oral immunomodulators did not influence the safety of mirikizumab.

Population pharmacokinetic data analyses indicated that the clearance of mirikizumab was not impacted by concomitant administration of 5‑ASAs (5‑aminosalicylic acid), corticosteroids or oral immunomodulators (azathioprine, 6-mercaptopurine, thioguanine, and methotrexate).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use an effective method of contraception during treatment and for at least 10 weeks after treatment.

Pregnancy

There is a limited amount of data from the use of mirikizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Omvoh during pregnancy.

Breast-feeding

It is unknown whether mirikizumab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Omvoh therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of mirikizumab on human fertility has not been evaluated (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions are upper respiratory tract infections (9.8 %, most frequently nasopharyngitis), headache (3.2 %), rash (1.3 %) and injection site reactions (10.8 %, maintenance period).

Tabulated list of adverse reactions

Adverse reactions from clinical studies (Table 1) are listed by MedDRA system organ class. The frequency category for each reaction is based on 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).

Table 1: Adverse reactions

MedDRA System organ class

Frequency

Adverse reaction

Infections and infestations

Common

Upper respiratory tract infectionsa

Uncommon

Herpes zoster

Immune system disorders

Uncommon

Infusion-related hypersensitivity reactions

Musculoskeletal and Connective Tissue Disorders

Common

Arthralgia

Nervous system disorders

Common

Headache

Skin and subcutaneous tissue disorders

Common

Rashb

General disorders and administration site conditions

Very common

Injection site reactionsc

Uncommon

Infusion site reactionsd

Investigations

Uncommon

Alanine aminotransferase increased

Uncommon

Aspartate aminotransferase increased

a Includes: acute sinusitis, COVID-19, nasopharyngitis, oropharyngeal discomfort, oropharyngeal pain, pharyngitis, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection.

b Includes: rash, rash macular, rash maculo-papular, and rash papular and rash pruritic.

c Reported during mirikizumab maintenance therapy where mirikizumab treatment is administered as subcutaneous injection.

d Reported during mirikizumab induction therapy where mirikizumab treatment is administered as intravenous infusion.

Description of selected adverse reactions

Infusion-related hypersensitivity reactions (induction therapy)

Infusion‑related hypersensitivity reactions were reported in 0.4 % of mirikizumab‑treated patients. All infusion‑related hypersensitivity reactions were reported as non-serious.

Injection site reactions (maintenance therapy)

Injection site reactions were reported in 10.8 % of mirikizumab‑treated patients. The most frequent reactions were injection site pain, injection site reaction and injection site erythema. These symptoms were reported as non‑serious, mild and transient in nature.

The results described above were obtained with the original formulation of Omvoh. In a double blind, 2-arm, randomised, single-dose, parallel design study in 60 healthy subjects comparing 200 mg mirikizumab (2 injections of 100 mg in a pre-filled syringe) of the original formulation with the revised formulation statistically significantly lower VAS pain scores were obtained with the revised (12.6) vs. the original formulation (26.1) 1 minute after injection.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased

In the first 12 weeks, ALT increased was reported in 0.6 % mirikizumab‑treated patients. AST increased was reported by 0.4 % mirikizumab‑treated patients. All adverse reactions were reported as mild to moderate in severity and non‑serious.

Overall mirikizumab treatment periods in the ulcerative colitis and Crohn's disease clinical development program (including the placebo‑controlled and open label induction and maintenance periods), there have been elevations of ALT to ≥ 3 x upper limit of normal (ULN) (2.3 %), ≥ 5 x ULN (0.7 %) and ≥ 10 x ULN (0.2 %) and AST to ≥ 3 x ULN (2.2 %), ≥ 5 x ULN (0.8 %) and ≥ 10 x ULN (0.1 %) in patients receiving mirikizumab (see section 4.4). These elevations have been noted with and without concomitant elevations in total bilirubin.

Immunogenicity

In the ulcerative colitis studies, up to 23 % of mirikizumab‑treated patients with 12 months of treatment developed anti‑drug antibodies, most of which were of low titer and tested positive for neutralising activity. Higher antibody titers in approximately 2 % of subjects treated with mirikizumab were associated with lower serum mirikizumab concentrations and reduced clinical response.

In the Crohn's disease study, 12.7% of mirikizumab-treated patients with 12 months of treatment developed anti-drug antibodies, most of which were of low titer and tested positive for neutralising activity. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics or effectiveness of mirikizumab.

No association was found between anti‑mirikizumab antibodies and hypersensitivity or injection-related events in either the ulcerative colitis or the Crohn's disease studies.

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

4.9. Overdose

Mirikizumab doses up to 2 400 mg intravenously and up to 500 mg subcutaneously have been administered in clinical trials without dose‑limiting toxicity. In the event of overdose, the patient must be monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment must be started immediately.