2.1 Recommended Evaluations and Immunizations Prior to Treatment Initiation

• Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with OMVOH [see Warnings and Precautions (5.3)].
• Obtain liver enzymes and bilirubin levels prior to initiating treatment with OMVOH [see Warnings and Precautions (5.4)].
• Complete all age-appropriate vaccinations according to current immunization guidelines [see Warnings and Precautions (5.5)].

2.2 Important Administration Instructions

• The 200 mg/2 mL prefilled pen and prefilled syringe are only for maintenance treatment of Crohn's disease.

2.3 Recommended Dosage for Ulcerative Colitis

2.4 Recommended Dosage for Crohn's Disease

2.5 Preparation and Administration Instructions for Intravenous Infusion

1. OMVOH for intravenous use is intended for administration by a healthcare provider using aseptic technique.
2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be a clear to opalescent, colorless to slightly yellow to slightly brown solution, and free of visible particles. Do not use OMVOH if it is cloudy or there are visible particles.
3. Prior to intravenous administration, determine the dose needed based on the patient's indication (see Table 1 below). For Crohn's disease, discard 45 mL of the infusion bag prior to adding vial contents. Withdraw the required amount of solution from the vial(s) using a 18 gauge to 21 gauge needle and transfer to an infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection (see Table 1 below). Do not mix with other drugs. Do not dilute or infuse through the same intravenous line with other solutions.

   Table 1: Intravenous Induction Dose and Volume of Diluent Required

   Indication	Intravenous Induction Dose	Number of OMVOH 300mg/15mL vials needed	Volume of 0.9% Sodium Chloride or 5% Dextrose Injection
   Ulcerative colitis	300 mg	1	50 mL, 100 mL, or 250 mL
   Crohn's disease	900 mg	3	100 mL or 250 mL

4. Gently invert the infusion bag to mix the contents. Do not shake the prepared infusion bag.
5. Connect the intravenous administration set (infusion line) to the prepared infusion bag and prime the line.
6. Infuse the diluted solution intravenously over a period of at least 30 minutes for the 300 mg dose; at least 90 minutes for the 900 mg dose. If stored refrigerated, allow the diluted solution in the infusion bag to warm to room temperature prior to the start of the intravenous infusion.
7. At the end of the infusion, flush the line with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
   • Administer the flush at the same infusion rate as used for OMVOH administration.
   • The time required to flush OMVOH solution from the infusion line is in addition to the minimum 30-minute infusion time.

2.6 Preparation and Administration Instructions for Subcutaneous Injection

• A full maintenance dose will require 2 prefilled pens or 2 prefilled syringes given as two consecutive injections, in any order.
• OMVOH is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject OMVOH after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of OMVOH according to the “Instructions for Use”, included with the packaged product.
• Before injection, remove OMVOH prefilled pens or OMVOH prefilled syringes from the refrigerator and leave at room temperature for 30 minutes if using the carton containing 100 mg/mL + 100 mg/mL or 45 minutes if using the carton containing 200 mg/2 mL + 100 mg/mL.
• Do not shake the prefilled pens or prefilled syringes.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be a clear to opalescent, colorless to slightly yellow to slightly brown solution, and free of visible particles. Do not use OMVOH if it is cloudy, discolored, or there are visible particles.
• Sites for injection include the abdomen, thigh, and back of the upper arm. Instruct patients to inject in a different location every time. For example, if the first injection was in the abdomen, administer the second injection (to complete a full dose) in another area of the abdomen, or upper arm, or thigh. Administration of OMVOH in the back of upper arm may only be performed by another person.
• Do not inject into areas where the skin is tender, bruised, erythematous, or indurated.
• OMVOH does not contain preservatives; therefore, discard any unused product. Do not reuse.
• If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing every 4 weeks.

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis during intravenous infusion, have been reported with OMVOH administration. Infusion-related hypersensitivity reactions, including mucocutaneous erythema and pruritus, were reported during induction [see Adverse Reactions (6.1)]. If a severe hypersensitivity reaction occurs, discontinue OMVOH immediately and initiate appropriate treatment.

5.2 Infections

OMVOH may increase the risk of infection [see Adverse Reactions (6.1)].

Do not initiate treatment with OMVOH in patients with a clinically important active infection until the infection resolves or is adequately treated.

In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing OMVOH. Instruct patients to seek medical advice if signs or symptoms of clinically important acute or chronic infection occur. If a serious infection develops or an infection is not responding to standard therapy, monitor the patient closely and do not administer OMVOH until the infection resolves.

5.3 Tuberculosis

Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with OMVOH.

Do not administer OMVOH to patients with active TB infection. Initiate treatment of latent TB prior to administering OMVOH. Consider anti-TB therapy prior to initiation of OMVOH in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after OMVOH treatment.

In clinical trials, subjects were excluded if they had evidence of active TB, a past history of active TB, or were diagnosed with latent TB at screening.

5.4 Hepatotoxicity

A case of drug-induced liver injury (alanine aminotransferase [ALT] 18x the upper limit of normal (ULN), aspartate aminotransferase [AST] 10x ULN, and total bilirubin 2.4x ULN) in conjunction with pruritus was reported in a clinical trial subject following a longer than recommended induction regimen. OMVOH was discontinued. Liver test abnormalities eventually returned to baseline.

Evaluate liver enzymes and bilirubin at baseline and for at least 24 weeks of treatment. Monitor thereafter according to routine patient management.

Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction.

5.5 Immunizations

Avoid use of live vaccines in patients treated with OMVOH. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy with OMVOH, complete all age-appropriate vaccinations according to current immunization guidelines. No data are available on the response to live or non-live vaccines in patients treated with OMVOH.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

7.1 CYP450 Substrates

Increased concentrations of cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation associated with certain diseases including Crohn's disease may suppress the formation of CYP450 enzymes. Therapeutic proteins, including mirikizumab-mrkz, that decrease the concentrations of these pro-inflammatory cytokines may increase the formation of CYP450 enzymes resulting in decreased CYP450 substrate exposure. Upon initiation or discontinuation of OMVOH in patients treated with concomitant CYP450 substrates, monitor drug concentrations or other therapeutic parameters, and adjust the dosage of the CYP450 substrate as needed. See the prescribing information of specific CYP450 substrates.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of OMVOH have not been established in pediatric patients.

8.5 Geriatric Use

Of the 795 OMVOH-treated subjects in the two ulcerative colitis clinical studies, 64 subjects (8%) were 65 years of age and older, while 10 subjects (1%) were 75 years of age and older. Of the 715 OMVOH-treated subjects in the Crohn's disease clinical study, 22 subjects (3%) were 65 years of age and older, while 6 subjects (1%) were 75 years of age and older). These clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. No clinically meaningful differences in the pharmacokinetics of mirikizumab-mrkz were observed in subjects 65 years of age and older compared to younger adult subjects [see Clinical Pharmacology (12.3)].

OMVOH for intravenous infusion for ulcerative colitis and Crohn's disease

OMVOH (mirikizumab-mrkz) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow to slightly brown solution in a single-dose vial for intravenous infusion after dilution. Each mL contains 20 mg of mirikizumab-mrkz, anhydrous citric acid (0.4 mg), polysorbate 80 (0.5 mg), sodium chloride (8.8 mg), sodium citrate (2.1 mg), and Water for Injection. The OMVOH solution has a pH range of 5.0 to 6.0.

OMVOH (mirikizumab-mrkz) injection 100 mg/mL prefilled pen or prefilled syringe for subcutaneous use for ulcerative colitis and Crohn's disease

OMVOH (mirikizumab-mrkz) injection is a sterile, preservative free, clear to opalescent, colorless to slightly yellow to slightly brown solution for subcutaneous use available as 100 mg of mirikizumab-mrkz in a 1 mL single-dose prefilled pen or single-dose prefilled syringe. The prefilled pen and prefilled syringe contain a 1 mL glass syringe with a fixed 27-gauge ½ inch needle. The OMVOH 100 mg prefilled pen and prefilled syringe are manufactured to deliver 100 mg of mirikizumab-mrkz.

Each mL is composed of 100 mg mirikizumab-mrkz, histidine (0.1 mg), L-histidine hydrochloride monohydrate (0.9 mg), mannitol (33 mg), polysorbate 80 (0.3 mg), sodium chloride (2.9 mg), and Water for Injection. The OMVOH solution has a pH range of 5.0 to 5.8.

OMVOH (mirikizumab-mrkz) injection 200 mg/2 mL prefilled pen or 200 mg/2 mL (100 mg/mL) prefilled syringe for subcutaneous use for Crohn's disease

OMVOH (mirikizumab-mrkz) injection is a sterile, preservative free, clear to opalescent, colorless to slightly yellow to slightly brown solution for subcutaneous use. The 2 mL prefilled pen and prefilled syringe each contain a 2 mL glass syringe with a fixed 27-gauge 8 mm needle. The OMVOH 200 mg prefilled pen and prefilled syringe are manufactured to deliver 200 mg of mirikizumab-mrkz.

Each mL is composed of 100 mg mirikizumab-mrkz, histidine (0.1 mg), L-histidine hydrochloride monohydrate (0.9 mg), mannitol (33 mg), polysorbate 80 (0.3 mg), sodium chloride (2.9 mg), and Water for Injection. The OMVOH solution has a pH range of 5.0 to 5.8.

12.1 Mechanism of Action

Mirikizumab-mrkz is a humanized IgG4 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor.

IL-23 is involved in mucosal inflammation and affects the differentiation, expansion, and survival of T cell subsets, and innate immune cell subsets, which represent sources of pro-inflammatory cytokines. Research in animal models has shown that pharmacologic inhibition of IL-23p19 can ameliorate intestinal inflammation.

Mirikizumab-mrkz inhibits the release of pro-inflammatory cytokines and chemokines.

12.2 Pharmacodynamics

In both study UC-1 (induction) and study UC-2 (maintenance), a positive relationship was observed between mirikizumab-mrkz average concentration and rates of clinical remission and clinical response [see Clinical Studies (14.1)].

Mirikizumab exposure response relationships have not been fully characterized in subjects with Crohn's disease.

12.3 Pharmacokinetics

Mirikizumab-mrkz exhibited linear pharmacokinetics with dose-proportional increase in exposure over a dose range of 60 to 2400 mg given as an intravenous injection or over a dose range of 200 to 400 mg given as a subcutaneous injection, in healthy volunteers. There was no apparent accumulation of mirikizumab-mrkz concentrations in serum over time when administered as a subcutaneous injection every 4 weeks to subjects with ulcerative colitis or Crohn's disease. The estimated exposure parameters of mirikizumab-mrkz at steady state are summarized in Tables 5 for ulcerative colitis and 6 for Crohn's disease.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of mirikizumab-mrkz or of other mirikizumab products.

During the 52-week treatment period in studies UC-1 and UC-2, 23% (88/378) of OMVOH-treated subjects at the recommended dosage and evaluable for assessment, developed anti-mirikizumab-mrkz antibodies (referred to as anti-drug antibodies (ADA)). Of those who developed ADA, 33/88 (38%) developed titers ≥1:160. Of these 33 OMVOH-treated subjects, 10 had reduced serum trough concentrations of mirikizumab-mrkz compared to subjects who did not develop anti-mirikizumab-mrkz antibodies, and 5 of these 10 subjects did not achieve clinical response at Week 52. There is insufficient data to assess whether the observed ADA-associated pharmacokinetic changes reduced effectiveness. There is no identified clinically significant effect of ADA on the safety of OMVOH over the treatment duration of 52-weeks.

During the 52-week treatment period in study CD-1, 13% (79/622) of OMVOH-treated subjects at the recommended dosage and evaluable for assessment developed ADA. There is no identified clinically significant effect of ADA on the pharmacokinetics, effectiveness, or safety of OMVOH over the treatment duration of 52-weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of mirikizumab-mrkz.

No organ weight or histopathology effects were observed in the male or female reproductive tract in sexually mature cynomolgus monkeys that received subcutaneous mirikizumab-mrkz once weekly for 26 weeks, at a dose of 100 mg/kg (at least 2 times the MRHD of mirikizumab-mrkz, based on exposure comparisons).

14.1 Ulcerative Colitis

The safety and efficacy of OMVOH was evaluated in two randomized, double-blind, placebo-controlled clinical studies, one induction study [UC-1 (NCT03518086)] and one maintenance study [UC-2 (NCT03524092)], in adult subjects with moderately to severely active ulcerative colitis who had inadequate response, loss of response, or failed to tolerate any of the following: corticosteroids, 6-mercaptopurine, azathioprine, biologic therapy (TNF blocker, vedolizumab), or tofacitinib. The 12-week intravenous induction study (UC-1) was followed by the 40-week subcutaneous randomized withdrawal maintenance study (UC-2).

14.2 Crohn's Disease

The safety and efficacy of OMVOH was evaluated in a randomized, double-blind, placebo-controlled study [CD-1 (NCT03926130)] in adult subjects with moderately to severely active Crohn's disease who had an inadequate response, loss of response, or intolerance to corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate), and/or biologics (TNF blockers, integrin receptor antagonists).

In CD-1, the efficacy population consisted of 679 subjects who were randomized 3:1 at Week 0 to receive OMVOH 900 mg by intravenous infusion at Week 0, Week 4, and Week 8 followed by a dosage of 300 mg by subcutaneous injection at Week 12 and then every 4 weeks for 40 weeks, or placebo. Subjects had a mean age of 36 years (range 18 to 74 years); 42% were female; and 71% identified as White, 25% as Asian, <1% as American Indian or Alaska Native, 1% as Black or African American, and 2% as another racial group or did not report their racial group. Subjects were permitted to use stable doses of oral corticosteroids (prednisone ≤30 mg/day or equivalent, extended-release budesonide 9 mg/day), immunomodulators (6-mercatopurine, azathioprine, or methotrexate) and/or aminosalicylates. At baseline, 31% of subjects were receiving oral corticosteroids, 26% were receiving immunomodulators, and 44% were receiving aminosalicylates.

At baseline, 47% had a loss of response, inadequate response, or intolerance to one or more biologic therapy.

Disease activity at baseline was assessed by the Crohn's Disease Activity Index (CDAI) and the Simple Endoscopic Score for Crohn's disease (SES-CD). Moderately to severely active CD was defined by a CDAI of ≥220 and an SES-CD ≥7 (centrally read) for subjects with ileal-colonic disease or ≥4 for subjects with isolated ileal disease. At baseline, subjects had a median CDAI of 329 and SES-CD of 12.

The coprimary endpoints of clinical remission by CDAI and endoscopic response by SES-CD were assessed at Week 52. Secondary efficacy endpoints included endoscopic response at Week 12 and endoscopic remission and corticosteroid-free clinical remission at Week 52 (see Table 9).

Storage and Handling

• Store refrigerated at 2°C to 8°C (36°F to 46°F).
• Do not freeze. Do not use OMVOH if it has been frozen.
• Do not shake.
• Keep OMVOH in the original carton to protect from light until the time of use.
• OMVOH is sterile and preservative-free. Discard any unused portion.
• If needed, the prefilled pen or prefilled syringe may be stored at room temperature up to 30°C (86°F) for up to 2 weeks in the original carton to protect from light. Once OMVOH has been stored at room temperature, do not return to the refrigerator. If these conditions are exceeded, OMVOH must be discarded.
• The vial, prefilled pen, and prefilled syringe are not made with dry natural rubber latex.