Rheumatoid Arthritis Safety

SELECT IMPORTANT SAFETY INFORMATION: WARNING RELATED TO SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS

SERIOUS INFECTIONS: Olumiant-treated patients are at increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Interrupt treatment with Olumiant if a serious infection occurs until the infection is controlled. Olumiant should not be given to patients with active tuberculosis. Test for latent TB before and during therapy, except for COVID-19; treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test.

MORTALITY: Higher rate of all-cause mortality, including sudden cardiovascular death was observed with another Janus kinase (JAK) inhibitor vs. tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients.

MALIGNANCIES: Malignancies have also occurred in patients treated with Olumiant. Higher rate of lymphomas and lung cancers was observed with another JAK inhibitor vs. TNF blockers in RA patients.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE): Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) was observed with another JAK inhibitor vs. TNF blockers in RA patients.

THROMBOSIS: Thrombosis has occurred in patients treated with Olumiant. Increased incidence of pulmonary embolism, venous and arterial thrombosis was observed with another JAK inhibitor vs. TNF blockers.

Olumiant Safety

This Olumiant RA safety data set includes over 2500 patients enrolled in 6 randomized, double-blind, placebo-controlled studies (three phase 2, three phase 3) and a long-term extension study. Patients were randomized to placebo (n=1070), Olumiant 2mg (n=479), or higher dose which is not approved for RA (n-997).

Common Adverse Reactions for RA¹

Common Adverse Events — The following adverse reactions occurred in greater than or equal to 1% of patients with RA in placebo-controlled trials from weeks 0 to 16.

The adverse reactions reported for patients taking Olumiant 2 milligrams/day (n=479) were upper respiratory infections (16.3%), nausea (2.7%), herpes zoster (1.0%), and herpes simplex (0.8%).

The adverse reactions reported for patients taking placebo (n=1070) were upper respiratory infections (11.7%), nausea (1.6%), herpes zoster (0.4%), and herpes simplex (0.7%).

In both treatment groups, upper respiratory infections included acute sinusitis, acute tonsillitis, chronic tonsillitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinobronchitis, sinusitis, tonsillitis, tracheitis, and upper respiratory tract infection.

In both treatment groups, herpes simplex included eczema herpeticum, genital herpes, herpes simplex, ophthalmic herpes simplex, and oral herpes.

Additional adverse drug reaction occurring in fewer than 1% of patients: acne.

Patients in this data set were receiving background cDMARDs.

Discontinuation rates¹

Discontinuation Rates Table — The following safety results are for overall treatment discontinuations due to adverse events (AEs) in patients with moderately to severely active rheumatoid arthritis. Data are presented as the number of patients with an event followed by the rate per 100 patient years in parentheses. Patients in this data set were receiving background conventional disease-modifying antirheumatic drugs.

In weeks 0 to 16, the number of patients discontinuing due to AEs was 17 (12.1 per 100 patient-years) in the Olumiant 2 milligrams (mg)/day arm and 35 patients (11.4 per 100 patient-years) in the placebo arm.

In weeks 0 to 52, the number of patients discontinuing due to AEs in the Olumiant 2 mg/day arm was 31 (9.2 per 100 patient-years).

Adverse Events of Special Interest¹

Infections, malignancy, and thrombosis

Adverse Events of Special Interest Table — The following safety results are adverse events of special interest observed in patients with moderately to severely active rheumatoid arthritis (RA). Data are presented as the number of patients with an event followed by the rate per 100 patient years in parentheses. Patients in this data set were receiving background conventional disease-modifying antirheumatic drugs.

From weeks 0-16, serious infections were reported in 13 patients (4.2 per 100 patient-years) assigned to placebo and 5 patients (3.6 per 100 patient-years) treated with Olumiant 2 milligrams (mg)/day. From weeks 0-52, serious infections were reported in 14 patients (4.2 per 100 patient-years) treated with Olumiant 2 mg/day. In the 0 to 52 week exposure population, the most commonly reported serious infections were pneumonia, herpes zoster, and urinary tract infection. Although there were no tuberculosis (TB) events reported for placebo or Olumiant 2 mg in this time period, TB events were reported in patients receiving a higher dose, which is not approved for RA.

From weeks 0-16, opportunistic infections were reported in 2 patients (0.6 per 100 patient-years) assigned to placebo and 0 patients treated with Olumiant 2 mg/day. From weeks 0-52, opportunistic infections were reported in 1 patient (0.3 per 100 patient-years) treated with Olumiant 2 mg/day. Opportunistic infections excluded TB.

From weeks 0-16, malignancy was reported in 0 patients assigned to placebo and 1 patient (0.7 per 100 patient-years) treated with Olumiant 2 mg/day. From weeks 0-52, malignancy was reported in 2 patients (0.6 per 100 patient-years) treated with Olumiant 2 mg/day. Malignancy excluded non-melanoma skin cancer (NMSC).

From weeks 0-16, arterial thrombosis was reported in 1 patient (0.3 per 100 patient-years) assigned to placebo and 2 patients (1.4 per 100 patient-years) treated with Olumiant 2 mg/day. From weeks 0-52, arterial thrombosis was reported in 3 patients (0.9 per 100 patient-years) treated with Olumiant 2 mg/day.

From weeks 0-16, venous thrombosis was reported in 0 patients assigned to placebo and 0 patients treated with Olumiant 2 mg/day. From weeks 0-52, venous thrombosis was reported in 2 patients (0.6 per 100 patient-years) treated with Olumiant 2 mg/day.

Lilly is conducting long-term safety studies, including post-marketing studies, to continue to evaluate the safety of Olumiant. Certain adverse events, such as malignancy, require longer observation periods and larger patient exposure to ascertain risk.

PY=patient years

Laboratory abnormalities

Lab Abnormalities during 16 weeks of treatment — The following safety results are for laboratory abnormalities during a 16-week treatment period in patients with moderately to severely active rheumatoid arthritis (RA) in the Olumiant 2 milligram (mg)/day arm (n=479) and the placebo arm (n=1070). Patients in this data set were receiving background conventional disease-modifying antirheumatic drugs.

Neutropenia, defined as neutrophil counts <1000 cells/mm³, occurred in 0.6% of patients in the Olumiant 2 mg/day arm and in 0.0% of patients in the placebo arm.

Platelet elevations, defined as an increase in platelet counts above 600,000 cells/mm³, occurred in 1.1% of patients in the Olumiant 2 mg/day arm and in 1.1% of patients in the placebo arm.

Liver enzyme elevations were observed in patients treated with Olumiant. Alanine aminotransferase (ALT) elevations ≥3 times the upper limit of normal (ULN) occurred in 1.7% of patients in the Olumiant 2 mg/day arm and in 1.0% of patients in the placebo arm. Aspartate aminotransferase (AST) elevations ≥3 times ULN occurred in 1.3% of patients in the Olumiant 2 mg/day arm and in 0.8% of patients in the placebo arm. In a phase 3 study of disease-modifying antirheumatic drug (DMARD) naive patients, during the 24-week treatment period, ALT and AST elevations ≥3 times ULN occurred in 1.9% and 0% of patients treated with methotrexate (MTX) monotherapy, 1.9% and 1.3% of patients treated with baricitinib higher dose monotherapy, and 4.7% and 1.9% of patients treated with baricitinib higher dose plus MTX. Baricitinib is not approved at higher doses for RA.

Lipid elevations were observed in patients treated with Olumiant at week 12. The mean change from baseline in low-density lipoprotein (LDL) cholesterol increased by 8 mg/dL in the Olumiant 2 mg/day arm and decreased by 1 mg/dL in the placebo arm. The mean change from baseline in high-density lipoprotein (HDL) cholesterol increased by 7 mg/dL in the Olumiant 2 mg/day arm and 0 mg/dL in the placebo arm. The mean change from baseline in triglycerides increased by 7 mg/dL in the Olumiant 2 mg/day arm and decreased by 2 mg/dL in the placebo arm. The mean LDL/HDL ratio remained stable.

Creatine phosphokinase (CPK) elevations were observed within one week of starting Olumiant and plateaued after 8 to 12 weeks. At week 16, the mean change from baseline in CPK was 37 IU/L in the Olumiant 2 mg/day arm and 2 IU/L in the placebo arm.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; LDL=low-density lipoprotein; HDL=high-density lipoprotein; MTX=methotrexate; CPK=creatinine phosphokinase.

References

Olumiant [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021.
Data on file. Lilly USA, LLC. DOF-BA-US-0004.

IMPORTANT SAFETY INFORMATION

WARNINGS:

SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS

SERIOUS INFECTIONS - Patients treated with Olumiant are at risk for developing serious infections that may lead to hospitalization or death. Most patients with rheumatoid arthritis (RA) who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt Olumiant until the infection is controlled. Reported infections include:

Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Olumiant should not be given to patients with active tuberculosis. Test patients, except those with COVID-19, for latent TB before initiating Olumiant and during therapy. If positive, start treatment for latent infection prior to Olumiant use.
Invasive fungal infections, including candidiasis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of Olumiant prior to initiating therapy in patients with chronic or recurrent infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Olumiant including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

The most common serious infections reported with Olumiant included pneumonia, herpes zoster, and urinary tract infection. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus were reported with Olumiant. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Avoid use of Olumiant in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Olumiant in patients: with chronic or recurrent infection; who have been exposed to TB; with a history of a serious or an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection.

The risks and benefits of treatment with Olumiant in COVID-19 patients with other concurrent infections should be considered.

Consider anti-TB therapy prior to initiation of Olumiant in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with Olumiant. If a patient develops herpes zoster, interrupt Olumiant treatment until the episode resolves. The impact of Olumiant on chronic viral hepatitis reactivation is unknown. Screen for viral hepatitis in accordance with clinical guidelines before initiating Olumiant.

MORTALITY
In a large, randomized, postmarketing safety study in RA patients 50 years of age and older with at least one cardiovascular risk factor comparing another Janus kinase (JAK) inhibitor to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Olumiant.

MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with Olumiant. In RA patients treated with another JAK inhibitor, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers and an additional increased risk of overall malignancies were observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Olumiant, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

NMSCs have been reported in patients treated with Olumiant. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

MAJOR ADVERSE CARDIOVASCULAR EVENTS
In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction [MI], and stroke) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue Olumiant in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Olumiant, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur.

THROMBOSIS
Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with Olumiant compared to placebo. In addition, there were cases of arterial thrombosis. Many of these adverse events were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid Olumiant in patients at risk. Discontinue Olumiant and promptly evaluate patients with symptoms of thrombosis.

HYPERSENSITIVITY
Reactions such as angioedema, urticaria, and rash that may reflect drug hypersensitivity have been observed in patients receiving Olumiant, including serious reactions. If a serious hypersensitivity reaction occurs, promptly discontinue Olumiant while evaluating the potential causes of the reaction.

GASTROINTESTINAL PERFORATIONS
Gastrointestinal perforations have been reported in Olumiant clinical studies. Monitor Olumiant-treated patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Promptly evaluate patients who present with new onset abdominal symptoms for early identification of gastrointestinal perforation.

LABORATORY ABNORMALITIES
Neutropenia – Olumiant treatment was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm3) compared to placebo. Evaluate at baseline and thereafter according to routine patient management.

In patients with RA or alopecia areata (AA), avoid initiation or interrupt Olumiant treatment in patients with an ANC <1000 cells/mm3. In patients with COVID-19, avoid initiation or interrupt Olumiant treatment in patients with an ANC <500 cells/mm3.

Lymphopenia – Absolute lymphocyte count (ALC) <500 cells/mm3 were reported in Olumiant clinical trials. Lymphocyte counts less than the lower limit of normal were associated with infection in patients treated with Olumiant, but not placebo. Evaluate at baseline and thereafter according to routine patient management.

In patients with RA or AA, avoid initiation or interrupt Olumiant treatment in patients with an ALC <500 cells/mm3. In patients with COVID-19, avoid initiation or interrupt Olumiant treatment in patients with an ALC <200 cells/mm3.

Anemia – Decreases in hemoglobin levels to <8 g/dL were reported in Olumiant clinical trials. Evaluate at baseline and thereafter according to routine patient management.

In patients with RA or AA, avoid initiation or interrupt Olumiant treatment in patients with hemoglobin <8 g/dL. In patients with COVID-19, there is limited information regarding use of Olumiant in patients with hemoglobin less than 8 g/dL.

Liver Enzyme Elevations – Olumiant treatment was associated with increased incidence of liver enzyme elevation compared to placebo. Increases of alanine transaminase (ALT) ≥5x upper limit of normal (ULN) and increases of aspartate transaminase (AST) ≥10x ULN were observed in patients in Olumiant clinical trials.

Evaluate at baseline and thereafter according to routine patient management. Promptly investigate the cause of liver enzyme elevation to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt Olumiant until this diagnosis is excluded.

Lipid Elevations – Treatment with Olumiant was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Assess lipid parameters approximately 12 weeks following Olumiant initiation in patients with RA or AA. Manage patients according to clinical guidelines for the management of hyperlipidemia.

VACCINATIONS
Avoid use of live vaccines with Olumiant. Update immunizations in patients with RA or AA prior to initiating Olumiant therapy in agreement with current immunization guidelines.

ADVERSE REACTIONS
In RA trials, the most common adverse reactions (≥1%) reported with Olumiant were: upper respiratory tract infections, nausea, herpes simplex, and herpes zoster.

In COVID-19 trials, the most common adverse reactions (≥1%) reported with Olumiant were: ALT ≥3x ULN, AST ≥3x ULN, thrombocytosis (platelets >600,000 cells/mm3), creatine phosphokinase >5x ULN, neutropenia (ANC <1000 cells/mm3), DVT, PE, and urinary tract infection.

In AA trials, the most common adverse reactions (≥1%) reported with Olumiant were: upper respiratory tract infections, headache, acne, hyperlipidemia, creatine phosphokinase increase, urinary tract infections, liver enzyme elevations, folliculitis, fatigue, lower respiratory tract infections, nausea, genital Candida infections, anemia, neutropenia, abdominal pain, herpes zoster, and weight increase.

PREGNANCY AND LACTATION
Based on animal studies, Olumiant may cause fetal harm when administered during pregnancy. Advise pregnant women and women of reproductive potential of the potential risk to a fetus. Consider pregnancy planning and prevention for women of reproductive potential. Advise women not to breastfeed during treatment with Olumiant and for 4 days after the last dose.

HEPATIC AND RENAL IMPAIRMENT
Olumiant is not recommended in patients with RA or AA and severe hepatic impairment or severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m2).

Olumiant should only be used in patients with COVID-19 and severe hepatic impairment if the potential benefit outweighs the potential risk. Olumiant is not recommended in patients with COVID-19 who are on dialysis, have end-stage renal disease, or with eGFR <15 mL/min/1.73m2.

BA HCP ISI ALL 14SEP2022

Please click to access full Prescribing Information, including Boxed Warning about Serious Infections, Mortality, Malignancy, Major Adverse Cardiovascular Events, and Thrombosis, and Medication Guide.

INDICATIONS

Alopecia Areata

Olumiant is indicated for the treatment of adult patients with severe alopecia areata.

Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants.

Rheumatoid Arthritis

Olumiant is a Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) blockers.

Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants, such as azathioprine and cyclosporine.

COVID-19

Olumiant is a Janus kinase (JAK) inhibitor indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).