What are the side effects of Zepbound (ozanimod)?

Side Effects of Zepbound (Ozanimod)

Zepbound (ozanimod) is generally well tolerated with manageable side effects, though it carries important cardiovascular, immunological, and hepatic risks that require screening and monitoring. 1

Common Side Effects

The most frequently reported adverse reactions include:

• Upper respiratory tract infections occur in a significant proportion of patients and represent the most common adverse event 2, 3
• Hepatic transaminase elevations are common but typically transient and asymptomatic, occurring in ≥4% of patients 2, 3
• Fatigue may develop and in some cases can lead to treatment discontinuation 1
• Transient nausea has been reported in real-world studies 1
• Headache occurs frequently, particularly in ulcerative colitis patients 2
• Back pain, orthostatic hypotension, urinary tract infections, and hypertension each occur in ≥4% of patients 2

Cardiovascular Effects

Transient cardiac effects occur due to S1P receptor binding in the heart but are mitigated by the built-in dose titration schedule: 1

• Transient reductions in heart rate and atrioventricular conduction occur within the first 5 hours of initial dosing but do not typically require treatment or extended monitoring 1
• First-degree AV blocks may occur transiently and asymptomatically 4
• No cases of symptomatic bradycardia or second/third-degree AV block were reported in phase 3 trials 5
• First-dose cardiac monitoring is not required in the United States due to the titration regimen 2, 3

Important contraindications exist for patients with significant cardiac disease: 2

• Contraindicated if myocardial infarction, unstable angina, stroke, or TIA occurred within the last 6 months 2
• Contraindicated with decompensated heart failure requiring hospitalization or Class III/IV heart failure 2
• Contraindicated with Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sino-atrial block unless a functioning pacemaker is present 1, 2

Immunological and Infectious Risks

Lymphocyte reduction is an expected pharmacodynamic effect that increases infection susceptibility: 6

• Absolute lymphocyte count (ALC) decreases by 41-45% after 10 weeks of treatment 6
• ALC typically returns to normal within 30 days after discontinuation 6
• Treatment must be discontinued if ALC falls below 0.2 × 10^9/L 6
• Complete blood count should be obtained before treatment initiation and monitored during therapy 2

Infection risks are generally low but require vigilance: 1

• Serious infections occurred in ≤1.6% of patients in clinical trials, including appendicitis, gastroenteritis, nasopharyngitis, otitis externa, pyelonephritis, and vestibular neuronitis 1
• Increased risk of nasopharyngitis has been noted 4
• Do not start ozanimod in patients with active infections and monitor for infections during treatment and for 3 months after discontinuation 2
• Progressive multifocal leukoencephalopathy (PML) is a potential risk; withhold ozanimod at the first sign or symptom suggestive of PML 2

Hepatic Effects

Liver enzyme elevations are common but rarely lead to discontinuation: 1

• Transient asymptomatic hepatotoxicity occurs but is typically mild 4
• Abnormal liver function tests led to treatment discontinuation in only 0.4% of patients during both induction and maintenance periods 1
• No patients met criteria for Hy's law suggesting drug-induced liver injury, and no severe liver injury occurred 1
• Obtain liver enzyme results before initiation and periodically during treatment; discontinue if there is evidence of liver injury without other cause 2

Ophthalmologic Effects

Macular edema risk is low but higher in patients with preexisting risk factors: 1, 2

• Macular edema occurred in ≤0.4% of patients in clinical trials 1
• Risk is increased in patients with diabetes mellitus and uveitis 2
• Baseline fundus evaluation including the macula should be obtained near the start of treatment 2
• Periodic fundus evaluations should be conducted while on therapy and any time there is a change in vision 2
• Consider discontinuing ozanimod if macular edema develops 2

Malignancy Risk

Cancer incidence was low in clinical trials: 1

• Cancer occurred in ≤0.9% of patients, including two cases of basal cell carcinoma, two cases of colorectal cancer, and one case of breast cancer 1
• Skin examination prior to or shortly after starting treatment and periodically thereafter is recommended; suspicious skin lesions should be evaluated 2

Respiratory Effects

Pulmonary function may decline: 2

• May cause a decline in pulmonary function; assess pulmonary function (e.g., spirometry) if clinically indicated 2
• Severe untreated sleep apnea is a contraindication 2

Blood Pressure Effects

Hypertension may develop or worsen: 1, 2

• Increased blood pressure can occur during treatment 2
• One patient with a history of hypertension developed hypertensive urgency and discontinued ozanimod in real-world data 1
• Monitor blood pressure during treatment 2

Critical Drug Interactions

Ozanimod has serious contraindications and interactions due to its monoamine oxidase-B inhibition: 1, 2

Absolute Contraindications:

• Monoamine oxidase inhibitors (MAOIs) including selegiline, phenelzine, linezolid, isocarboxazid, and tranylcypromine are contraindicated due to risk of hypertensive crisis 1, 2

Serious Interactions Requiring Avoidance:

• Opioid drugs (meperidine, methadone, tramadol, oxycodone, hydrocodone, morphine, codeine, fentanyl) may cause serious adverse reactions including hypertensive crisis 1
• Serotonergic/adrenergic drugs (SSRIs, SNRIs, tricyclic antidepressants) may cause serious adverse reactions including hypertensive crisis 1
• Sympathomimetic drugs (pseudoephedrine, phenylephrine, amphetamines, midodrine, clonidine, albuterol) may cause hypertensive crisis 1

Medications Requiring Caution:

• Anti-arrhythmic drugs (Class Ia or III), QT-prolonging drugs, beta-blockers, and calcium channel blockers may have additive cardiac effects; cardiology consultation is recommended 1
• CYP2C8 inhibitors (gemfibrozil, clopidogrel) may increase exposure to active metabolites of ozanimod 1
• CYP2C8 inducers (rifampin) may reduce ozanimod efficacy 1
• Immunosuppressive medications (ciclosporin, tacrolimus, azathioprine, methotrexate) may have additive immunosuppressive effects 1

Dietary Restrictions

Tyramine-containing foods require caution: 1

• Patients should avoid consuming foods or drinks containing high amounts of tyramine (>150 mg) due to potential for severe hypertension based on in vitro findings that ozanimod inhibits monoamine oxidase-B 1
• Foods that are aged, fermented, cured, smoked, and pickled should be consumed in moderation 1

Vaccination Considerations

Live attenuated vaccines should be avoided: 2

• Avoid use of live attenuated vaccines during and for up to 3 months after treatment with ozanimod 2
• Non-replicating vaccines may be acceptable based on clinical experience 1

Fetal Risk and Pregnancy

Ozanimod poses fetal risk: 2

• Women of childbearing potential should use effective contraception during treatment and for 3 months after stopping ozanimod 2

Comparative Safety Profile

Ozanimod demonstrates favorable tolerability compared to other therapies: 7, 5

• Lower incidence of treatment-emergent adverse events compared to interferon beta-1a (74.7% vs 83.0%) 5
• Fewer treatment discontinuations due to adverse events compared to interferon beta-1a 5
• Favorable benefit-risk profile versus fingolimod with lower risks of extended first-dose monitoring, conduction abnormalities, bradycardia, herpetic infections, and abnormal liver enzymes 7
• No black-box warnings unlike some TNF inhibitors and JAK inhibitors 1