Does Zymfentra Make You Tired? Understanding Fatigue and Your Medication

October 8, 2025 •

4 min read

While initial clinical trial data didn't list fatigue as one of the most common adverse reactions, it has been reported by patients taking Zymfentra and other infliximab products during postmarketing surveillance. This feeling of unusual tiredness can stem from the medication itself, the underlying inflammatory bowel disease (IBD) it treats, or as a sign of a more serious complication.

Quick Summary

Fatigue is a potential side effect of Zymfentra for IBD, though not universally experienced. This tiredness can be a direct drug effect, related to the chronic inflammatory condition, or indicate a complication like infection or anemia. Consulting a doctor is crucial for diagnosis and management.

Key Points

Possible Side Effect: Fatigue is a potential side effect reported in postmarketing surveillance for Zymfentra (infliximab-dyyb), though not listed as a most common adverse reaction in initial trials.
Signal of Serious Complications: Unusual weakness or fatigue while on Zymfentra could be a sign of a more serious issue, such as a severe infection, heart failure, anemia, or liver injury.
IBD-Related Fatigue: Fatigue is a common symptom of inflammatory bowel disease (IBD) itself, making it difficult to pinpoint the exact cause without medical evaluation.
Timing Matters: Some patients on biologics report experiencing fatigue in the period immediately following an injection or infusion.
Management is Possible: Strategies like adjusting dose timing (if approved by a doctor), managing underlying IBD activity, and lifestyle changes can help mitigate fatigue.
Medical Consultation is Key: Any new or worsening fatigue on Zymfentra should be reported to a healthcare provider to rule out complications and determine the best course of action.

Zymfentra and its mechanism of action

Zymfentra (infliximab-dyyb) is a subcutaneous (SC) injection used as a maintenance treatment for moderately to severely active Crohn's disease and ulcerative colitis in adults. It is a biologic medication known as a tumor necrosis factor (TNF) blocker. TNF-alpha is a protein in the body that can cause inflammation. In conditions like IBD, an overproduction of TNF-alpha contributes to inflammation in the digestive tract. Zymfentra works by binding to and blocking the activity of TNF-alpha, which helps to reduce inflammation and manage disease symptoms.

Before beginning Zymfentra, patients must complete an initial intravenous (IV) induction regimen with an infliximab product. This shifts patients to a convenient at-home, self-administered subcutaneous injection given every two weeks.

Why Zymfentra can cause fatigue

There are several reasons why a patient might experience fatigue while on Zymfentra, and it is important to distinguish between them with your healthcare provider.

Direct medication side effect

While not among the most frequently cited adverse reactions in clinical trials, fatigue and malaise were reported in postmarketing experience with the subcutaneous infliximab product. This suggests that for some individuals, the medication itself or the process of injecting a biologic may lead to tiredness.

Signal of an underlying medical issue

Fatigue can also be a symptom of more serious health issues that are associated with Zymfentra use. For this reason, it is crucial to report unusual tiredness to your doctor promptly.

Serious Infections: Zymfentra can lower the immune system's ability to fight infections, increasing the risk of serious infections that could lead to hospitalization or death. Fatigue, fever, and flu-like symptoms are common signs of an infection.
Anemia: Low red blood cell levels, or anemia, are reported as a potential side effect and can cause unusual weakness and fatigue.
Heart Failure: New or worsening congestive heart failure has been reported with TNF blockers, and common symptoms include fatigue, shortness of breath, and swelling in the legs and feet.
Liver Injury: In rare cases, infliximab products have been linked to serious liver problems. Extreme fatigue, fever, jaundice, and abdominal pain are signs of liver injury.
Lupus-like Syndrome: A lupus-like syndrome can develop, with symptoms including joint pain, rash, and fatigue.

Chronic inflammation and IBD-related fatigue

Patients with chronic inflammatory diseases like Crohn's and ulcerative colitis frequently experience fatigue, even when their symptoms are well-controlled. This can be due to the persistent low-grade inflammation, poor nutrient absorption from a damaged gut, or psychological stress related to managing a chronic illness. As a result, it can be challenging to determine if fatigue is from the medication, the underlying disease, or both. A study on biologics noted that almost half of patients reporting fatigue described it as occurring around the time of their injection, but also acknowledged that fatigue is a common baseline symptom of inflammatory conditions.

How Zymfentra's potential for fatigue compares to other biologics


Feature	Zymfentra (Infliximab-dyyb, subcutaneous)	Entyvio (Vedolizumab, subcutaneous)
Mechanism	TNF-alpha blocker, works systemically	Integrin receptor antagonist, gut-selective
Route	Subcutaneous injection	Subcutaneous injection
Fatigue	Reported as a postmarketing adverse event, can signal other issues	Listed as a more common, and sometimes post-injection, side effect
Other Common Side Effects	Headache, injection site reactions, abdominal pain, diarrhea, infections (including COVID-19)	Headache, nausea, joint pain, infections (including common cold), injection site reactions
Key Consideration	Systemic effect of TNF blockade could influence energy levels, especially in context of IBD.	Post-dosing fatigue has been specifically reported with vedolizumab, which has a gut-specific mechanism.

Managing fatigue while on Zymfentra

If you experience fatigue while taking Zymfentra, your first step should always be to discuss it with your healthcare provider. They can help determine the cause and develop an appropriate management plan.

Rule out complications: Your doctor will need to evaluate if the fatigue is a symptom of a serious side effect, such as infection, anemia, or a heart or liver issue.
Adjust dosage or timing: For some medications, shifting the timing of the dose can help. For example, if allowed by your doctor, taking the injection in the evening might help you sleep through the initial peak of tiredness. Never adjust your dose or timing without medical supervision.
Lifestyle modifications: Address lifestyle factors that can contribute to fatigue, such as sleep hygiene, stress management, and nutrition. Regular, moderate exercise, as tolerated and approved by your doctor, can sometimes help boost energy levels.
Treat the underlying disease: If disease activity is still contributing to your fatigue, further optimizing your IBD treatment plan may be necessary.
Monitor other symptoms: Keep a record of your fatigue levels along with any other symptoms you experience. This can help your doctor see patterns and determine if the fatigue is linked to other side effects or your IBD.

Conclusion

While Zymfentra is a valuable maintenance treatment for IBD, it can potentially cause fatigue, either directly or as a symptom of a more serious side effect. It is also important to remember that chronic diseases like Crohn's and ulcerative colitis cause fatigue on their own due to persistent inflammation. If you notice unusual or worsening tiredness after starting Zymfentra, immediate communication with your healthcare team is essential. By distinguishing between medication-induced, disease-related, and complication-related fatigue, your doctor can guide you toward effective management strategies to improve your quality of life. The ultimate goal is to maintain remission while minimizing side effects and addressing all factors that contribute to tiredness.

Frequently Asked Questions

Fatigue has been reported as a potential side effect of infliximab products, including the subcutaneous formulation Zymfentra, based on postmarketing experience. However, it is not listed among the most common adverse reactions reported in the main clinical trials for Zymfentra.

Yes. Chronic inflammatory conditions like Crohn's disease and ulcerative colitis are often associated with fatigue due to ongoing inflammation and other related symptoms. It can be difficult to distinguish between disease-related and medication-induced fatigue, which is why a medical evaluation is important.

You should contact your doctor immediately if you experience unusual or severe fatigue, especially if it is accompanied by other symptoms like fever, chills, abdominal pain, or swelling. This could be a sign of a serious infection or other complication.

Possibly, but you should only do so after consulting your healthcare provider. For some medications, adjusting the injection time, such as taking it in the evening, can help manage fatigue. However, any change to your medication schedule requires a doctor's approval.

Yes. Beyond fatigue, Zymfentra has serious warnings regarding an increased risk of infection, certain types of cancer, liver injury, heart failure, and neurologic reactions. It is important to review the boxed warnings and full prescribing information with your doctor.

While fatigue is reported with infliximab products in general, some studies have noted a pattern of fatigue occurring shortly after injection or infusion with biologics like infliximab. The specific impact on fatigue from the subcutaneous formulation (Zymfentra) versus intravenous (other infliximab products) may vary by individual.

In addition to a doctor's assessment, lifestyle strategies can help. These include maintaining good sleep hygiene, staying hydrated, eating a balanced diet, and engaging in regular, gentle exercise as tolerated. Managing the underlying IBD and stress levels is also crucial.