Most Zilretta side effects are mild and resolve within a few days to a couple of weeks. Because Zilretta is an extended-release formulation, its active ingredient (triamcinolone acetonide) stays in the knee joint much longer than a standard cortisone shot, which means some effects can linger longer than you might expect from a typical injection. Here’s what to expect and when side effects should clear.
Why Zilretta’s Side Effects Differ From Standard Cortisone
Zilretta uses tiny microspheres to release its steroid slowly into the joint over weeks, rather than dumping it all at once. FDA pharmacology reviews show measurable drug levels inside the joint at 12 weeks after a single injection, with concentrations dropping below detectable levels by week 16 to 20. A standard cortisone injection, by comparison, is essentially gone from the joint within a few weeks.
The tradeoff is that Zilretta produces far less systemic exposure. Peak blood levels of the steroid are roughly 91% lower than those from a standard triamcinolone injection, and total early systemic exposure is about 90% lower. That means whole-body side effects like sleep disruption and mood changes are less likely with Zilretta, though they can still happen.
Joint Pain and Swelling After the Injection
Some people experience a “post-injection flare,” meaning the knee gets more swollen or painful in the first day or two after the shot. This is one of the most commonly reported reactions. It typically settles down within 24 to 72 hours as the initial irritation from the injection itself resolves. Icing the knee and resting it during this window usually helps.
Joint swelling was one of the adverse reactions reported in at least 1% of patients during Zilretta’s clinical trials. If swelling persists beyond a few days, worsens significantly, or comes with redness and warmth, that pattern is worth a call to your doctor since it can overlap with signs of joint infection, which is rare but serious.
Systemic Effects: Sleep, Mood, and Blood Sugar
Because some of the steroid does reach the bloodstream, you may notice effects beyond the knee. Corticosteroids as a class can cause insomnia, mood swings, irritability, or a jittery “wired” feeling. Zilretta’s prescribing information lists these as possible corticosteroid-related reactions, though its clinical trials found that the overall rate and type of adverse reactions were similar to placebo. In practice, when these effects do occur, they tend to be milder than with a standard cortisone shot because of the lower systemic dose.
The timing is different, though. A study in patients with type 2 diabetes found that blood sugar elevations peaked later with Zilretta compared to a standard injection: the median time to hit peak glucose was 34 hours with Zilretta versus 13 hours with the standard shot. And glucose took a median of 44 hours to reach a threshold of 250 mg/dL, compared to just 6 hours with standard cortisone. So if you have diabetes and notice blood sugar changes, they may be more gradual in onset but stretch out over several days rather than spiking sharply on day one. Plan to monitor your glucose a bit more closely for the first week after your injection.
For people without diabetes, any systemic steroid effects like poor sleep or mood shifts typically fade within one to two weeks as the initial burst of systemic absorption tapers off.
Less Common Side Effects
The most frequently reported side effects in Zilretta’s clinical trials, each occurring in at least 1% of patients, were sinus infections, cough, bruising at the injection site, and joint swelling. These are generally short-lived. Bruising fades over one to two weeks. A sinus infection or cough, if related to mild immune suppression from the steroid, resolves on its own timeline but isn’t unique to Zilretta.
Rare but serious allergic reactions, including anaphylaxis, are possible with any injectable corticosteroid. Symptoms like a rash, swelling of the face or throat, difficulty breathing, or trouble swallowing would appear within minutes to hours of the injection and require immediate emergency care.
What Repeat Injections Mean for Side Effects
A Phase 3b trial followed 208 patients who received one Zilretta injection, 179 of whom went on to get a second shot (the median gap between injections was about 16.6 weeks). The study found no evidence of cumulative harm. X-ray data collected over a full year showed no signs of bone damage, cartilage loss, stress fractures, or accelerated joint narrowing. The side effect profile after the second injection was consistent with what was seen after the first.
This matters because repeated standard cortisone injections carry a well-known concern about cartilage damage over time. Zilretta’s extended-release design keeps the drug concentrated locally while limiting repeated systemic surges, which appears to reduce that structural risk, at least over the one-year follow-up period studied.
A Practical Timeline
- First 1 to 3 days: Post-injection flare (increased pain or swelling at the knee) is most likely during this window and usually resolves on its own.
- First 1 to 2 weeks: Systemic effects like sleep changes, mood shifts, or blood sugar fluctuations, if they occur, generally peak and taper during this period.
- Weeks 2 to 6: Lingering mild effects should be resolving. The drug is still active in the joint and providing pain relief, but side effects from systemic absorption have largely cleared.
- Weeks 12 to 20: Drug levels in the joint gradually drop below measurable thresholds. Any joint-related effects tied to the medication itself should be gone by this point.
If any side effect persists beyond two weeks, worsens instead of improving, or feels severe at any point, that’s a reasonable threshold for contacting your prescriber. Most people, however, find that Zilretta’s side effects are both milder and shorter-lived than what they’ve experienced with standard cortisone injections.