Zilretta is FDA-approved as a single injection, and its label explicitly states it is “not intended for repeat administration.” In practice, however, many doctors do give a second injection based on data from a phase 3b clinical study that found two injections spaced roughly 12 to 24 weeks apart were well tolerated with no unexpected safety concerns. Understanding the gap between the official label and real-world practice is key to knowing what to expect.
What the FDA Label Says
The FDA approved Zilretta as a one-time, 32 mg injection into the knee for osteoarthritis pain. The prescribing information includes a clear limitation: the efficacy and safety of repeat administration “have not been evaluated” as part of the original approval process. This means the drug was technically approved for a single use, and the label has not been updated to reflect repeat dosing.
That said, an FDA label limitation is not the same as a ban. It signals that repeat use wasn’t part of the pivotal trials that led to approval. Doctors can still prescribe Zilretta again based on their clinical judgment and the evidence that has emerged since.
Evidence on a Second Injection
A phase 3b open-label study enrolled 208 patients to specifically test whether a second Zilretta injection was safe and effective. Of those patients, 86% received a second injection. The median time between injections was about 16.6 weeks, with individual patients receiving their second dose anywhere from roughly 11 to 27 weeks after the first. The study allowed patients to choose a second injection at week 12, 16, 20, or 24 based on when their pain returned.
Both injections were well tolerated. Adverse event rates were actually slightly lower after the second injection (35%) than after the first (41%). Most side effects were mild, unrelated to the drug itself, and resolved without intervention. Importantly, X-rays taken at 52 weeks showed no signs of cartilage destruction, bone death, stress fractures, or significant bone changes beneath the joint surface. These are the serious joint complications that doctors watch for with repeated steroid use.
Pain relief from the second injection was comparable to the first. About 85% of patients saw at least a 30% improvement in pain scores four weeks after their second dose, and roughly 68% achieved a 50% or greater improvement. Those numbers were only slightly lower than after the first injection, suggesting the drug doesn’t lose much effectiveness the second time around.
How Long Each Injection Lasts
Zilretta uses tiny biodegradable microspheres (about 45 micrometers across) to release the steroid gradually over approximately 12 weeks. These microspheres are too large to escape the joint through the small gaps between cells, so the medication stays concentrated where it’s needed rather than flooding into your bloodstream.
In clinical trials, patients experienced at least a 50% reduction in pain from weeks 2 through 16. By comparison, a standard steroid injection hit that same threshold only at week 6. Around 20% of patients still reported zero pain at week 16. Most people can expect meaningful relief for about three to four months, though the exact duration varies.
This timeline is why the repeat-dosing study spaced injections 12 to 24 weeks apart. Once the microspheres have fully dissolved and pain returns, a second injection becomes a reasonable consideration.
What This Means for Yearly Limits
There is no published guideline setting a maximum number of Zilretta injections per year. The only formal clinical data covers two injections over 52 weeks. No studies have evaluated three or more injections in the same knee.
Based on the available evidence, the practical ceiling is roughly two to three injections per knee per year if each dose lasts 12 to 16 weeks. But most doctors will be cautious about exceeding two doses annually, since that is the extent of what has been studied. Repeated corticosteroid exposure in a joint, regardless of formulation, carries a theoretical risk of accelerating cartilage breakdown over time, and Zilretta has only been cleared of that concern through one year of data with two injections.
Insurance and Coverage Considerations
Because the FDA label says Zilretta is not intended for repeat administration, insurance coverage for a second injection can be inconsistent. Some payers, including certain Medicaid programs, follow the label language strictly and authorize only a single injection. Medicare coverage varies by local carrier, and prior authorization requirements are common.
If your doctor recommends a repeat injection, their office may need to submit clinical justification or appeal an initial denial. The phase 3b safety data supporting a second dose can strengthen that case, but approval is not guaranteed. It’s worth asking your provider’s billing team about your plan’s specific policy before scheduling.
Lower Blood Sugar Impact for Diabetic Patients
One reason some patients and doctors prefer Zilretta over a standard steroid injection is its reduced effect on blood sugar. In a phase 2 study of patients with both knee osteoarthritis and type 2 diabetes, Zilretta raised average blood glucose levels by about 15 mg/dL over the first three days, compared to 34 mg/dL for a standard steroid injection. Patients who received Zilretta spent about 63% of those three days in a healthy blood sugar range (70 to 180 mg/dL), versus only 50% for those who received the standard formulation.
This matters for repeat dosing because each injection carries a smaller metabolic cost. If you have diabetes and are considering a second Zilretta injection, the blood sugar disruption is likely to be modest, though you should still monitor your levels closely in the days following any corticosteroid injection.