Short answer: Low blood sugar (hypoglycemia) is the most common Humulin R U-500 side effect, and the label says severe lows may develop as long as 18 to 24 hours after an injection. Other listed reactions are allergic and injection site reactions, skin pits or thickening, lumps under the skin, weight gain and swelling. The label gives no trial percentages. It has no boxed warning.
What Humulin R U-500 is approved for: Humulin R U-500 is a concentrated human insulin approved to improve blood sugar control in adults and children with diabetes who need more than 200 units of insulin per day (section 1). Its safety and effectiveness with other insulins or by insulin pump have not been determined (section 1.1).
Source
HUMULIN R U-500 (insulin human) injection, for subcutaneous use, prescribing information, Patient Information and Instructions for Use. Eli Lilly. DailyMed, version published September 2, 2026. DailyMed setid b60e8dd0-1d48-4dc9-87fd-e14675255e8c
No. The current Humulin R U-500 label has no boxed warning.
These are the label's own numbers from the Adverse Reactions section. Where the label compares with placebo (a dummy treatment), both columns are shown, so you can see how much more often a reaction happened on Humulin R U-500.
| Reaction | What the label says |
|---|---|
| Hypoglycemia | The most commonly observed adverse reaction in patients using insulin, including Humulin R U-500 |
| Allergic reactions | Severe, life-threatening generalized allergy, including anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, low blood pressure and shock |
| Lipodystrophy | Thickening (lipohypertrophy) or thinning (lipoatrophy) of fat at repeated injection sites; may affect absorption |
| Localized cutaneous amyloidosis | Lumps at the injection site; injecting into them has raised blood sugar, and switching to normal skin has lowered it |
| Injection site reactions | hematoma, pain, bleeding, redness, nodules, swelling, discoloration, itching, warmth and injection site mass |
| Weight gain | Attributed to the anabolic effects of insulin |
| Peripheral edema | Sodium retention and swelling, particularly when poor control is improved by intensified insulin |
| Immunogenicity | Anti-insulin antibodies may form and may require dose adjustment; the rate with Humulin R U-500 is unknown |
These reactions come from post-approval use. The label says it is not always possible to estimate their frequency, and it gives no percentages or placebo comparison.
Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of Humulin R U-500.
In a clamp study of 24 healthy obese volunteers, single doses of 50 and 100 units started acting in under 15 minutes on average and lasted a mean of 21 hours (range 13 to 24 hours).
The most common side effects listed for patients are low blood sugar, allergic reactions including injection site reactions, skin thickening or pits at the injection site, itching and rash.
The Warnings and Precautions part of the label lists these. Each line gives the label's heading and what it means in plain words.
Who should not use it. Humulin R U-500 is not used during an episode of low blood sugar, or by people allergic to it or its ingredients.
Never share a pen. A KwikPen is never shared, even if the needle is changed, because of the risk of passing on blood-borne infections.
Changes in insulin regimen. Changing insulin strength, maker, type, injection site or method can cause high or low blood sugar, so changes are made under close supervision with more glucose checks.
Low blood sugar, including late lows. Hypoglycemia is the most common reaction to insulin, and severe episodes can cause seizures or death. With Humulin R U-500, severe lows may develop as long as 18 to 24 hours after an injection. Awareness of lows may be reduced with long diabetes, nerve damage, beta-blockers or repeated lows.
Never draw it into a syringe. U-500 is 5 times as concentrated as U-100 insulin. The KwikPen shows the actual units with no conversion, and drawing insulin from the pen into a syringe can cause overdose and severe low blood sugar.
Serious allergic reactions. Severe, life-threatening whole-body allergy, including anaphylaxis, can occur; Humulin R U-500 is stopped if it does.
Low potassium. All insulins shift potassium into cells and can cause low potassium, which untreated can cause breathing paralysis, heart rhythm problems and death.
Heart failure with TZDs. Thiazolidinediones (such as pioglitazone) with insulin can cause fluid retention that may lead to or worsen heart failure.
From the Patient Information that comes with Humulin R U-500:
Dose Track has a side-effect log. Each entry records the symptom, a severity (none, mild, moderate, severe or life-threatening), the date and an optional note, and can be tied to a specific dose or logged on its own. The history screen shows what you logged over time, which makes it easier to tell your prescriber when a reaction started and whether it is easing. The app records what you enter; it does not judge whether a symptom is serious. For anything on the label's call-your-doctor list, call your doctor.
This page is what the FDA label says, in plain words. It is not medical advice. Follow your prescriber, and ask them or your pharmacist about anything here.