Rates in the US, Canadian and European documents
The US table pools SURMOUNT-1 and SURMOUNT-2, two 72-week trials, and its footnote groups bruising, erythema (redness), pruritus (itching), pain, rash and the general term injection site reaction under one heading. [1] Canada prints the same pool with patient counts, adds a three-trial figure that includes SURMOUNT-3, and gives a much longer list of counted terms: haematoma, haemorrhage, hypersensitivity, induration, inflammation, irritation, oedema, paraesthesia and swelling at the site as well. [6] Zepbound® has no EU document; the European information for tirzepatide, sold there as Mounjaro®, reports its weight-management and sleep apnea trials separately. [7]
| Source and trial pool | Zepbound® or tirzepatide | Placebo |
|---|---|---|
| US label, Table 1, SURMOUNT-1 and -2 [1] | 5 mg 6% · 10 mg 8% · 15 mg 8% | 2% |
| Canadian monograph, Table 2, patients [6] | 5 mg 36 (5.7%) · 10 mg 77 (8.1%) · 15 mg 77 (8.2%) | 17 (1.8%) |
| Canada, SURMOUNT-1, -2 and -3 pooled [6] | 8.0% | 1.8% |
| EU, tirzepatide weight-management trials [7] | 8.0% | 1.8% |
| EU, tirzepatide sleep apnea trials [7] | 8.2% | 2.6% |
What a typical reaction looks like
Across tirzepatide’s phase 3 programme, redness and itching were the most frequent signs; the worst reaction a person had was mild for 91% and moderate for 9%, and none was classed as serious. [7] The examples Canada’s patient information expects a user to notice are rash, itching, irritation, pain and bruising. [6]
MedlinePlus says some soreness is expected after an injection under the skin. Redness, swelling, red streaks spreading from the spot or a fever are different: they suggest infection and are a reason to contact your provider. [10] The Zepbound® sleep apnea trials, with 467 adults, reported reactions similar to the weight trials and no separate site figure. [1][6]
Antibodies: an association, not a cause
Most people on Zepbound® made antibodies against tirzepatide: 64.5% (1,591 of 2,467) in the weight trials and 60.6% in the sleep apnea trials. [1] Neutralising antibodies against tirzepatide’s action at the GIP or GLP-1 receptor were uncommon in the weight trials, at 2.8% and 2.7%, and none were found in the sleep apnea trials. [1]
People with antibodies had injection site reactions far more often: 11.3% against 1% in the US pool, and 13.6% against 1.8% across four SURMOUNT trials in Canada. [1][6] Allergic-type reactions showed a smaller gap (6.2% against 3% in the US pool). [1] The label reports this as a difference between groups; it does not say antibodies cause the reactions, and it found no clinically significant effect of them on drug levels or on effectiveness. [1]
Three US devices, three sets of instructions
Each Zepbound® presentation has its own FDA-approved Instructions for Use. The steps below are the ones that bear on what happens at the skin.
| Step | Single-dose pen [3] | Single-dose vial with syringe [4] | KwikPen, 4 doses [5] |
|---|---|---|---|
| Where | Belly or thigh; back of upper arm by another person | Belly or thigh; another person can also use the back of the upper arm | Thigh or belly at least 2 inches from the navel; back of upper arm by another person |
| Needle | Built in; do not touch it | New syringe and needle every time; never share them | New pen needle every time; prime before each weekly dose |
| Holding | Press up to 10 seconds; done when the grey plunger shows | Leave the needle in at least 5 seconds after pushing the plunger | Push the knob in, count slowly to 5; the dose icon must show before removing |
| Blood on the skin | A drop of liquid or blood is normal; press with cotton or gauze, do not rub | Press with gauze, do not rub | Press lightly with gauze or cotton, do not rub |
Why the instructions keep moving the site
All three leaflets and the label ask you to change the injection site with every dose; you may stay in the same body area as long as the exact spot is new. [1][3][5] The vial leaflet gives the reason: rotating is meant to cut the chance of two skin changes, lipodystrophy (dents or thicker patches of skin) and localised cutaneous amyloidosis (lumps). [4] Canada’s patient information makes the same point in plain words, skin thinning, thickening or lumps. [6]
The vial leaflet also lists places to avoid: skin with pits, thickening or lumps; skin that is tender, bruised, scaly or hard; scars or damaged skin; and a site used for another medicine. Zepbound® is not to be mixed with any other medicine. [4] Choosing among the belly, thigh and upper arm does not change how much tirzepatide reaches the blood, according to the label’s pharmacology section. [1]
Benzyl alcohol in the multi-dose forms
The single-dose pen and single-dose vial contain tirzepatide with salt, a phosphate buffer and water. The multi-dose vial and the KwikPen, which each hold four doses, add preservatives: every dose contains 5.4 mg of benzyl alcohol, plus glycerin and phenol. [1]
In Canada, Zepbound® is supplied only as the KwikPen. Its monograph says benzyl alcohol may cause allergic reactions, lists allergy to it among reasons not to use Zepbound®, and asks that people with liver or kidney impairment be told about a possible build-up leading to metabolic acidosis; patients taking other benzyl alcohol medicines are asked to tell their healthcare professional. [6] None of the documents compares site reaction rates between the preserved and unpreserved forms.
Two more KwikPen rules are safety rules rather than skin rules: a KwikPen belongs to one person only, even with a fresh needle, since sharing can pass on blood-borne infections; and the KwikPen is not recommended for self-injection by people with visual impairment. [1][5]
Reports from outside the trials
A pharmacovigilance study of the US FDA reporting system covered 25,212 tirzepatide reports from mid-2022 to the end of 2023. Injection site haemorrhage, or bleeding, stood out with 1,610 reports and a reporting odds ratio of 27.8, and the authors described it as not previously listed; women reported injection site reactions more often than men. [8] Canada’s definition of an injection site reaction does include haemorrhage. [6] Spontaneous reports show that an event is reported more often than expected, not how many users are affected, and the abstract does not split results by brand or device.
One published case describes a man in his 70s who developed a rash on his lower abdomen after switching from dulaglutide to tirzepatide; it faded once tirzepatide was stopped. [9] A single case shows that a reaction can appear even after another GLP-1 medicine was tolerated, but it cannot show how often that happens.
Local reaction or allergy
An allergic reaction is counted separately from a site reaction. In the US pool, hypersensitivity reactions occurred in 5% on each dose against 3% on placebo, mostly rashes and itching; those within a day of the dose affected 2.1% against 0.4%. [1] Serious allergy, including anaphylaxis and angioedema, has been reported with tirzepatide, and anyone with a known serious hypersensitivity to it or to an ingredient must not use Zepbound®. [1]
The Medication Guide tells you to stop Zepbound® and get medical help right away for any of these: a very rapid heartbeat, fainting or dizziness, a severe rash or itch, trouble breathing or swallowing, or swelling of the lips, tongue, face or throat. [2] MedlinePlus describes anaphylaxis as an emergency that calls for 911 or local emergency services at once. [11]
None of the Zepbound® documents recommends a cream, tablet or ice for a site reaction. If you want to try something, ask a pharmacist or your prescriber first, and mention any reaction that keeps returning. [1][2]
Zepbound®, Mounjaro® and KwikPen® are registered trademarks of Eli Lilly and Company. PepLabo is not affiliated with or endorsed by Eli Lilly and Company.
When to get help
The signs and contact information below come from this article’s sourced guidance.
Emergency
- A swollen face, lips, tongue or throat; difficulty breathing or swallowing; fainting or a racing heartbeat
Contact: Stop Zepbound® and call emergency services (911 or local number)
- Severe rash or itching, especially away from the injection spot
Contact: Stop Zepbound® and get medical help right away
Medication Guide [2]
Today
- Redness or swelling that spreads, red streaks from the site, or fever
Contact: Your health care provider, the same day (possible infection)
MedlinePlus [10]
- The grey plunger or KwikPen dose icon is not showing and you are unsure the dose went in
Contact: Lilly (1-800-545-5979) or your prescriber; do not repeat the injection
At your next appointment
- Pits, thickened skin or lumps at sites you use
Contact: Your prescriber; avoid injecting there meanwhile
Vial Instructions for Use [4]; Canadian patient information [6]
- Liver or kidney problems, or other medicines with benzyl alcohol, while using the KwikPen
Contact: Your healthcare professional
Canadian monograph [6]
- Site reactions that keep coming back or bother you
Contact: Your prescriber
Medication Guide [2]