Short answer: In the label's endometriosis trials, the most common Lupron Depot 3.75 mg side effects were hot flashes or sweats (84% vs 29% on placebo), headache (32% vs 6%), vaginitis (28% vs 0%), depression or mood swings (22% vs 3%) and general pain. Many reflect low estrogen. It has no boxed warning; loss of bone density, which limits treatment length, is its first listed risk.
What Lupron Depot 3.75 mg is approved for: Lupron Depot 3.75 mg is a GnRH agonist approved to manage endometriosis, including pain relief and shrinking lesions, alone or with norethindrone acetate add-back; and, with iron, to improve blood counts before surgery in women with anemia from fibroids when 3 months of hormone suppression is needed (sections 1.1 and 1.2). This page covers only the 3.75 mg monthly gynecologic label, not the 11.25 mg or prostate cancer labels.
Source
LUPRON DEPOT 3.75 mg (leuprolide acetate for depot suspension), for intramuscular use, prescribing information. AbbVie. DailyMed, version published September 22, 2025. DailyMed setid 00c486b0-bd7b-4898-834d-8c656e5e73cb
No. The current Lupron Depot 3.75 mg 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 Lupron Depot 3.75 mg.
| Adverse reaction | LUPRON DEPOT 3.75 mg (%) N=166 | Danazol (%) N=136 | Placebo (%) N=31 |
|---|---|---|---|
| Hot flashes/sweats* | 84 | 57 | 29 |
| Headache* | 32 | 22 | 6 |
| Vaginitis* | 28 | 17 | 0 |
| Depression/emotional lability* | 22 | 20 | 3 |
| General pain | 19 | 16 | 3 |
| Weight gain/loss | 13 | 26 | 0 |
| Nausea/vomiting | 13 | 13 | 3 |
| Decreased libido* | 11 | 4 | 0 |
| Dizziness | 11 | 3 | 0 |
| Acne | 10 | 20 | 0 |
| Skin reactions | 10 | 15 | 3 |
| Joint disorder* | 8 | 8 | 0 |
| Edema | 7 | 13 | 3 |
| Paresthesias | 7 | 8 | 0 |
| GI disturbances* | 7 | 6 | 3 |
| Neuromuscular disorders* | 7 | 13 | 0 |
| Breast changes/tenderness/pain* | 6 | 9 | 0 |
| Nervousness* | 5 | 8 | 0 |
Reactions marked * are a possible effect of decreased estrogen. Danazol is another endometriosis medicine used as a comparator; the placebo group was small (31 women).
| Adverse reaction | LUPRON DEPOT 3.75 mg (%) N=166 | Placebo (%) N=163 |
|---|---|---|
| Hot flashes/sweats* | 73 | 18 |
| Headache* | 26 | 18 |
| Vaginitis* | 11 | 2 |
| Depression/emotional lability* | 11 | 4 |
| Asthenia | 8 | 5 |
| General pain | 8 | 6 |
| Joint disorder* | 8 | 3 |
| Edema | 5 | 1 |
| Nausea/vomiting | 5 | 4 |
| Nervousness* | 5 | 1 |
Reactions marked * are a possible effect of decreased estrogen. Asthenia means weakness or lack of energy.
| Adverse reaction | Controlled study LD-Only (%) N=51 | Controlled study LD/N (%) N=55 | Open-label study LD/N (%) N=136 |
|---|---|---|---|
| Hot flashes/Sweats | 98 | 87 | 57 |
| Headache/Migraine | 65 | 51 | 46 |
| Depression/Emotional Lability | 31 | 27 | 34 |
| Insomnia/Sleep Disorder | 31 | 13 | 15 |
| Nausea/Vomiting | 25 | 29 | 13 |
| Pain | 24 | 29 | 21 |
| Vaginitis | 20 | 15 | 8 |
| Asthenia | 18 | 18 | 11 |
| Dizziness/Vertigo | 16 | 11 | 7 |
| Weight Gain | 12 | 13 | 4 |
| Decreased Libido | 10 | 4 | 7 |
| Androgen-Like Effects (acne, alopecia) | 4 | 5 | 18 |
LD-Only = Lupron Depot 3.75 mg alone; LD/N = Lupron Depot 3.75 mg plus norethindrone acetate 5 mg daily (add-back). No placebo group.
Lumbar spine bone density over 52 weeks: -6.3% on Lupron Depot 3.75 mg alone vs -1.0% with norethindrone add-back (controlled study) and -1.1% (open-label study) (Table 9). Twelve months after stopping, it was still -2.2% in the Lupron-only group (Table 10).
In women with fibroids, 3 months of Lupron Depot 3.75 mg lowered spinal bone density by a mean 2.7%, with a trend toward recovery 6 months after stopping.
In the 6 monotherapy studies, 1.8% stopped early because of hot flashes. In the 1-year add-back studies, 18% stopped in each arm of the controlled study and 13% in the open-label study.
Serious adverse reactions: urinary tract infection (1.9%), kidney stone (0.7%) and depression (0.7%).
Lipids: triglycerides rose above normal in 12% of women with endometriosis. With norethindrone add-back, HDL cholesterol fell about 15% to 19% at week 24 and the LDL/HDL ratio rose about 39% to 43% (Table 6); levels returned to baseline after treatment.
Reported after approval across Lupron Depot products: serious skin reactions, anaphylaxis, mood swings including suicidal thoughts, convulsions, serious liver injury, spinal fracture, blood clots, heart attack, stroke and pituitary apoplexy (often within 2 weeks of the first dose).
The Warnings and Precautions part of the label lists these. Each line gives the label's heading and what it means in plain words.
Loss of bone mineral density. Lupron Depot 3.75 mg causes a low-estrogen state that reduces bone density, and some loss may not reverse after stopping. Treatment length is limited for this reason. For endometriosis, norethindrone add-back reduces the loss; retreatment is only with add-back, after a bone density check.
Harm to an unborn baby. It may cause fetal harm and is contraindicated in pregnancy. Pregnancy is excluded before starting if clinically indicated. It is not a contraceptive; a non-hormonal method is advised if contraception is needed (section 8.3).
Severe skin reactions. Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS and AGEP have been reported with GnRH agonists, including Lupron Depot. It is stopped if one is suspected and not restarted if confirmed.
Allergic reactions. Anaphylaxis has been reported. Asthma events occurred in women with past asthma, sinusitis or allergies.
Initial flare of symptoms. After the first dose, sex hormones briefly rise above baseline, so symptoms may get worse in the first days before easing with continued treatment.
Convulsions. Seizures have been reported after approval in women on GnRH agonists, with and without other medicines or conditions.
Depression. Depression may start or worsen, especially with a history of depression. Women are watched closely, and new or worsening depression may lead to referral.
From the Patient Counseling Information (section 17) that comes with Lupron Depot 3.75 mg:
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.