Depo-SubQ Provera 104 Side Effects: What to Expect and When to Call Your Doctor

Depo-SubQ Provera 104 is a highly effective contraceptive and endometriosis treatment, but like all medications, it comes with a side effect profile that patients should know before starting. This guide covers everything from expected changes in your menstrual cycle to serious warnings you must not ignore — including the December 2025 meningioma update.

The Most Common Side Effect: Changes to Your Period

The side effect most patients notice first is a change in their menstrual bleeding pattern. This is expected and not dangerous for most women. Here's what typically happens:

First 2–3 months: You may have more days of bleeding or spotting than usual.

After 6–12 months: Periods often become irregular, lighter, or disappear entirely. By the end of 1 year, many women stop having periods.

After stopping: Your period will return eventually, though it may take several months to over a year. Fertility may also be delayed.

Other Common Side Effects of Depo-SubQ Provera 104

Weight gain: Studies showed an average gain of 3–4 pounds in the first year and 7–8 pounds after 2 years of use.

Headaches: Mild to moderate headaches are commonly reported, particularly in the first few months.

Mood changes / depression: Some patients experience mood changes, low mood, or worsened depression. If you have a history of depression, inform your provider and watch for any changes.

Decreased libido: Reduced sex drive has been reported by some users.

Abdominal discomfort: Mild bloating or cramping may occur, particularly after the injection.

Injection site reactions: Dimpling, indentation, lump/nodule, or skin discoloration at the injection site have been reported. These are more common with subcutaneous injections and may persist.

Fluid retention: Progestins can cause fluid retention; patients with conditions like heart disease or kidney problems should discuss this with their provider.

The Black Box Warning: Bone Mineral Density Loss

Depo-SubQ Provera 104 carries a

black box warning regarding bone mineral density (BMD) loss. Long-term use causes BMD loss that may not be completely reversible, increasing the risk of osteoporosis and fractures later in life, especially after menopause. This is why the FDA recommends using it for no longer than 2 years unless no adequate alternatives exist.

Adolescents using this medication during a critical bone-building period may face additional risks. Talk to your provider about calcium supplementation, vitamin D intake, and weight-bearing exercise to support bone health while on this medication.

The December 2025 FDA Update: Meningioma Risk

In December 2025, the FDA updated the Depo-SubQ Provera 104 label to include a warning about a possible increased risk of meningioma — a typically benign brain tumor — associated with long-term use. The risk appears to be primarily associated with use of 1+ years, with the highest odds identified in studies after 4+ years of use. Key things to know:

The absolute risk of meningioma is still low for most patients.

Depo-SubQ Provera 104 is already recommended for use no longer than 2 years — consistent with the meningioma risk timeline.

The drug must be discontinued if a meningioma is diagnosed.

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Serious Side Effects: When to Call Your Doctor Immediately

Seek immediate medical care if you experience any of the following:

Blood clot symptoms: Sudden leg pain or swelling, chest pain, shortness of breath, coughing up blood, or sudden vision problems.

Possible meningioma symptoms: New persistent headaches, changes in vision, hearing loss or ringing in the ears (tinnitus), new onset of seizures, or changes in memory.

Allergic reaction: Swelling of the mouth, lips, face, or throat; hives; trouble breathing. Serious anaphylaxis has been reported — seek emergency care immediately.

Severe abdominal pain: May indicate ectopic pregnancy if pregnancy occurs while using Depo-SubQ Provera 104. Contact your provider right away.

Jaundice (yellowing of skin or eyes): May indicate liver problems. Discontinue and contact your provider.

Side Effects Are Not a Reason to Skip Your Next Injection

If you're experiencing side effects that concern you, talk to your provider before stopping. Stopping without a plan can leave you without contraceptive protection or endometriosis pain management. If you're looking for your next injection, medfinder can help you locate which pharmacies near you have it in stock.

Also see: Depo-SubQ Provera 104 Drug Interactions: What to Avoid and What to Tell Your Doctor.