Premphase 28 Day Side Effects: What You Need to Know

Premphase 28 Day is a hormone replacement therapy (HRT) that combines Conjugated Estrogens with Medroxyprogesterone Acetate to treat menopause symptoms like hot flashes, night sweats, and vaginal dryness. Like all hormone therapies, it comes with potential side effects — some mild and temporary, others that need immediate medical attention.

This guide covers the most common and serious side effects based on FDA labeling, who may be at higher risk, and when you should contact your doctor right away.

What Is Premphase 28 Day?

Premphase 28 Day is a 28-day oral tablet kit made by Pfizer. It uses a two-phase approach: for the first 14 days, you take a maroon tablet containing 0.625 mg of Conjugated Estrogens alone. For days 15 through 28, you take a light-blue tablet containing 0.625 mg Conjugated Estrogens plus 5 mg Medroxyprogesterone Acetate. This phased design mimics a more natural hormone cycle while protecting the uterine lining from the effects of unopposed estrogen.

For a deeper dive into how this medication works, see our guide on how Premphase 28 Day works.

Common Side Effects

The following side effects are reported most frequently in clinical trials. Many of these are mild and may improve as your body adjusts to the medication over the first few weeks or months:

• Headache — One of the most commonly reported side effects. Over-the-counter pain relievers like Acetaminophen or Ibuprofen can help.
• Breast pain or tenderness — Especially common during the first few months of treatment. Usually decreases over time.
• Abdominal pain — Mild stomach discomfort or cramping may occur.
• Back pain — Some women experience new or worsening back pain.
• Nausea — Taking the tablet with food may help reduce nausea.
• Flatulence — Gas and bloating are common but typically not severe.
• Depression or mood changes — Hormone therapy can affect mood. If you notice persistent sadness or mood swings, tell your doctor.
• Weakness (asthenia) — Feeling unusually tired or weak.
• Dysmenorrhea — Menstrual-like cramps or irregular bleeding, especially in the early months.
• Vaginal discharge (leukorrhea) — An increase in vaginal discharge is possible.
• Itching (pruritus) — Mild skin itching that usually resolves on its own.

Serious Side Effects

Premphase 28 Day carries a boxed warning — the FDA's most serious warning category — about several major health risks. While these side effects are less common, they can be life-threatening:

• Blood clots (deep vein thrombosis and pulmonary embolism): Estrogen-progestin therapy increases the risk of blood clots in the legs (DVT) and lungs (PE). Symptoms include sudden leg swelling, pain, shortness of breath, or chest pain. Seek emergency care immediately.
• Stroke: The Women's Health Initiative (WHI) study found an increased risk of stroke in women taking estrogen plus progestin therapy. Warning signs include sudden numbness, confusion, trouble speaking, or severe headache.
• Heart attack (myocardial infarction): The WHI also reported increased risk of heart attack. Seek emergency care for chest pain, pressure, or pain radiating to the arm or jaw.
• Invasive breast cancer: Long-term use of estrogen plus progestin therapy has been associated with an increased risk of breast cancer. Regular mammograms and breast self-exams are important.
• Probable dementia: In women 65 and older, the WHI Memory Study (WHIMS) found an increased risk of probable dementia with estrogen plus progestin therapy.
• Gallbladder disease: Estrogen therapy increases the risk of gallbladder disease requiring surgery.
• Severe hypercalcemia: In women with cancer and bone metastases, estrogen therapy may cause dangerously high calcium levels.
• Cholestatic jaundice: Yellowing of the skin or eyes with dark urine can indicate liver problems.
• Visual abnormalities: Retinal vascular thrombosis can cause sudden vision changes. Report any sudden vision loss or changes immediately.

Who May Be at Higher Risk

Certain groups face additional concerns when taking Premphase 28 Day:

• Women 65 and older: Higher risk of probable dementia and stroke with estrogen-progestin therapy.
• Women with a history of blood clots: Premphase 28 Day is contraindicated if you have a history of DVT, PE, stroke, or heart attack.
• Women with a history of or active breast cancer: This medication is contraindicated in known or suspected breast cancer.
• Women with liver disease: Hepatic impairment is a contraindication due to the risk of cholestatic jaundice.
• Women with clotting disorders: Protein C, Protein S, or Antithrombin deficiency increases the risk of blood clots.
• Pregnant or breastfeeding women: Premphase 28 Day is not indicated during pregnancy or lactation. Estrogen decreases the quantity and quality of breast milk.

For a complete list of who should not take this medication, see our post on what is Premphase 28 Day.

How to Manage Common Side Effects

Many side effects of Premphase 28 Day are manageable and tend to improve over time. Here are some practical tips:

• For headaches: Stay hydrated, maintain a regular sleep schedule, and use over-the-counter pain relief as needed.
• For nausea: Take your tablet with a meal or a snack. If nausea persists, talk to your doctor about timing adjustments.
• For breast tenderness: Wear a supportive bra and consider reducing caffeine. This side effect often improves after the first 2 to 3 months.
• For mood changes: Track your mood and share patterns with your doctor. Regular exercise, adequate sleep, and stress management can help.
• For bloating and gas: Eat smaller meals, avoid carbonated drinks, and stay physically active.
• For irregular bleeding: Some spotting or breakthrough bleeding is normal in the first few months. If it continues beyond 3 to 6 months, let your doctor know.

The general FDA guideline for HRT is to use the lowest effective dose for the shortest duration needed. If side effects are bothersome, your doctor may be able to adjust your treatment plan or explore alternatives to Premphase 28 Day.

When to Call Your Doctor

Contact your doctor or seek emergency care if you experience any of the following while taking Premphase 28 Day:

• Sudden leg swelling, warmth, or pain (possible blood clot)
• Shortness of breath or chest pain (possible pulmonary embolism or heart attack)
• Sudden severe headache, numbness, confusion, or trouble speaking (possible stroke)
• Sudden vision changes or loss
• Yellowing of the skin or eyes (jaundice)
• New breast lumps
• Severe abdominal pain
• Persistent or heavy vaginal bleeding beyond the first few months

Final Thoughts

Most women who take Premphase 28 Day experience only mild side effects that improve over time. However, the serious risks — particularly blood clots, stroke, and breast cancer — are real and important to understand before starting treatment. Work closely with your doctor to monitor your health, attend regular check-ups, and report any new or unusual symptoms promptly.

If you're ready to fill your prescription, Medfinder can help you check which pharmacies have Premphase 28 Day in stock.