Raloxifene (Evista)

What is Raloxifene (Evista)?

Raloxifene was developed by Eli Lilly. The US FDA approved it in 1997 for preventing osteoporosis in postmenopausal women, later for treating it, and in 2007 for reducing the risk of invasive breast cancer. It is now widely available as a low-cost generic.

Raloxifene belongs to a group of medicines called selective estrogen receptor modulators (SERMs), the same family as tamoxifen and clomiphene. It is not a hormone, not hormone replacement therapy (HRT) and not a steroid. It is sometimes described as a "designer estrogen" because it was built to keep estrogen's benefits for bone while avoiding its effects on breast and womb.

Chemical structure and composition

Raloxifene's benzothiophene core sets it apart from tamoxifen, which has a triphenylethylene structure. This difference is a key reason raloxifene does not stimulate the lining of the womb the way tamoxifen can.

Only about 2% of a swallowed dose reaches the bloodstream unchanged, because the liver and gut quickly attach sugar-like molecules to it (glucuronidation). The drug then cycles between the gut and liver, which helps explain its long half-life and once-daily dosing.

How does Raloxifene work?

Estrogen acts through estrogen receptors found in many tissues. After menopause, estrogen falls, and bone loss speeds up. Simply replacing estrogen protects bone but can stimulate breast and womb tissue. Raloxifene gets around this by acting differently depending on the tissue.

Why does it act differently in each tissue?

When raloxifene binds to the estrogen receptor, it changes the receptor's shape in a particular way. Each tissue has its own mix of helper proteins (co-activators and co-repressors) that respond to that shape. In bone, the combination switches estrogen-like genes on; in breast, it switches them off. This tissue-selective behavior is what the "selective" in SERM refers to.

What results can be expected?

In the large MORE trial of women with osteoporosis, raloxifene reduced the risk of new spine fractures by about 30 to 50% over three years, depending on whether women already had a fracture. It did not significantly reduce hip or other non-spine fractures. In the same and follow-up studies, the risk of invasive breast cancer fell substantially.

In the STAR trial, raloxifene was compared with tamoxifen for breast cancer prevention in high-risk women. Raloxifene was somewhat less effective at preventing invasive breast cancer over the long term, but caused fewer womb cancers, fewer blood clots and fewer cataracts.

Uses of Raloxifene

Raloxifene does not treat existing breast cancer and does not completely remove breast cancer risk. It also has some off-label uses, for example in boys with persistent pubertal breast enlargement (gynecomastia), under specialist care.

Who is it for?

• Postmenopausal women with osteoporosis or low bone density, especially if spine fractures are the main concern
• Postmenopausal women at higher risk of breast cancer, such as those with a strong family history or certain biopsy findings
• Women who want bone protection plus breast cancer risk reduction and who have a low risk of blood clots and stroke
• Women who cannot take or prefer to avoid other osteoporosis medicines such as bisphosphonates

For women whose main worry is hip fracture, other medicines such as bisphosphonates or denosumab are usually preferred, because raloxifene has not been shown to protect the hip.

Who should not take it?

• Women with a current or past blood clot (deep vein thrombosis, pulmonary embolism or retinal vein thrombosis)
• Women who are pregnant, may become pregnant, or are breastfeeding
• Premenopausal women
• Women with existing heart disease or at high risk of stroke, unless the doctor judges benefits clearly outweigh risks
• People allergic to raloxifene or any tablet ingredient
• Men, except in specialist off-label use

How to take Raloxifene

Raloxifene is simple to take: one 60 mg tablet by mouth, once a day, at any time of day, with or without food.

Calcium and vitamin D

Raloxifene works best when the body has enough building materials for bone. Most women are advised to get enough calcium (from diet and, if needed, supplements) and vitamin D. Your doctor will suggest amounts that suit you.

Practical tips

• Link your daily dose to a routine, such as breakfast or brushing your teeth.
• Missed dose: take it as soon as you remember the same day. If it is almost time for the next dose, skip the missed one. Never take two tablets at once.
• Before long periods of immobility (surgery, long hospital stays, bed rest), you may be told to stop raloxifene at least 3 days beforehand to lower clot risk. Restart only when you are fully mobile again, as your doctor advises.
• On long journeys, walk around and move your legs regularly.
• Keep active with weight-bearing exercise and avoid smoking; both help bones and lower clot risk.
• Storage: room temperature, dry, out of reach of children.

Precautions, monitoring and interactions

Raloxifene carries a boxed warning, the most serious kind, for two risks: blood clots in the veins and lungs, and death from stroke in women who have heart disease or are at increased risk of heart problems. Your doctor will weigh these against your benefits before prescribing.

• Blood clots: the risk is highest in the first few months. Smoking, obesity, immobility and a personal or family history of clots all raise it further.
• Stroke: in the RUTH trial of women with or at high risk of heart disease, raloxifene did not reduce heart attacks and slightly increased the risk of fatal stroke.
• Heart disease: raloxifene should not be used to prevent heart disease.
• Liver problems: levels can rise in liver impairment; use with caution.
• High triglycerides: women whose triglycerides rose sharply on estrogen therapy should have levels checked, as raloxifene can raise them too.
• Unexplained vaginal bleeding: this is not expected on raloxifene and should be investigated.
• Breast changes: continue regular breast checks and mammograms; raloxifene lowers but does not remove cancer risk.

Monitoring

Drug interactions

Sports and drug testing

Raloxifene, like other SERMs, is on the World Anti-Doping Agency (WADA) list of hormone and metabolic modulators, banned at all times. Athletes need a Therapeutic Use Exemption for medical use.

Side effects of Raloxifene

Most women take raloxifene without serious problems, but side effects are common, especially in the first months.

Common side effects

• Hot flashes (more likely in the first 6 months)
• Leg cramps, often at night
• Swelling of the hands, ankles or feet (peripheral edema)
• Flu-like symptoms
• Joint pain
• Sweating

Less common side effects

• Headache, including migraine
• Nausea or stomach upset
• Rash
• Breast tenderness
• Gallbladder problems
• Raised triglycerides

Managing common problems

Serious side effects

Get emergency help right away for:

• Pain, swelling, warmth or redness in one leg (possible deep vein thrombosis)
• Sudden shortness of breath, chest pain or coughing up blood (possible pulmonary embolism)
• Sudden change or loss of vision (possible clot in the eye)
• Sudden weakness or numbness on one side, face drooping, confusion or trouble speaking (possible stroke)
• Severe allergic reaction with swelling of the face or throat
• Unexplained vaginal bleeding

Raloxifene compared with other options

Compared with HRT, raloxifene does not stimulate the breast or womb and does not relieve menopause symptoms (it can worsen hot flashes). Compared with tamoxifen, it causes fewer womb cancers and clots. Compared with bisphosphonates, it does not protect the hip as well but adds breast cancer risk reduction.

Legal status

Raloxifene is a prescription-only medicine in the United States, United Kingdom, European Union, India, Australia, Canada and most other countries. It is not a controlled substance. Products sold online "for research" or for bodybuilding are unregulated and may not contain what the label says.

Conclusion

Raloxifene (Evista) is a once-daily 60 mg tablet that helps postmenopausal women in two ways: it protects the spine from osteoporosis fractures and lowers the risk of invasive breast cancer. It does this by acting like estrogen on bone while blocking it in breast and womb tissue. Its main risks, blood clots and, in women with heart disease, fatal stroke, mean it is not right for everyone, and it does not protect the hip as well as some other bone medicines. For the right woman, with calcium, vitamin D, exercise and regular reviews, it is a well-studied and useful option. Talk to your doctor to see whether it fits your health and goals.