Tamoxifen

Is tamoxifen safe?

For women with oestrogen-receptor-positive breast cancer, tamoxifen is one of the most effective and best understood medicines in oncology, and its benefits outweigh its risks; even the US boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary says so. In a pooled analysis of 20 trials and 21,457 women, five years of tamoxifen cut breast cancer deaths by about a third over the following 15 years.

The risks are real but uncommon: womb cancer, blood clots and stroke, each affecting a few women per thousand per year, mostly over 50. Hot flushes are the side effect most women actually notice. The catch most people never hear about is an interaction: some common antidepressants, including paroxetine and fluoxetine, can blunt its effect.

We score tamoxifen 69. A lower score than drugs like statins does not mean it is a poor choice. It reflects a powerful hormone drug with a boxed warning, and the decision to take it or stop it belongs with your oncology team.

Tamoxifen and antidepressants: the CYP2D6 problem

Tamoxifen itself is fairly weak. The liver turns it into endoxifen, which the US Soltamox label says binds the oestrogen receptor about 100 times more strongly, and the key enzyme for that step is CYP2D6CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary. Drugs that strongly block CYP2D6 lower endoxifen by 65 to 75%, according to the UK label, which adds that people born with little working CYP2D6 also have lower endoxifen levels.

Whether that changes outcomes has been argued over since the mid-2000s. A 2010 study of 2,430 Ontario women on tamoxifen found that the more of their treatment overlapped with paroxetine, the higher the risk of dying of breast cancer: 25%, 50% and 75% overlap went with 24%, 54% and 91% higher risk. Other SSRIs showed no such link. A later study found no effect, but the MHRA concluded that the mechanism and overall evidence were strong enough to act on.

The UK label advises avoiding these strong CYP2D6 blockers whenever possible:

• paroxetine and fluoxetine (antidepressants)
• bupropion (an antidepressant and smoking-cessation drug)
• quinidine (a heart rhythm drug)
• cinacalcet (for parathyroid disease)

The US Soltamox label is more cautious in tone, saying the effect is "not well established", but does not dispute the drop in endoxifen. Prescribers usually choose an antidepressant with little effect on CYP2D6 instead. Do not stop an antidepressant abruptly; ask your doctor about switching.

Womb cancer, clots and stroke

Tamoxifen blocks oestrogen in the breast but mimics it in the womb lining, which explains the main serious risk. The US label gives these rates from the NSABP P-1 prevention trial, per 1,000 women a year:

The extra womb cancers were seen mainly in women aged 50 and over. The UK label says women under 50 in the prevention trials had no extra womb cancer or lung clots. Almost all were early-stage, and 29 of the 33 in the first analysis were found in women who had symptoms, which is why any unexpected vaginal bleeding needs checking.

Clots in the legs and lungs are two to three times more likely on tamoxifen, says the UK label, and more so with chemotherapy, obesity, age and immobility. The labels also list cataracts, liver changes, low platelet counts and, rarely, severe skin reactions. The UK label also warns that it can prolong the QT intervalQT prolongationA delay in the heart's electrical recovery between beats, seen on an ECG. Some medicines cause it, and in rare cases it leads to a serious heart rhythm problem.More in the glossary on an ECG.

Hot flushes and day-to-day side effects

In the NSABP B-14 trial, hot flushes affected 64% of women on tamoxifen against 48% on placebo, vaginal discharge 30% against 15%, and irregular periods 25% against 19%. The US label describes most side effects as relatively mild and rarely severe enough to stop treatment, though in practice many women find years of hot flushes hard going. In men with breast cancer, loss of libido and erectile problems have led some to stop.

Overdose and dependence

Tamoxifen has a wide margin. The labels describe no overdose deaths; very high doses in cancer trials caused tremor, unsteadiness and dizziness that cleared after stopping. It is not addictive and has no withdrawal syndromeDrug dependenceThe body's adaptation to a drug taken regularly, so that stopping it suddenly causes withdrawal symptoms. It is not the same as addiction.More in the glossary. Get medical advice after any large overdose: Poison Help on 1-800-222-1222 in the US, NHS 111 in the UK.

Who should be careful

Talk to your doctor or pharmacist before starting tamoxifen, or adding a medicine to it, if you:

• take an antidepressant, especially paroxetine, fluoxetine or bupropion
• take warfarin, whose effect tamoxifen strongly increases (for prevention, the labels rule the combination out)
• have had a clot in a leg or lung, or have a family history of clots
• are booked for surgery or a long period of immobility
• could become pregnant
• have a heart rhythm problem or take QT-prolongingQT prolongationA delay in the heart's electrical recovery between beats, seen on an ECG. Some medicines cause it, and in rare cases it leads to a serious heart rhythm problem.More in the glossary drugs

How we scored it

Track record (97), dependence (98) and overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (88) are strong. Serious side effects (50) reflect womb cancer, clots and stroke, uncommon but sometimes fatal, and the boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary holds regulatory warnings at 40. Interactions (55) reflect the CYP2D6CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary antidepressants and warfarin.