Letrozole

Is letrozole safe?

For women past the menopause with hormone-sensitive breast cancer, letrozole is a safe, thoroughly tested treatment, and it avoids the womb cancer and clot risks that come with tamoxifen. What it does instead is take oestrogen almost to zero, which thins bones, raises cholesterol and makes joints ache. In BIG 1-98, a trial of 8,010 women, about 15 in 100 on letrozole had a fracture over roughly eight years, against 11 in 100 on tamoxifen.

There are few interactions, an overdose of the tablets is not known to be dangerous, and it is not addictive. The one firm rule is pregnancy: letrozole is contraindicatedContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary, which matters because fertility clinics use it widely off-label.

We score letrozole 81, the same as anastrozole and well above tamoxifen's 69.

Letrozole vs tamoxifen: BIG 1-98 and MA.17

BIG 1-98 compared five years of letrozole with five years of tamoxifen, or a switch from one to the other after two years. Early on, letrozole cut disease-free survival events by 21%. After 12.6 years of follow-up the gap had narrowed to 9% and was no longer clearly significant, partly because many women on tamoxifen crossed over to letrozole once the first results were out.

The side effects, from the US label at a median of 96 months:

MA.17 tested letrozole against placebo in 5,187 women who had already finished five years of tamoxifen. It was stopped early because letrozole worked: four-year disease-free survival was 93% against 87%. Across all trials, the EBCTCG found aromatase inhibitors cut 10-year breast cancer deaths by about 15% compared with tamoxifen.

Bones, cholesterol and the heart

In a two-year bone study, the spine lost a median 4.1% of its density on letrozole while it held steady on tamoxifen. The UK label asks for a bone density scan before treatment in women at risk and treatment for osteoporosis when needed. Raised cholesterol was reported in 52% of women on letrozole against 29% on tamoxifen, almost all of it mild, and 29% needed cholesterol-lowering drugs.

The heart signal is real but small. A 2021 analysis of BIG 1-98 found more ischaemic heart disease on letrozole than on tamoxifen (hazard ratio 1.81), while tamoxifen carried twice the risk of clots. Part of the gap may come from tamoxifen lowering cholesterol (by about 10–20%, says the UK tamoxifen label) rather than from letrozole raising risk. The authors advised weighing past heart problems when choosing.

Joint and muscle pain is the reason most women give up. In a US study of 503 women starting letrozole or exemestane, 32% stopped within two years because of side effects, 24% because of joint and muscle symptoms. Tendonitis, trigger finger and, rarely, tendon rupture are on the UK label.

Letrozole for fertility and the 2005 birth-defect scare

Letrozole lowers oestrogen briefly, which makes the brain release more of the hormones that ripen an egg. That is why fertility clinics use a short course early in the cycle to trigger ovulation, mainly in polycystic ovary syndrome. Neither the US nor the UK label includes this use, and Novartis told Canadian doctors in 2005 that it is outside the licence.

In 2005, a Montreal clinic reported major birth defects in 4.7% of 150 babies conceived after letrozole, against 1.8% in more than 36,000 births at a local hospital. Novartis, with Health Canada, then wrote to doctors on 17 November 2005 that the drug is contraindicatedContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary before the menopause and that ovulation induction is outside its licence. Fertility specialists criticised the study for comparing older infertile women with young fertile ones.

Later evidence was reassuring. A Canadian study of 911 newborns found major malformations in 1.2% after letrozole against 3.0% after clomiphene. A US trial of 750 women with polycystic ovary syndrome found more live births with letrozole (27.5% against 19.1%) and no significant difference in birth defects. The labels still forbid letrozole during pregnancy, and the US label notes post-marketing reports of miscarriage and birth defects.

Overdose, interactions and misuse

Isolated overdoses of up to 25 tablets caused no serious reactions. There is no antidote, so care is supportive. Get advice after any large overdose: Poison Help on 1-800-222-1222 in the US, NHS 111 in the UK.

Tamoxifen lowers letrozole levels by 38%, and oestrogen-containing medicines can blunt it. The UK label urges caution with drugs cleared by CYP2C19CYP450 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 or CYP2A6 that have a narrow margin, such as phenytoin and clopidogrel. Letrozole is not addictive, but it is sold illegally alongside steroids. In March 2018 a Llanelli man was jailed for 40 months for selling unlicensed letrozole, tamoxifen, steroids and painkillers across the EU, after an MHRA investigation. WADA bans it in sport.

Who should be careful

Talk to your oncology team or pharmacist before starting letrozole, or adding a medicine to it, if you:

• may not be past the menopause, or could become pregnant
• have osteoporosis, past fractures or other risks for weak bones
• have heart disease or high cholesterol
• have cirrhosis or severe liver disease, which roughly doubles exposure
• take HRT, vaginal oestrogen, phenytoin or clopidogrel
• drive for a living and feel tired or dizzy on it

A lower score than some everyday medicines is no reason to stop letrozole. Any change belongs with your oncology team.

How we scored it

Dependence (98), track record (95) 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 (92) are strong, and interactions (83) are few. Serious side effects (60) reflect fractures, joint pain and a small heart signal, offset by fewer clots and womb cancers than tamoxifen. Regulatory warnings (76) reflect the pregnancy contraindicationContraindicationA situation in which a medicine should not be used, because the risk clearly outweighs any benefit, such as a known allergy to it.More in the glossary and the 2005 warning about fertility use.