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Research · Medication

Benzopyrones

A Cochrane review of 15 benzopyrone trials for limb lymphedema could not draw conclusions because the trials were poorly reported. An Australian crossover trial found less limb swelling on coumarin. A US trial in 140 women found no difference from placebo, with liver test changes in 6%. Australia cancelled coumarin medicines after 10 liver reactions, 2 of them fatal.

Add to Bio HackChecked 2026-11-09
Status
Not FDA-approved for any use in the US. In Australia, coumarin was a prescription medicine for lymphedema from July 1993, and its registration was cancelled about three years later after liver reactions were reported.
Also called
coumarin, 5,6-benzo-alpha-pyrone, 5,6 BaP, 1,2-benzopyrone, benzo-pyrones, Lodema, Lympedim
Taken for
lymphedema, swelling, arm swelling after breast cancer, leg swelling, edema

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help0

No benefit shown in research yet.

Reported risks3

What people take it for, and what was found

Mixed results1

Limited

Lymphedema of the arms and legs

Small trials found opposite results: coumarin reduced excess limb fluid in one crossover, while a trial in 140 women after breast cancer found no change in arm volume.

The numbers and sources
Effect
A Cochrane review included 15 trials, 8 of them of coumarin. Meta-analysis was not done because of poor trial quality, and the authors could not draw conclusions about limb volume, pain or discomfort [1]. In a crossover trial of 400 mg a day against placebo for six months each, coumarin reduced excess arm fluid from 46% to 26% above normal and excess leg fluid from 25% to 17% (p < 0.001), and 93% of patients preferred it [2]. In 140 women with arm lymphedema after breast cancer, 200 mg twice a day against placebo for six months each did not change arm volume. The affected arm grew by 21 mL during placebo and 58 mL during coumarin (P 0.80), and 15% on coumarin against 10% on placebo said the medication helped a moderate or large amount (P 0.19) [3]. A 2022 review of lymphedema drug trials noted that earlier meta-analyses had cast doubt on the positive benzopyrone results [4].
Population
31 people with arm lymphedema after mastectomy and 21 with leg lymphedema in Australia [2]. 140 women with arm lymphedema after breast cancer treatment in the US [3]. Trials in the Cochrane review included five in India or China that added anti-filarial drugs [1].
Sources
[1], [2], [3], [4]
Caveats
The two most detailed trials reached opposite results [2][3]. Three trials in the Cochrane review involved the same researcher [1]. The Australian trial authors note this coumarin is not an anticoagulant [2].

Risks

Reported risks3

LimitedVery common

Nausea and diarrhea

One small trial found mild nausea or diarrhea in 7 of 52 patients during coumarin, which stopped after the first month.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In the Australian trial, mild nausea or diarrhea occurred in 7 patients on coumarin. None withdrew, and the effects stopped after the first month [2].
Population
52 patients with limb lymphedema [2].
Sources
[2]
Caveats
One small trial.
ModerateCommon

Liver toxicity

Shown to raise blood test signs of liver toxicity in 6% of women in one trial. French case reports include one liver transplant and two likely deaths.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In the US trial, 6% of women had blood test evidence of liver toxicity on coumarin [3]. A French pharmacovigilance survey reviewed 34 cases of raised liver enzymes up to June 1996 and judged 15 likely or probably caused by coumarin. ALT exceeded 10 times normal in 68%, 41% were hospitalized, one needed a liver transplant and two others likely died of liver failure [5]. A woman in Sri Lanka developed abnormal liver tests on Lympedim that led to stopping the drug [6]. A risk assessment found that clinical data reveal a subgroup of people more susceptible to coumarin's liver toxicity than the animals studied, and derived a tolerable daily intake of 0.1 mg per kg of body weight [7].
Population
140 women in an RCT [3]. Case reports to French regional centers and the manufacturer [5]. A single case [6].
Sources
[3], [5], [6], [7]
Caveats
Most French cases occurred 2 to 6 months into treatment at about 90 mg a day [5]. The cause of the higher susceptibility in some people is not known [7].
ModerateHow often is not known

Withdrawal from the market

Australia cancelled coumarin medicines for lymphedema about three years after approval, after ten liver events including two deaths. France and other countries also withdrew it.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Coumarin became available in Australia as a prescription treatment for lymphedema in July 1993. Ten liver adverse events, including two deaths, were reported to the Australian Drug Evaluation Committee, and the registration of coumarin medicines was cancelled about three years after they became available. Products applied to the skin were cancelled shortly after [8]. Coumarin was also withdrawn from the market in France and other countries for liver toxicity [9]. A 2007 review describes it as banned in some countries [10].
Population
Regulatory actions in Australia [8], France and other countries [9][10].
Sources
[8], [9], [10]
Caveats
The Australian regulator's 2019 review dates the cancellation by citing a 1996 World Health Organization source [8].

Claims tested and not found

  1. That coumarin reduces arm lymphedema after breast cancer treatment. In 140 women, arm volume and symptom questionnaires did not differ from placebo over six months [3].

Sources

  1. Badger C, Preston N, Seers K, Mortimer P. Benzo-pyrones for reducing and controlling lymphoedema of the limbs. Cochrane Database of Systematic Reviews. 2004. https://doi.org/10.1002/14651858.CD003140.pub2
  2. Casley-Smith JR, Morgan RG, Piller NB. Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone. New England Journal of Medicine. 1993. https://doi.org/10.1056/NEJM199310143291604
  3. Loprinzi CL, Kugler JW, Sloan JA, et al. Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. New England Journal of Medicine. 1999. https://doi.org/10.1056/NEJM199902043400503
  4. Walker J, Tanna S, Roake J, Lyons O. A systematic review of pharmacologic and cell-based therapies for treatment of lymphedema (2010-2021). Journal of Vascular Surgery: Venous and Lymphatic Disorders. 2022. https://doi.org/10.1016/j.jvsv.2021.09.004
  5. Andréjak M, Gersberg M, Sgro C, et al. French pharmacovigilance survey evaluating the hepatic toxicity of coumarin. Pharmacoepidemiology and Drug Safety. 1998. https://pubmed.ncbi.nlm.nih.gov/15073959/
  6. Satarasinghe RL, Jayawardana MA. Lympidem (a coumarin derivative) induced reversible hepatotoxicity in an adult Sri Lankan. Drug Metabolism and Drug Interactions. 2009. https://doi.org/10.1515/dmdi.2009.24.1.89
  7. Abraham K, Wöhrlin F, Lindtner O, et al. Toxicology and risk assessment of coumarin: focus on human data. Molecular Nutrition & Food Research. 2010. https://doi.org/10.1002/mnfr.200900281
  8. Therapeutic Goods Administration. Safety review: coumarin for use in topical listed medicines. Version 1.0. 2019. https://www.tga.gov.au/sites/default/files/safety-review-coumarin-listed-medicines.pdf
  9. Pitaro M, Croce N, Gallo V, et al. Coumarin-Induced Hepatotoxicity: A Narrative Review. Molecules. 2022. https://doi.org/10.3390/molecules27249063
  10. Farinola N, Piller NB. CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients? Pharmacogenomics. 2007. https://doi.org/10.2217/14622416.8.2.151

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