Publications

Published: April 2000

Interactions with St. John's Wort (Hypericum perforatum) Preparations

Prescriber Update 20: 42-48
April 2000

Medsafe Editorial Team

Complementary healthcare products containing St John's wort are available through direct marketing and from pharmacies, health food shops, supermarkets and complementary healthcare practitioners. They are used for a variety of conditions including the symptoms of depression. A number of clinical trials published in peer reviewed journals have commented favourably on the safety and efficacy of products containing standardised extracts of this botanical substance.

A recently published study1 found a clinically significant reduction in serum levels of indinavir, a protease inhibitor used to treat HIV infection, when it was used with a St John's wort preparation. A second article2 described two cases of heart transplant rejection in patients taking St John's wort with cyclosporin. There had previously been individual reports suggesting interactions with other medicines may be occurring. There have, however, been no reported deaths associated with use of St John's wort.

Why do St John's wort preparations interact with other medicines?

It appears that St John's wort preparations may interact with medicines either by increasing the rate of their metabolism or increasing levels of neurotransmitters. The effect on metabolism appears to occur by induction of certain cytochrome P450 isoenzymes in the liver and gut (particularly CYP 3A4, but also 1A2 and 2C9) reducing the blood levels and effectiveness of some medicines.

Many medicines, including carbamazepine and phenytoin, are potent enzyme inducers which act at the CYP 3A4 site. Several naturally occurring substances including grapefruit juice, red wine and broccoli have also been found to have effects on these enzyme systems.3

St John's wort may also increase the levels in the brain of the neurotransmitter serotonin by an additive or potentiating effect on other medicines. Medicines which may interact with St John's wort in this way include the selective serotonin reuptake inhibitor (SSRI) antidepressants (e.g. fluoxetine, paroxetine), other antidepressants affecting serotonin levels (e.g. nefazodone), and some migraine treatments (e.g. sumatriptan, naratriptan). These additive interactions may result in a variety of symptoms such as mental state changes, autonomic dysfunction (sweating, increased blood pressure) and motor effects consistent with increased serotonin.

Which medicines interact with St John's wort?

The table below lists medicines for which there is varying degrees of evidence of a possible interaction with St John's wort. For some (e.g. cyclosporin, warfarin, indinavir, carbamazepine) the loss of clinical effectiveness is potentially serious. The table gives an indication of the nature and strength of the evidence of interaction, describes the effect of an interaction should it occur, and provides advice on the management of patients. For some of the medicines listed there is at present no more than a theoretical possibility of interaction.

The table is not exhaustive, but it covers the information available to date. Other medicines not included in this list therefore may also interact with St John's wort preparations. In general, the following medicines are not likely to interact with St John's wort preparations:

How should patients be managed?

The levels of active ingredients within products containing St John's wort may vary from batch to batch and from one preparation to another. The degree of interaction with prescribed medicines may also vary. Hence, for some conditions the table advises discontinuing St John's wort. For these patients, in light of the currently available information, it is not advisable to attempt to stabilise them on suitable doses of a St John's wort preparation and the medication treating the condition.

When patients stop taking St John's wort preparations, the loss of enzyme induction may result in increased blood levels of interacting medicines possibly leading to toxicity. Any toxicity may take several days to present.

Those who need to stop St John's wort should have the management of their depression reviewed.

Reporting suspected interactions

Medical practitioners and pharmacists are asked to report suspected interactions, and adverse reactions, to St John's wort to the Centre for Adverse Reactions Monitoring, University of Otago, PO Box 913, Dunedin. Copies of the reporting form can be obtained from the Centre at the above address or can be downloaded from this web site.

 

MEDICINES INTERACTING WITH ST JOHN'S WORT (SJW)

Patients taking these medicines should not start taking St John's wort preparations without seeking medical advice
Medicine Evidence base Evidence and effect of interaction Suggested management of patients already taking St John's wort preparations
HIV protease inhibitors
(indinavir, nelfinavir, ritonavir, saquinavir)
Strong A clinical study has demonstrated reduced blood levels with possible loss of HIV suppression. Measure HIV RNA viral load and stop SJW. Review management of depression.
Immunosuppressants
(cyclosporin, tacrolimus)
Strong Case reports have demonstrated reduced blood levels with transplant rejection. Check cyclosporin or tacrolimus blood levels and stop SJW. Levels may increase on stopping SJW. The dose of immunosuppressant may need adjusting. Review management of depression.
HIV non-nucleoside reverse transcriptase inhibitors
(efavirenz, nevirapine, delavirdine)
Theoretical Reduced blood levels with possible loss of HIV suppression is theoretically possible. Measure HIV RNA viral load and stop SJW. Review management of depression
Warfarin Moderate Case reports of reduced anticoagulant effect and need for increased warfarin dose have been reported. Check INR and stop SJW. Monitor INR closely as this may rise on stopping SJW. The dose of warfarin may need adjusting. Review management of depression
Anticonvulsants (carbamazepine, phenobarbitone, phenytoin) Theoretical Reduced blood levels with risk of seizures theoretically possible. Check anticonvulsant levels and stop SJW. Anticonvulsant levels may increase on stopping SJW. The dose of anticonvulsant may need adjusting. Review management of depression
Digoxin Moderate Isolated case reports of reduced blood levels have been reported. Theoretical loss of control of heart rhythm or heart failure. Check digoxin levels and stop SJW. Digoxin levels may increase on stopping SJW. The dose of digoxin may need adjusting. Review management of depression.
SSRIs and related antidepressants
(citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, nefazodone)
Moderate Small numbers of case reports of increased serotonergic effects have been reported. Weigh the benefits of continuing SJW against possible adverse effects. Review management of depression.
Triptans  (sumatriptan, naratriptan, rizatriptan, zolmitriptan) Weak Increased serotonergic effects with increased chance of adverse reactions theoretically possible. Weigh the benefits of continuing SJW against possible adverse effects. Review management of depression.
Oral contraceptives Weak Small numbers of case reports of breakthrough bleeding, contraceptive failure theoretically possible but no case reports of contraceptive failure have been reported. Weigh the benefits of continuing SJW against theoretical possibility of reduced contraceptive efficacy. Review management of depression.
Theophylline Theoretical Reduced blood levels and loss of bronchodilator effect theoretically possible. Check theophylline levels and review use of SJW. Weigh the benefits of continuing SJW against possible adverse effects. Theophylline levels may increase on stopping SJW. The dose of theophylline may need adjusting. Review management of depression.

Note: Other medicines not included in this list may also interact with St John's wort.

A consumer leaflet is available on this site.  Copies were posted to general practitioners, selected specialists, community and hospital pharmacies, and complementary healthcare practitioners and retailers on 31 March 2000.

References
  1. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St. John's wort.  Lancet 2000;355:547-8.
  2. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart transplant rejection due to Saint John's wort.  Lancet 2000;355:548-9.
  3. A list of the many substances that have been demonstrated to produce interactions, due to effects on hepatic enzyme systems, can be found at http://www.dml.georgetown.edu/depts/pharmacology/davetab.html