Letter Concerning Recent Warnings About Drug Interactions with St. John's Wort

March 2, 2000

Jane Henney, M.D., Commissioner

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20854

Dear Dr. Henney:

British physicians and patients are now being forcefully warned--for many more drugs than American physicians or patients--about potentially serious, clinically important drug interactions between the unregulated herbal St. John's Wort (Hypericum perforatum) and a large number of prescription drugs. For ten widely-used drugs or classes of drugs, the British government's Committee on the Safety of Medicines is warning doctors and patients to stop the use of St. John's Wort in people using any of these drugs and urging that patients be warned not to start the use of St. John's Wort if they are already using these prescription drugs. For some of these drugs, however, patients are urged to see their pharmacist or doctor before stopping St. John's Wart as the dose of the prescription medicine may need to be altered to prevent adverse effects.

The United Kingdom's Committee on Safety of Medicines warned on February 29, 2000 that St. John's Wort should not be used with the following list of widely used prescription drugs because of the possible serious consequences:

  • carbamazepine (Tegretol)
  • citalopram (Celexa)
  • cyclosporin (Sandimmune, Neoral)
  • digoxin (Lanoxin)
  • fluoxetine (Prozac)
  • fluvoxamine (Luvox)
  • naratriptan (Amerge)
  • oral contraceptives
  • paroxetine (Paxil)
  • phenobarbital (Luminal)
  • phenytoin (Dilantin)
  • rizatriptan (Maxalt)
  • sertraline (Zoloft)
  • sumatriptan (Imitrex)
  • theophylline (Theo-Dur and many others)
  • warfarin (Coumadin)
  • zolmitriptan (Zomig)

We have reprinted immediately following the Committee on Safety of Medicines warnings sent to doctors and pharmacists for your reference:

Fact Sheet for Health Care Professionals

Table 1 Clinically Important Interactions of SJW

Drug

Effect of interaction on drug

Suggested management of patients already taking SJW preparations

HIV protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir)

Reduced blood levels with possible loss of HIV suppression.

Measure HIV RNA viral load and stop SJW.

HIV non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine)

Reduced blood levels with possible loss of HIV suppression.

Measure HIV RNA viral load and stop SJW.

Warfarin

Reduced anticoagulant effect and need for increased warfarin dose.

Check INR and stop SJW. Monitor INR closely as this may rise on stopping SJW. The dose of warfarin may need adjusting.

Cyclosporin

Reduced blood levels with risk of transplant rejection.

Check cyclosporin blood levels and stop SJW. Cyclosporin levels may increase on stopping SJW. The dose of cyclosporin may need adjusting.

Oral contraceptives

Reduced blood levels with risk of unintended pregnancy and breakthrough bleeding.

Stop SJW.

Anticonvulsants (carbamazepine, phenobarbitone, phenytoin)

Reduced blood levels with risk of seizures.

Check anticonvulsant levels and stop SJW. Anticonvulsant levels may increase on stopping SJW. The dose of anticonvulsant may need adjusting.

Digoxin

Reduced blood levels and 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.

Theophylline

Reduced blood levels and loss of control of asthma or chronic airflow limitation.

Check theophylline levels and stop SJW. Theophylline levels may increase on stopping SJW. The dose of theophylline may need adjusting.

Triptans (sumatripan, naratripan, rizatripan, zolmitripan)

Increased serotonergic effects with increased incidence of adverse reactions.

Stop SJW.

SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Increased serotonergic effects with increased incidence of adverse reactions.

Stop SJW.

 

Patients taking drugs listed in Table 1 should not start taking SJW preparations

Notes:

1. The action of many other drugs depends on their rate of metabolism and thus other drugs may also interact with St. John's Wort preparations.

2. St. John's Wort preparations are unlikely to interact with topical medicines with limited systemic absorption and non-psychotropic medicines which are excreted renally.


FACT SHEET FOR THE PUBLIC

Important Safety information for people taking St. John's Wort preparations

St. John's Wort (SJW) preparations are unlicensed herbal remedies. Their levels of active ingredients can vary from one preparation to another. They are widely used in the U.K. being available from pharmacies, health food shops, and herbal practitioners. St. John's Wort preparations may interfere (interact) with medicines, stopping them from working properly. If you are taking medicines, it may not be safe for you to take St. John's Wort preparations. The advice in the box is provided below to help you understand how this may affect you.

I am currently taking a St. John's Wort preparation, and I am not taking any medicine(s).

Advice: If you buy a medicine from a pharmacy or are prescribed by your doctor, you must tell your pharmacist or doctor about the St. John's Wort preparation.


I am already taking medicine(s) but I would like to take the St. John's Wort preparation.

Advice: You must not take a St. John's Wort preparation until you have checked with your pharmacist or doctor that it is safe for you to do so.


Epilepsy or fits: I am on tablets for epilepsy/fits and I am also taking a St. John's Wort preparation.

Transplants: I am on tablets following a transplant and I am also taking a St. John's Wort preparation.

Asthma or chronic bronchitis: I am on theophylline tablets for my chest and I am also taking a St. John's Wort preparation.

Heart condition: I am taking digoxin for a heart condition and I am also taking a St. John's Wort preparation.

Blood clots: I am taking warfarin to thin my blood and I am also taking a St. John's Wort preparation.

Advice for patients with any of these conditions: You will need to stop taking the St. John's Wort preparation as it may stop your medicine from working properly. However, you should see your pharmacist or doctor before stopping the St. John's Wort preparation as the dose of your medicine may need to be altered to prevent side effects.


Contraceptive pill: I am on the pill and I am also taking a St. John's Wort preparation.

Advice: You should stop taking the St. John's Wort preparation as it may stop your pill from working. Continue to take your contraceptive pill as normal. There is no need to see your pharmacist or doctor urgently, however, mention it when you next consult your doctor or are dispensed with a medicine.


Migraine: I take treatment for migraine and am also taking a St. John's Wort preparation.

Depression: I am on treatment for depression and am also taking a St. John's Wort preparation.

Advice: You should stop taking the St. John's Wort preparation as it may stop your medicine from working. There is no need to see your pharmacist or doctor urgently, however, mention it when you next consult your doctor or are dispensed with a medicine.


HIV: I am HIV positive and am also taking a St. John's Wort preparation.

Advice: You should stop taking the St. John's Wort preparation and see your doctor who may suggest you have your HIV viral load checked.


I am currently taking both a St. John's Wort preparation and a prescribed medicine not mentioned above.

Advice: Tell your pharmacist or doctor that you are taking a St. John's Wort preparation when you are next dispensed with a medicine or consult your doctor.



  • It is important to always tell your pharmacist or doctor about any herbal remedy or over the counter medicine that you are taking.
  • For further information, call NHS Direct on 08 45 46 47.

We are aware from the Food and Drug Administration's (FDA) February 10, 2000 Public Health Advisory that the agency has contacted manufacturers to add warnings to the professional product labeling of indinavir (Crixivan) and other antiretroviral drugs used to treat AIDS that when these drugs are used in combination with St. John's Wort the blood concentrations of the AIDS drugs may be significantly decreased. In the same letter, in a short paragraph entitled "Other Drugs", FDA mentioned categories of drugs, but not specific drugs which could have harmful interactions with St. John's Wort:

Other drugs 

Based on this study and reports in the medical literature, St. John's Wort appears to be an inducer of an important metabolic pathway, cytochrome P450. As many prescription drugs used to treat conditions such as heart disease, depression, seizures, certain cancers or to prevent conditions such as transplant rejection or pregnancy (oral contraceptives) are metabolized via this pathway, health care providers should alert patients about these potential drug interactions to prevent loss of therapeutic effect of any drug metabolized via the cytochrome P450 pathway.

Seeking labeling changes only for the antiretroviral drugs as indicated in FDA's February 10th Advisory is an insufficient response to a serious public health hazard. We strongly urge the FDA to immediately issue a warning to American physicians and patients about all of these drugs and require warnings be included in the labeling for the above listed drugs about the potentially serious consequences that can result when St. John's Wort is used in combination with any of the drugs listed above.

Once viewed as the gold standard for drug regulation, FDA's image and reality have been not only tarnished but corroded. It is the United Kingdom, but not the United States, which has taken Rezulin and Halcion off the market and which now moves more swiftly and definitively concerning the harmful or potentially harmful effects of interactions between St. John's Wort and the large number of drugs listed above.

We hope for an immediate response to this urgent situation.



Sincerely,

Sidney M. Wolfe, M.D.

Director

Public Citizen's Health Research Group

Larry D. Sasich, Pharm.D., M.P.H

Public Citizen's Health Research Group

cc:

Janet Woodcock, M.D., Director

Center for Drug Evaluation and Research (HFD-001)

Murray M. Lumpkin, M.D. , Deputy Center Director (Review Management)

Center for Drug Evaluation and Research (HFD-002)

Susan Alpert, Ph.D., M.D., Director of Food Safety

Center for Food Safety and Applied Nutrition