P&T News: Nov/Dec 1999
Barbara A. Mutnick, R.Ph., M.H.P.
Peer Review Status: Internally Peer Reviewed by
Howard R. Knapp, M.D., Professor and Director of Clinical
Pharmacology, Department of Internal Medicine
Total confidentiality is assured by not including the patient's name or registration number on the MedWatch form. Also, individual reporter's names are not included. If the FDA requires additional information, the name of the patient's physician is supplied only after permission for disclosure is received.
MedWatch Program and Newly Released Drugs
Clinical trials effectively assess efficacy and risk-benefit ratios, but they are generally not large enough or of long enough duration to provide all the information on a new drug's safety. Vigilant post-marketing surveillance must be performed by all health care professionals in order to continue the necessary monitoring of newly marketed agents. New data are used to update the prescribing information of recently approved agents. Table 1 lists some of the recent labeling changes in prescription products prompted by submission of adverse drug event reports to the MedWatch Program. Of note, three drugs (astemizole, grepafloxacin, and rotavirus vaccine) were withdrawn from the U.S. market due to serious adverse drug reactions, and a fourth drug (trovafloxacin/alatrofloxacin) now has limited distribution due to the potential to cause severe liver toxicity.
The Importance of Reporting Dietary Supplement Adverse
Events
In September, 1999, the University of Iowa was honored by a visit
from Jane Henney, M.D., the Commissioner of the Food and Drug
Administration. One of the points she stressed during her lecture was
the need for vigilant monitoring and reporting to the FDA of product
problems and adverse events caused by dietary supplements.
Dietary supplements include vitamins, herbs, other botanicals, amino acids, dietary substances to supplement the diet, and any concentrate, metabolite, constituent, extract, or combination of these agents.1
The reliance on alternative medicine or treatment known as "unconventional therapy" has grown tremendously in recent years in the U.S. Theories to explain the increase in these alternative forms of health care include:
1. Patient dissatisfaction with conventional treatments because of lack of effect, presence of adverse effects, or perceptions that such treatments are too impersonal, highly technical, or costly;2. The need for personal control is met by viewing the use of non-conventional therapy as more empowering to the patient;
3. Alternative forms of therapy tend to be attractive because they are seen as more compatible with patients' value systems.2
As with other non-traditional approaches to medicine, the dietary supplement industry has grown dramatically. Surveys indicate that more than half of the U.S. adult population uses dietary supplements, and in 1997 Americans spent $12.8 billion on these products.1
Regulation and Post-Marketing Surveillance of Dietary
Supplements
In 1994, the Dietary Supplement and Health Education Act (DSHEA)
was passed by the Congress to amend the Federal Food, Drug, and
Cosmetic Act in an attempt to regulate herbs, vitamins, and other
substances. Several provisions of the act apply only to dietary
supplements. DSHEA no longer requires these agents to undergo
premarketing safety evaluations that are required of other drugs;
yet, the Act allows manufacturers to make claims about nutritional
supplements that had previously only been allowed for drugs.3 Under
DSHEA, a dietary supplement is adulterated if it or one of its
ingredients presents "a significant or unreasonable risk of illness
or injury" when used as directed on the label or under normal
conditions. New dietary ingredients are considered adulterated when
there is inadequate information to provide reasonable assurance that
the ingredient will not present a significant or unreasonable risk of
illness or injury. Manufacturers of dietary supplements can not claim
that their products diagnose, prevent, mitigate, treat, or cure a
specific disease. They can, however, describe effects on the
"structure or function" of the body or the "well-being" achieved by
the product's use. Claims such as: "helps maintain cardiovascular
function" or "helps promote urinary tract health" are acceptable as
they do not contain express or implied references to specific
diseases. This type of description must be accompanied by a statement
that such claims have not been evaluated by the FDA. Companies
marketing a supplement with these types of claims are required to
notify the FDA within 30 days after a product bearing such a
statement has been marketed.3
Approval by the FDA to guarantee efficacy or safety is not required. Manufacturers must assure the safety of dietary supplements, but are not mandated to report problems to the FDA. Essentially, DSHEA places the burden on the FDA to prove that a product presents a significant or unreasonable risk of illness or injury under the label's conditions of use before it can be removed from the marketplace.4 Table 2 lists some recent FDA warnings about dietary supplements.
The Special Nutritional Adverse Event Monitoring System (SN/AEMS) was established in 1993 following the establishment of the Office of Special Nutritionals. The SN/AEMS system which is part of the Center for Food Safety and Applied Nutrition (CFSAN) provides a monitoring system for identifying potentially serious public health problems, but currently lacks many necessary tools. There is no premarketing testing database, no mandatory reporting by manufacturers, no registration of firms and product lists, no good manufacturing practice requirements, nor does a mature database system exist at their disposal.
In spite of the lack of a premarketing database, the SN/AEMS serves as a critical source of information about the safety of dietary supplements.4 Inherent strengths and weakness exist in the program. One strength is that of clinician contribution. Because of their involvement with patient care, health professionals can identify and document adverse events in the setting in which they occur and can provide in-depth information that is key to any post-marketing surveillance system.
One limitation of the system is underreporting; consumers and health professionals may not recognize the link between the use of a particular product and a subsequent injury or illness. This problem is compounded by the underreporting of the use of dietary supplements by many patients. A study conducted by patient interview demonstrated that less than 30% of people who sought remedies outside of conventional medicine informed their physicians of their use of these remedies.5,6 Health care providers must carefully question patients, encourage reporting of any alternative therapies, and be suspect of any drug or dietary supplement that may have been implicated in a harmful effect experienced by a patient.
Other limitations to post-marketing surveillance include questionable report quality because of the difficulty in assuring the reliability and validity of collected data. Unlike clinical trials, biases cannot be assessed and controlled for in post-marketing surveillance. Estimates of exposure population can not be arrived at with this type of data collection.
Some traditional herbal products display known toxicities (e.g., calamus, comfrey, and sassafras all have been shown to have carcinogenic actions). Other products,especially those from overseas, may contain such adulterants as lead, arsenic, mercury, or pesticides.1 Even drugs that are not toxic in themselves may potentiate or antagonize the actions of other drugs or dietary supplements (e.g., St. John's Wort interacts not only with another herbal product, Ma Huang, but also with OTC decongestants and prescription antidepressants). They may have other pharmacologic effects than those that are claimed on the label. For example, gingko biloba, which is sold to aid in mental alertness and concentration, also has an antiplatelet effect.
In addition to the lack of scientifically controlled trials to assess the claims of these products, safety and purity are also important issues. There is usually no proper dosing information, no standard measurement of active ingredients, no guarantee that all ingredients contained within the product are listed, and no real warnings or precautionary statements on the labeling.1 The FDA is in the process of publishing manufacturing standards for dietary supplements, but they are currently not available.
Patients who use dietary supplements should be encouraged to use products whose labeling include:7
But even adherence to these guidelines cannot assure that patients will be free from adverse events or drug-drug interactions. Prescribers must be vigilant to patients' use of these products, and along with the consumer and all health professionals, have a heightened awareness of the potential dangers associated with these untested products. Information about previously reported product problems can be viewed on the SN/AEMS web report at http://vm.cfsan.fda.gov/~aemsfull.html. Any reported problems with dietary supplements are forwarded to the SN/AEMS via the FDA's MedWatch program.
Any suspected adverse reactions in UIHC patients should be reported to the UIHC Adverse Drug Reaction Reporting program. Please contact the Department of Pharmaceutical Care Drug Information Center for assistance in reporting adverse reactions associated with the use of dietary supplements or other medications.
References
1. Ann Intern Med 1999;131:161-3.
2. JAMA 1998;279:1548-53.
3. Am J Health Sys Pharm 1998;55:1239-40.
4. The FDA Home Page (resource on World Wide Web). URL:http:www.verity.fda.gov/search 97c. Available from Internet. Accessed 1999 Nov 30.
5. N Engl J Med 1993;328:246-52.
6. Mayo Clin Proc 1999;74:531-2.
7. South Dakota J Med 1999;52:53-4.
DRUGS ADDED TO STOCK
BASILIXIMAB Injection: 20 mg vial
Basiliximab (Simulect(R)&endash; Novartis) is an immunosuppressive
agent indicated for the prophylaxis of acute organ transplantation in
patients undergoing renal transplantation.
CERIVASTATIN Tablets: 0.3 mg, 0.4 mg
Cerivastatin (Baycol(R)&endash; Bayer) is an HMG-CoA reductase
inhibitor. For patients requiring approximately 30% LDL-C reduction,
it is a more cost-effective choice than fluvastatin or pravastatin
for lowering a patient's lipid levels to within the recommended
limits.
COAGULATION FACTOR VIIa, RECOMBINANT Injection: 1.2 mg, 4.8 mg
Coagulation Factor VIIa (NovoSeven(R) &endash; NovoNordisk) is
indicated for the treatment of bleeding episodes in hemophilia A or B
patients with inhibitors to Factor VII or Factor IX.
LACTOBACILLUS GG Capsules: 10 billion active cells
Lactobacillus GG (Culterelle(R) &endash; CAG) is a probiotic agent
that is used for the management of C. difficile-associated colitis,
antibiotic-associated diarrhea, and other gastrointestinal bacterial
overgrowth syndromes.
For information regarding newly marketed drugs, drug-drug interactions, adverse drug reactions, or other medication-related questions, contact the Drug Information Center at 6-2600. The Center is open Monday through Friday (except holidays) from 8 am to 5 pm.
MIGLITOL Tablets: 25 mg, 50 mg, 100 mg
Miglitol (Glyset(R) &endash; Pharmacia & Upjohn) is an inhibitor
of alpha-glucosidases that is indicated for the treatment of
non-insulin-dependent diabetes mellitus alone or in combination with
a sulfonylurea.
ORLISTAT Capsules: 120 mg
Orlistat (Xenical(R)&endash; Roche) is a selective inhibitor of fat
absorption that is indicated for the management of obesity.
POLYETHYLENE GLYCOL 3350 Powder
Polyethylene glycol 3350 (Miralax(R)- Braintree) acts as an osmotic
agent that is indicated for the treatment of constipation.
QUINUPRISTIN/DALFOPRISTIN Injection: 500 mg
Quinupristin 30%/dalfopristin 70% (Synercid(R) &endash; Rhone Poulenc
Rorer) is indicated for the treatment of serious or life-threatening
infections associated with vancomycin-resistant Enterococcus faecium
(VREF).
NOTE: The prescribing of quinupristin/dalfopristin is restricted to attending staff physicians from the Division of Infectious Diseases.
TEMOZOLOMIDE Capsules: 5 mg, 20 mg, 100 mg, 250 mg
Temozolomide (Temodal(R) &endash; Schering Plough) is an
antineoplastic agent indicated for the treatment of patients with
anaplastic astrocytomas who have relapsed on conventional therapy.
ZANAMIVIR Powder for Inhalation: 5 mg
Zanamivir (Relenza(R) &endash; Glaxo Wellcome) is indicated for
treatment of influenza A and B in patients who have been symptomatic
for less than 48 hours.
NOTE: The prescribing of zanamivir is restricted to influenza season.
ADDITIONAL ACTIONS
HEPATITIS B VACCINE A 5 mcg per 0.5 ml preservative-free pediatric formulation (Recombivax HBÒ Preservative Free) has been added to stock.
NOTE: Restricted to use for infants less than 6 months of age.
GANCICLOVIR ORAL SUSPENSION The concentration of this extemporaneously compounded suspension is now 100 mg per ml.
SOTALOL ORAL SUSPENSION The concentration of this extemporaneously compounded suspension is now 5 mg per ml.
PANCRELIPASE/PANCREATIN ORAL CAPSULES Two new strengths have been added to stock. Each capsule of enteric-coated microspheres of Ultrase MT 18® contains: lipase 18,000 units, protease 58,500 units and amylase 58,500 units. Each capsule of enteric-coated microspheres of Ultrase MT 20® contains: lipase 20,000 units, protease 65,000 units, and amylase 65,000 units.
DRUGS DELETED FROM STOCK
ACARBOSE TABLETS Replaced by miglitol (Glyset®) tablets.
ANTHRALIN 0.5% OINTMENT (ANTHRA&endash;DERM®) Deleted due to low use. Coal tar preparations are available.
CHLORAL HYDRATE 500 MG SUPPOSITORIES Not available from any manufacturer. A 325 mg suppository is available.
EPINEPHRINE 1:200 SUSPENSION FOR INJECTION Sus-phrine® has been discontinued by the manufacturer. Epinephrine 1:1000 injection is available.
FLUVASTATIN TABLETS Replaced by cerivastatin (Baycol®) tablets.
ISOPROTERENOL ORAL INHALER Medihaler-ISO® has been discontinued by the manufacturer. Albuterol and metaproterenol inhalers are available.
ROTAVIRUS VACCINE (ROTASHIELD®) Withdrawn from the market due to reports of intussusception.
TERBUTALINE ORAL INHALER Brethaire® has been discontinued by the manufacturer. Albuterol and metaproterenol inhalers are available.
VITAMIN A ORAL SOLUTION (AQUASOL-A®) Discontinued by manufacturer. Vitamin A capsules are available.