Drug Safety Monitor

NEW DRUG SAFETY INFORMATION: 1998

When drugs are approved by the FDA for marketing in the Untied States they typically have been tested in a few thousand preselected patients in controlled trials with stringent criteria. Easily recognized and frequent drug reactions generally are discovered during premarketing trials. However, unexpected adverse reactions or drug interactions often occur once the drug is marketed and used in larger, more varied populations. The importance of monitoring, documenting and disseminating information regarding postmarketing surveillance is essential in optimizing patient drug therapy. It is a monumental task for physicians to keep up with new information regarding both older and newly marketed agents. With the advent of internet technology, the FDA has implemented a web site which summarizes new safety information about drugs, dietary supplements, biologics, medical devices and other topics of interest. This site provides summaries of "Dear Health Professional Letters" and other safety/health advisory notifications by the FDA. The summaries are listed in reverse chronological order and the site is maintained by the FDA and updated periodically as needed. The site for 1998 safety information summaries may be accessed at the following URL:

http://www.fda.gov/medwatch/safety/1998/safety98.htm

This is an important resource that all health professionals should be aware of. Significant drug safety advisories for 1998 are briefly summarized in Table 1. Readers are encouraged to visit the particular website (specific URLs are provided) for more complete information. The Drug Information Center also posts significant safety alerts via e-mail as needed.

Table 1. Summary of Significant Drug Safety Summaries: 1998

Astemizole
(Hismanal)
February 1998		 New contraindications include use in patients with severe hepatic impairment or coadministration with clarithromycin, troleandomycin or mibefradil* (*product withdrawn in June 1998). Precautionary list of substances not recommended for coadministration with astemizole was expanded to include SSRI reuptake inhibitors (fluoxetine, fluvoxamine, paroxetine, sertraline), Protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir) and zilueton or other potent P450 CYP34A inhibitors. Patients advised against coadministration with grapefruit juice because of its potential to influence astemizole metabolism.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/hisman.htm
FDA Announcement: http://www.fda.gov/bbs/topics/ANSWERS/ANS00848.html
Bromfenac
(Duract)
February 1998
June 1998		 February: Product labeling revisions include a boxed warning describing the potential for hepatic reactions (ie,jaundice, fatal hepatitis and liver failure) which have been reported in patients taking this product for >1 month. This NSAID is not indicated for long term use and should only be used for a limited period (10 days or less) in the management of acute pain. Patients should be advised to take medication as directed.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/duract.htm
FDA Announcement: http://www.fda.gov/bbs/topics/ANSWERS/ANS00849.html

June: Bromfenac voluntarily withdrawn from the US market by the manufacturer based on postmarketing reports of severe hepatic failure resulting in 4 deaths and 8 liver transplants. Eleven of 12 cases were associated with chronic use of the product (> 10 days, the maximum recommended duration of treatment). The other case was in a patient with pre-existing significant liver disease.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/duract3.htm
FDA Announcement: http://www.fda.gov/bbs/topics/ANSWERS/ANS00879.html
Questions and Answers: http://www.fda.gov/cedr/news/duract/qa.htm
Carbamazepine
Suspension (Tegretol)
March 1998		 Report describing the development of an orange rubbery mass passed in patient’s stool after ingesting Tegretol suspension immediately followed by Thorazine (chlorpromazine) solution. Mixing Tegretol suspension with liquid formulations of chlorpromazine or thioridazine also result in the precipitation of a rubbery orange mass. Advise patients against simultaneous administration of these products until further information is available.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/tegret.htm
Cholestin
May 1998		 FDA announces that this product, which is promoted as a dietary supplement to reduce cholesterol levels, is not a dietary product but rather is an unapproved drug according to the guidelines of the Food, Drug and Cosmetics Act. This decision was based on the discovery that the product contains lovastatin, an already approved and marketed prescription drug in the United States.
FDA Announcement: http://www.fda.gov/bbs/topics/ANSWERS/ANS00871.html
Cisapride
(Propulsid)
June 1998		 "Boxed Warning Section" warns about serious cardiac arrhythmias (ie, ventricular tachycardia or fibrillation, torsades de pointes, and QT prolongation) reported in patients taking cisapride. New contraindications include but not limited to drug interactions with other drugs that inhibit cytochrome P450 3A4, such as antibiotics (oral and IV erythromycin, clarithromycin, troleandomycin), antidepressants (nefazadone), antifungals (oral and IV fluconazole, itraconazole, oral ketoconazole).
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/propul.htm
FDA Announcement: http://www.fda.gov/bbs/topics/ANSWERS/ANS00879.html
Heparins, Low Molecular Weight

Ardeparin (Normiflo)

Dalteparin (Fragmin)

Danaproid (Orgaran)

Enoxaparin (Lovenox)
December 1997

 FDA health advisory regarding a potential safety problem associated with the concurrent use of low molecular weight heparins (LMWHs) with spinal or epidural anesthesia. A spinal puncture may cause bleeding/hematomas within the spinal column and increased pressure on the spinal cord, resulting in permanent paralysis if not detected and treated immediately. Careful monitoring for signs and symptoms of neurologic injury is recommended in patients receiving LMWHs or heparinoids. This alert was based on more than 30 postmarketing reports (as of November 1997) of patients who had developed bleeding within the spinal column with the concurrent use of enoxaparin. The FDA has requested the addition of this information in LMWH product information as boxed warning.

FDA announcment: http://www.fda.gov/medwatch/safety/1997/antico.htm
Questions and Answers: http://www.fda.gov/medwatch/safety/1998/lovq&a.htm
Isotretinoin (Accutane)
February 1998		 Revisions in product information "Warnings Section" documenting isolated case reports of depression, pyschosis and suicidal thoughts and actions. Althoug most reports have been reversible once the drug was withdrawn, discontinuation of therapy may be insufficient and further evaluation may be necessary. Mechanism of action not established. Although adverse experiences are uncommon, potential consequences are significant and clinicians should monitor for new behavioural signs and symptoms.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/accuta.htm
FDA announcement: http://www.fda.gov/bbs/topics/ANSWERS/ANS00852.html
Mibefradil (Posicor)
June 1998		 Voluntary market withdrawal occurred June 8, 1998 based on postmarketing information regarding serious numerous drug interactions. Manufacturer also provides important information regarding drug interactions and therapy substitution for mibefradil.

Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/poscor.htm
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/posico2.htm
FDA announcment: http://www.fda.gov/bbs/topics/ANSWERS/ANS00876.htm
Ritonavir (Norvir)
July 1998		 A shortage of ritonavir capsules occurred due to manufacturing difficulties, requires transfer of patients to oral solution during shortage. Patients are advised of conversion as follows:
6 capsules (100 mg each) = 7.5 ml of liquid (1.5 tsp)
4 capsules (100 mg each) = 5 mL of liquid (1 tsp)

Manfacturer Letter: http://www.fda.gov/medwatch/safety/1998/norvir.htm
Patient Information & Instructions: http://www.fda.gov/medwatch/safety/1998/norvi1.htm
Sildenafil
(Viagra)
May 1998
June 1998		 May 1998: Dear Doctor Letter re-emphasizes information regarding the contraindication for taking sildenafil concurrently with organic nitrates; potentially causing severe, unresponsive and sudden hypotension. A list of short acting and long acting nitrates are provided at Web site addresses.
Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/viagra.htm

June 1998: Summary of death reports in Viagra users received by FDA from March through June 1998
FDA Announcement: http://www.fda.gov/cder/consumerinfo/viagra/viagraupdate721.htm
Sleeping Buddha
March 1998		 FDA warns against taking dietary supplement "Sleeping Buddha" which contains an unlabeled prescription benzodiazepine (estazolam) that poses possible health risks, particularly to pregnant women. In addition, the product has not been submitted to FDA for review or approval for any uses.

FDA announcment: http://www.fda.gov/bbs/topics/NEWS/NEW00625.html
Terfenadine
(Seldane)
February 1998		 Voluntary withdrawal of all terfenadine containing antihistamine product lines in the United States because of the approval of a safer alternative drug (fexofenadine) which provides the same benefits without the potential for fatal drug interactions.

FDA announcment: http://www.fda.gov/bbs/topics/ANSWERS/ANS00853.html
Ticlopidine (Ticlid)
August 1998		 Revised labeling moves a known and potentially life-threatening adverse drug reaction, thrombotic thrombocytopenic purpura (TTP) to the boxed warning section of the product labeling and provides further information regarding diagnosis and management of TTP. TTP incidence peaks after about 3 to 4 weeks of therapy, and neutropenia peaks at approximately 4 to 6 weeks. Hematological and clinical monitoring for these disorders is recommended during the first 3 months of therapy.

Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/ticlid2.htm
Troglitazone
(Rezulin)
December 1997
July 1998		 July 1998: Changes in product labeling regarding more stringent liver function monitoring intended to reduce risk of severe liver injury.
  • Patients with moderately elevated baseline ALT levels (> 1.5 times the upper limit of normal) are not candidates for troglitazone therapy.
  • ALT levels should be monitored at the start of troglitazone therapy and monthly for 8 months, then every 2 months for the remainder of the first year and periodically thereafter.
  • Patients with moderately elevated ALT levels (>1.5-2 times the upper limit of normal) during troglitazone therapy, should have ALTs retested weekly until they return to normal levels or rise about 3 times the upper limit of normal, at which point therapy should be discontinued.

Dosing recommendation change: For patients unresponsive at 400 mg daily, dosage increase to 600 mg daily should occur only after one month of therapy. If not responsive at the increased dosage for one month, troglitazone should be discontinued and alternative therapies employed.

Manufacturer Letter: http://www.fda.gov/medwatch/safety/1998/rezuli.htm

Prepared by Joyce Generali,MS, RPh

KUMC Drug Information Center, ext 2328

 

 

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