Virtual Hospital: P & T News

P&T News: December 1995, Vol. 16, No. 6

Adverse Drug Reaction Reporting

Barbara A. Mutnic, R.Ph., M.H.P.
Peer Review Status: Internally Reviewed

Recently, David A. Kessler, M.D., the Commissioner of the Food and Drug Administration (FDA), addressed correspondence to fellow health care professionals to encourage participation in MedWatch. MedWatch is the FDA's program for reporting adverse effects caused by medications (including drugs and biological nutritional products, and medical devices, as well as defective medical and surgical products.

Drugs reach the market more quickly today than in the past. In 1994, the median time for the review and approval of a new drug was 19 months - 21% less time than in 1993. Although the FDA has maintained its high standards for reviewing the safety and effectiveness of new products, recent efforts have been made to significantly decrease the time required for such reviews. Clinical trials are effective at assessing 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 (Table 1).

Table 1. Limitations of Pre-marketing Clinical Trials

Short Duration

Effects that have a long latency period or develop with chronic use are not detected in these trials.

Narrow Population

Trial groups generally don't include special groups (e.g., pediatric or geriatric populations).

The groups are not always representative of the population that may be using the drug after approval (i.e., the study groups may lack underlying disease states or concomitant use of other medications).

Narrow Set of Indications

The indication for which the drug is being studied does not always include all uses for which the drug may ultimately be prescribed.

Small Size

Trial size is generally less than 3,000 to 4,000 subjects; rare adverse occurrences are difficult to detect.

_________
Adapted from: Goldman SA, Kennedy DL, Liebennan R. Clinical Therpeuncs and the Recognition of Drug Induced Disease. June 199S, Center for Drug Evaluation and Research, FDA .

Continued and close monitoring of newly marketed agents must be carried out through vigilant post-marketing surveillance performed by all health care professionals, thereby providing data to update prescribing information. Recent examples of such labeling changes prompted by the submission of adverse drug reaction (ADR) reports to the MedWatch Program are provided in Table 2.

Table 2. Labeling Changes Due to Post-marketing Surveillance

Cisapride (February 1995)

Concomitant administration with ketoconazole, itraconazole, miconazole, or troleandomycin potentiates QT prolongation and ventricular arrhythmias, including torsades de pointes. These combinations should be avoided.

Felbamate (October 1994)

Revised manufacturer's labeling to include a black box warning regarding a marked increase in the incidence of aplastic anemia and hepatic failure.

Ketorolac (December 1994)

Revised manufacturer's labeling includes black box warning regarding dosing guidelines, length of therapy, and new contraindications. These contraindications include patients with peptic ulcer disease, renal impairment, risk of bleeding, pending major surgery, and hypersensitivity to aspirin or other NSAIDs. Ketorolac should not be given intrathecally or epidurally.

Sumatriptan (October 1994)

Additional warnings were added to manufacturer's labeling including the need to establish a clear diagnosis of migraine and to evaluate the patient for underlying cardiovascular disease prior to use of the agent Information about a drug interaction with MAO-inhibitors was also added.

Importance of Reporting
An additional reason why adverse effects need to be reported is to prevent future ADRs. Complete documentation of the adverse event in the patient's medical record ensures appropriate therapy and follow-up, as well as prevention of subsequent occurrences. Prompt identification of ADRs can decrease morbidity and mortality, length of stay, health care costs, and liability.

Reporting of products that are subpotent, superpotent, or contaminated aids in the initiation of recalls. Also, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires institutions to report ADRs.

The Adverse Drug Reaction Reporting Program at UIHC
The Department of Pharmacy's Pharmacotherapy Evaluation and Consultation Service staff coordinate the UIHC's ADR Reporting Program. Reports are presented to the Pharmacy and Therapeutics Subcommittee for further review and approval prior to being forwarded to the FDA and manufacturer. Before the MedWatch form is sent to the FDA and manufacturer, the patient's attending physician reviews the form and makes recommendations.

The patient's name and registration number are not included on the forms, thereby assuring total confidentiality. Likewise, individual reporters' names are not included. In the event that additional information is required by the FDA, the name of the patient's physician is disclosed only after permission is received.

During fiscal year 1994-95, 518 ADRs were reviewed by the Pharmacy and Therapeutics Subcommittee; 69 of these were reported to the MedWatch Program. Of the 69 MedWatch forms completed, 16 (23%) involved recently marketed products. The sources for the 518 reports are shown in Figure 1. The top nine causative agents were: nonsteroidal anti-inflammatory agents (drug class), vancomycin, morphine, piperacillin, amoxicillin, phenytoin, heparin, ranitidine, and sulfamethoxazole/trimethoprim .

Graph

One of the goals of the UIHC ADR Reporting Program is to prevent future ADRs. An example of one such initiative is the ongoing Ketorolac Drug Use Evaluation. Patients placed on ketorolac injection are carefully evaluated to ensure that prescribed doses are appropriate and adjusted according to renal function. Duration of therapy, concomitant therapies, and the patient's allergies are also reviewed.

A second initiative instituted at the UIHC to prevent ADRs is the Pharmacy and Therapeutics Subcommittee approval of a hospital-wide intravenous vancomycin infusion rate policy. This policy was developed in response to vancomycin-induced red man syndrome - the single most frequently reported ADR (n=26, 6% of 441 reports) in fiscal year 1993-94. The number of reports of vancomycin-induced red man syndrome has significantly decreased (n=7, 1.8So of 392 reports) during the first nine months since the policy's initiation.

Summary
All health care professionals are reminded that it is their responsibility to report ADRs. Over the past several years, the number of ADRs reviewed by the Pharmacy and Therapeutics Subcommittee has increased each year, thereby providing sufficient data to identify trends and develop proactive initiatives to prevent subsequent ADRs. The continued cooperation of all health care professionals will ensure that this trend continues.

The Use of PICC Lines for TPN
Peripherally inserted central (venous) catheters (PICC lines) are being used increasingly for total parenteral nutrition (TPN) or other intravenous infusions. The Parenteral Nutrition Subcommittee has developed the following guidelines for the insertion and care of such catheters, to assure safety and prevent complications.

1. Before every insertion, sound clinical judgment must have determined the need for TPN through a central venous catheter.

2. Selection of PICC lines over conventional subclavian or ZHickman" catheters follows the reasoning and choice of the attending physician.

3. The patient must have suitable and adequate peripheral veins to allow the placement of these catheters.

4. Insertion of every catheter must follow the specific and detailed guidelines described in the manufacturer's insert. The following points are general guidelines that must be observed with all catheters.

A. The basilic and median basilic veins followed by the cephalic vein are most suitable for insertion.

B. Proper selection of the vein may facilitate successful insertion on the first try. Such lines must be inserted by or under the direct supervision of an experienced and qualified person. No more than three attempts should be made on one patient on one single day.

C. The desired length of the catheter should be measured from the point of insertion to the midpoint of the superior vena cava. This can be done with the measuring tape included in the kit, following the standard surface anatomy. Trace the vein from the antecubital space upward to the shoulder, then medially to the right border of the sternal notch, then down to the third sternocostal joint. The excess catheter should be cut (at a 45 degree angle) and discarded.

D. The arm of the patient is placed at 9O degrees from the patient's chest. A wide sterile field must be ensured and prepared with povidone iodine. Some catheters may be damaged from alcohol and acetone.

E. The catheter should not be moved back and forth within the introducer needle, and this introducer must be removed completely after 3 to 6 inches of the catheter have been advanced inside the vein. Guidewires, when present, should not protrude from the catheter, and should be at least 1 cm from the catheter tip.

F. Bending the patient's neck over to the side of the catheter may facilitate advancement of the catheter past the subclavian vein and into the superior vena cava. Advancement of all catheters, especially those with guidewires should be done gently to avoid perforation of the vein.

G. The catheter should be secured with Steri-strips0 or other tape provided in the kit. The tape must adhere directly to the catheter and skin, not to interposed gauze. TegadermX may be applied over the initial tape.

H. Do not use sutures to fix the catheter as sutures may kink and break the catheter.

I. At the end of insertion, check for a blood return and flush the catheter with saline and heparin. Obtain a chest X-ray and confirm proper positioning of the tip before use.

J. Occluded catheters should be replaced after moderate attempts at declotting have failed. Damaged catheters should be replaced without attempts at repair.

K. The initial dressing must be marked with date and time of insertion. A procedure note in the patient's clinical record must document the procedure and should include the length of the catheter, position of the tip on the X-ray, and other pertinent information.

L. A functioning PICC line may be used for any length of time, as long as it is not infected or damaged.

Approved: Pharmacy and Therapeutics Subcommittee, December 1995.

Pharmacy and Therapeutics Subcommittee Actions

Drugs Added to Stock

FLUVOXAMINE Tablets: 50 mg, 100 mg Fluvoxamine (Luvox0 - Solvay) is a selective serotonin reuptake inhibitor indicated for the treatment of obsessive compulsive disorder.

ISOSORBIDE MONONITRATE Sustained Release Tablets: 60 mg, 120 mg Isosorbide mononitrate (Imdur0 - Key/Schering) is a vasodilator indicated for the prevention of angina pectoris due to coronary artery disease.

NEFAZODONE Tablets: 100 mg, 150 mg, 200 mg, 250 mg Nefazodone (Serzone0 - BMS) is an antidepressant that inhibits the uptake of serotonin and norepinephrine.

Drugs Deleted From Stock

BOUINS FLUID Deleted due to low use. Available from the Surgical Pathology Laboratory, if needed.

CHLORAMPHENICOL CAPSULES Discontinued by the manufacturer. Chloramphenicol injection is available.

FOSCARNET INJECTION 12 grams per 500 ml This size was deleted due to low use. The 6 gram per 250 ml size remains in stock.

METICILLIN INJECTION Discontinued by the manufacturer. Nafcillin injection is available.

PROBUCOL (Lorelco0-Parke-Davis) Discontinued by the manufacturer. Other cholesterol lowering agents are available.

Additional Actions

CISAPRIDE SUSPENSION Cisapride (Propulsid0 - Janssen) 1 mg per ml suspension has been added to stock. This product replaced an extemporaneously compounded suspension.

IPRATROPIUM 0.02% INHALATION SOLUTION Ipratropium (Atrovent 0 - Boehringer Ingelheim) inhalation solution has been added to stock.

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Table 1. Limitations of Pre-marketing Clinical Trials
Short Duration	Effects that have a long latency period or develop with chronic use are not detected in these trials.
Narrow Population	Trial groups generally don't include special groups (e.g., pediatric or geriatric populations). The groups are not always representative of the population that may be using the drug after approval (i.e., the study groups may lack underlying disease states or concomitant use of other medications).
Narrow Set of Indications	The indication for which the drug is being studied does not always include all uses for which the drug may ultimately be prescribed.
Small Size	Trial size is generally less than 3,000 to 4,000 subjects; rare adverse occurrences are difficult to detect.
_________ Adapted from: Goldman SA, Kennedy DL, Liebennan R. Clinical Therpeuncs and the Recognition of Drug Induced Disease. June 199S, Center for Drug Evaluation and Research, FDA .

Table 2. Labeling Changes Due to Post-marketing Surveillance
Cisapride (February 1995)	Concomitant administration with ketoconazole, itraconazole, miconazole, or troleandomycin potentiates QT prolongation and ventricular arrhythmias, including torsades de pointes. These combinations should be avoided.
Felbamate (October 1994)	Revised manufacturer's labeling to include a black box warning regarding a marked increase in the incidence of aplastic anemia and hepatic failure.
Ketorolac (December 1994)	Revised manufacturer's labeling includes black box warning regarding dosing guidelines, length of therapy, and new contraindications. These contraindications include patients with peptic ulcer disease, renal impairment, risk of bleeding, pending major surgery, and hypersensitivity to aspirin or other NSAIDs. Ketorolac should not be given intrathecally or epidurally.
Sumatriptan (October 1994)	Additional warnings were added to manufacturer's labeling including the need to establish a clear diagnosis of migraine and to evaluate the patient for underlying cardiovascular disease prior to use of the agent Information about a drug interaction with MAO-inhibitors was also added.