Virtual Hospital: P & T News

P&T News: October 1994, Vol. 15, No. 4

Adverse Drug Reaction Reporting

Mary B. Ross, R.Ph. and Barbara A. Mutnick, R.Ph.
Peer Review Status: Internally Reviewed

Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality, hospital admissions, prolonged hospitalization, and increased health care costs. Various definitions of an ADR or drug-induced side effect have been developed; they are outlined in Table 1.

Importance of Reporting
There are a number of reasons why ADRs should be identified and reported to the Pharmacy and Therapeutics Subcommittee, the FDA, and the manufacturer. The most important reason is the need to update prescribing information and to prevent future ADRs. During clinical trials, drugs are generally studied in several hundred to several thousand relatively healthy patients, usually for only a limited duration of time. Patients on multiple drug therapy, pediatric patients, elderly patients, and patients with decreased renal and hepatic function are often excluded. Once the drug is commercially available, these exclusion criteria are no longer applicable, therapy may continue long-term, and previously undetected problems may be identified. Additionally, adverse effects may occur at such a low frequency that they are not being detected in the small numbers of patients included in the clinical trials; widespread use may uncover serious adverse effects. The most recent example of changes made as a result of ADRs reported to the FDA was the "black-box" warning for hepatic failure and aplastic anemia associated with felbamate therapy.

Prompt identification of ADRs can decrease morbidity and mortality, length-of-stay, health care costs, and liability. In addition, if identified, some ADRs are preventable and steps can be taken to prevent subsequent reactions. Examples include: diligent monitoring of renal function for patients receiving imipenem-cilastatin to prevent imipenem-induced seizures; and avoidance of long-acting benzodiazepines in the elderly to prevent drug accumulation that can result in confusion and falls.

An additional reason to document ADRs includes identification of subpotent, superpotent, or contaminated products. Clusters of reports of ADRs or lack of response have been instrumental in initiating product recalls.

Finally, institutions must report ADRs to be in compliance with Joint Commission on Accreditation of Health Care Organization (JCAHO) standards.

Table 1. Adverse Drug Reaction Definitions

The World Health Organization defines an adverse drug reaction as:

"Any response to a drug which is noxious, unintended, and which occurs at doses used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function."

The UIHC Pharmacy and Therapeutics Subcommittee has defined a significant adverse drug reaction as:

"Any reaction that meets the designation of fatal, severe (serious), or moderate. A fatal adverse effect is one that directly or indirectly contributes to the death of the patient. A severe or serious effect is one that is potentially life-threatening or toxic, causes permanent disability, requires intensive medical care, or requires hospitalization. If an adverse drug reaction requires treatment with drug therapy, requires a change in drug therapy, increases length of hospitalization, or causes temporary disability, it is classified as moderate."

The UIHC Pharmacy and Therapeutics Subcommittee has defined additional types of adverse drug reactions to be significant and reportable to the FDA. These are:

"New or unexpected reactions, including drug-drug interactions (i.e., not listed in the current manufacturer's labeling or occurring in a greater severity than listed);
Reactions occurring with increased frequency; or
Reactions associated with congenital anomalies."

UIHC criteria for classification of adverse drug reactions as FDA-reportable events are as follows:

Previously unreported or very unusual adverse drug reactions;
Severe adverse drug reactions (life-threatening, requiring intensive medical care, or causing permanent damage);
A reaction possibly, probably, or definitely contributing to a fatal outcome, either in a direct or indirect way; or
ADR reports of a single agent that appear to cluster or demonstrate a developing trend.

Reporting Forms
ADRs are reported to the FDA using the MedWatch Medical Products Reporting Program forms. Adverse experiences with medications (drugs and biologics), medical devices (including in vitro diagnostics), nutritional products (dietary supplements, medical foods, infant formulas), and other products regulated by the FDA should be reported using the MedWatch form. An exception to the use of the MedWatch form is the reporting of ADRs related to vaccines. The National Childhood Vaccine Injury Act imposes special reporting requirements for vaccines; they must be reported on the Vaccine Adverse Experience Reporting System (VAERS) form (Figure 1).

To facilitate reporting of ADRs by health care professionals at UIHC, wall-mounted pads of bright-yellow, pocket-sized ADR reporting cards are available on patient care areas. Completed cards should be forwarded to the Drug Information Center for follow-up by the Pharmacy and Therapeutics Subcommittee.

Vaccine Adverse Experience Reporting Systems (VAERS)
As a result of the National Childhood Vaccine Injury Act of 1986, health care providers are required to record and report information associated with the administration of certain vaccines and toxoids in any individual regardless of age (Table 2). The data obtained are used to monitor the safety of vaccines, and to identify individuals who have been injured by these vaccines and who may therefore be eligible for compensation.

The health care provider who administers any of these vaccines and toxoids is required to ensure that the following information is recorded in the patient's permanent medical record: date of administration; manufacturer and lot number of vaccine or toxoid; and name and title of the person who administered the vaccine. In addition, prior to vaccination, the health care provider must provide relevant vaccine and toxoid information to any adult or the parent or legal guardian of any child who will receive one of these vaccines or toxoids. The information must be provided prior to the administration of each dose.

Health care providers are also required to report through the VAERS certain adverse effects associated with these vaccines or toxoids that occur within the time frame specified in Table 2.

Adverse Drug Reaction Reporting at UIHC
At UIHC, ADR reporting is coordinated by the Pharmacy Department's Drug Information Center. Reports are then reviewed by the Pharmacy and Therapeutics Subcommittee prior to being recommended for forwarding to the FDA and manufacturer. Those ADRs recommended for forwarding are first sent to the patient's attending physician for review and approval and then on to the FDA and manufacturer.

ADR reports are sent to the FDA under the Pharmacy and Therapeutics Subcommittee's name; health care professionals' names are not included. Patient's names or registration numbers are not included on the form, and hence are kept confidential. If additional follow-up is requested by the FDA, the name of the patient's physician is disclosed only after receiving his/her permission. Additionally, the policy of protecting personal privacy is codified in FDA regulations.

During Fiscal Year 1993-94, 877 ADR reports were identified at UIHC; 441 of these reports were further identified as potentially significant and presented to the Pharmacy and Therapeutics Subcommittee for in-depth review. The reporting sources of these ADRs are depicted in Figure 2. Figure 3 illustrates the causative agents by drug category. Anti-infectives were the most frequently identified drugs. The top nine causative agents were vancomycin, gentamicin, ranitidine, diltiazem, piperacillin, digoxin, phenytoin, morphine, and sulfamethoxazole-trimethoprim.

The Pharmacy and Therapeutics Subcommittee has endorsed several initiatives designed to inform UIHC staff of emerging ADR trends and to identify preventable ADRs. P&T News articles have discussed: the etiology and prevention of red man syndrome secondary to vancomycin administration; mental status changes secondary to ranitidine, and the appropriate dosing adjustments required in the elderly and renally compromised patients who receive this drug; erythromycin-associated prolongation of the QT interval; appropriate dosing of ketorolac injection based on age, weight, and renal function; and dosing of imipenem-cilastatin based on renal function.

Summary
ADR reporting is the responsibility of all health care professionals at UIHC.

Form 24

Table 2: Reportable Events Following Vaccination

Vaccine/Toxoid

Event

Interval from Vaccination

Diphtheria-tetanus-pertussis (DTP), Pertussis (P), Diphtheria-tetanus-accellular pertussis (DTaP), or DPT/Polio Combined

A. Anaphylaxis or anaphylactic shock
B. Encephalopathy (or encephalitis)
C. Shock-collapse or hypotonic-hyporesponsive collapse[1]
D. Residual seizure disorder[1]
E. Any acute complication of sequela (including death of above events)
F. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2](such as convulsions)

A. 24 hours
B. 7 days
C. 7 days
D. (See Aids to Interpretation[1])
E. No limit
F. (See package insert)

Measles, Mumps, Rubella, Pediatric tetanus-diptheria (DT), Adult tetanus-diptheria (Td), or Tetanus Toxoid (T)

A. Anaphylaxis or anaphylactic shock
B. Encephalopathy (or encephalitis)[1]
C. Residual seizure disorder[1]
D. Any acute complication or sequela (including death) of above events
E. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2]

A. 24 hours
B. 15 days for measles, mumps and rubella vaccines; 7 days for DT, Td, and T toxoids
C. (See Aids to Interpretation[1])
D. No limit
E. (See package insert)

Oral Polio Vaccine

A. Parlytic poliomyelitis
-in a non-immunodeficients recipients
-in an immunodeficient recipient
-in a vaccine-associated community case
B. Any acute complication or sequela (including death) of above events
C. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2]

A1. 30 days
A2. 6 months
A3. No limit
B. No limit
C. (See package insert)

Inactivated Polio Vaccine

A. Anaphylaxis or anaphylactic shock
B. Any acute complication or sequela (including death) of above event
C. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2]

A. 24 hours
B. No limit
C. (See package insert)

[1] Aids to Interpretation:

Shock-collapse or hypotonic-hyporesponsive collapse may be evidence by signs or symptoms such as decrease in or loss of muscle tonE, paralysis (partial or complete), hemiplegia, hemiparesis, loss of color or turning pale white or blue, unresponsiveness to environmental stimuli, depression of or loss of consciousness, prolonged sleeping with difficulty arousing, or cardiovascular or respiratory arrest.

Residual seizure disorder may be considered to have occurred if no other seizure or convulsion unaccompanied by fever or accompanied by a fever of less than 102 degrees F occurred before the first seizure or convulsion after the administration of the vaccine involved.

AND, if in the case of measles-, mumps-, or rubella-containing vaccines, the first seizure or convulsion occurred within 15 days after vaccination OR in the case of any other vaccine, the first seizure or convulsion occurred within 3 days after vaccination involved.

AND, if two or more seizures or convulsions unaccompanied by fever or accompanied by a fever of less than 102 degrees F occurred within 1 year after vaccination.

The terms seizure and convulsion include grand mal, petit mal, absence, myoclonic, tonic-clonic, and focal motor seizures and signs. Encephalopathy means any significant acquired abnormality of, injury to, or impairment of function of the brain. Among the frequent manifestations of encephalopathy are focal and diffuse neurologic signs, increased intracranial pressure, or changes lasting at least 6 hours in level of consciousness, with or without convulsions. The neurologic signs and symptoms of encephalopathy may be temporary with complete recovery, or they may result in various degrees of permanent impairment. Signs and symptoms such as high-pitched and unusual screaming, persistent inconsolable crying, and bulging fontanel are compatible with an encephalopathy, but in and of themselves are not conclusive evidence of encephalopathy. Encephalopathy usually can be documented by slow wave activity on an electroencephalogram.

[2] The health-care provider must refer to the CONTRAINDICATION section of the manufacturer's package insert of each vaccine.

Source: Department of Health and Human Services

1994-95 Influenza Virus Vaccination Recommendations

Influenza ("flu") is an acute viral infection affecting the upper and/or lower respiratory tract. Symptoms of influenza commonly include fever, chills, cough, and soreness and aching of the arms and legs. Contrary to popular opinion, influenza is not the common cold or a gastrointestinal disease. Influenza can cause severe, even fatal, pulmonary complications, particularly in high-risk individuals.

The most effective method of preventing influenza is through annual vaccinations of high-risk individuals and their contacts using inactivated (i.e., non-infectious) influenza virus vaccine. Annual vaccinations are necessary because viral strains vary from year to year and immunity usually declines within six month of immunization. This year's vaccine contains A/Texas/36/91 (H1N1), A/Shangdong/9/93, and B/Panama/45/90 virus strains, which are thought to be most likely to occur in the United States this fall and winter.

Current Recommendations For Individuals Who Should Be Vaccinated.

Individuals at Increased Risk for Influenza-related Complications

Persons 65 years of age or older.
Residents of nursing homes and other chronic-care facilities housing persons of any age with chronic medical conditions.
Adults and children with chronic disorders of the pulmonary or cardiovascular systems, including children with asthma.
Adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications).
Children and teenagers (6 months to 18 years of age) who are receiving long-term aspirin therapy, and therefore may be at risk of developing Reye syndrome after influenza.

Groups That Can Transmit Influenza to High-Risk Individuals

Physicians, nurses, and other personnel in both hospital and outpatient-care settings who have contact with high-risk persons among all age groups, including infants.
Employees of nursing homes and chronic-care facilities who have contact with patients or residents.
Providers of home care to high-risk persons (e.g., visiting nurses, volunteer workers).
Household members (including children) of high-risk persons.

Additional Individuals Who May Be Vaccinated Include:

Persons wishing to reduce their chances of catching influenza.
Persons who provide essential community services.
Students or other persons in schools and colleges if outbreaks would cause major disruptions of school activities
Persons traveling to the tropics at any time of the year or to countries south of the equator during April through September.

Source: DC: Prevention and Control of Influenza: Part 1, Vaccines. Recommendations of the Immunization Practices Advisory Committee. MMWR. 1994;43(no.RR-9):1-13.

Pharmacy and Therapeutics Subcommittee Actions

Drugs Added to Stock

STAVUDINE Capsules: 15 mg, 20 mg, 30 mg, and 40 mg. Stavudine (d4T, Zerit® - Bristol-Myers Squibb) is an antiretroviral agent indicated for the treatment of adults with advanced HIV infection who are intolerant to zidovudine, didanosine, and zalcitabine, or who are experiencing significant clinical or immunologic deterioration while receiving those therapies.

DESMOPRESSIN Nasal S pray: 1.5 mg/ml. This contraction of desmopressin nasal spray (Stimate® - Armour) is indicated for the treatment of bleeding episodes in patients with mild to mod

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Table 2: Reportable Events Following Vaccination
Vaccine/Toxoid	Event	Interval from Vaccination
Diphtheria-tetanus-pertussis (DTP), Pertussis (P), Diphtheria-tetanus-accellular pertussis (DTaP), or DPT/Polio Combined	A. Anaphylaxis or anaphylactic shock B. Encephalopathy (or encephalitis) C. Shock-collapse or hypotonic-hyporesponsive collapse[1] D. Residual seizure disorder[1] E. Any acute complication of sequela (including death of above events) F. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2](such as convulsions)	A. 24 hours B. 7 days C. 7 days D. (See Aids to Interpretation[1]) E. No limit F. (See package insert)
Measles, Mumps, Rubella, Pediatric tetanus-diptheria (DT), Adult tetanus-diptheria (Td), or Tetanus Toxoid (T)	A. Anaphylaxis or anaphylactic shock B. Encephalopathy (or encephalitis)[1] C. Residual seizure disorder[1] D. Any acute complication or sequela (including death) of above events E. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2]	A. 24 hours B. 15 days for measles, mumps and rubella vaccines; 7 days for DT, Td, and T toxoids C. (See Aids to Interpretation[1]) D. No limit E. (See package insert)
Oral Polio Vaccine	A. Parlytic poliomyelitis -in a non-immunodeficients recipients -in an immunodeficient recipient -in a vaccine-associated community case B. Any acute complication or sequela (including death) of above events C. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2]	A1. 30 days A2. 6 months A3. No limit B. No limit C. (See package insert)
Inactivated Polio Vaccine	A. Anaphylaxis or anaphylactic shock B. Any acute complication or sequela (including death) of above event C. Events in recipients described in manufacturer's package insert as contraindications to additional doses of vaccine[2]	A. 24 hours B. No limit C. (See package insert)