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Amantadine: Does It Have a Role in the 
Prevention and Treatment of Influenza?

National Institutes of Health
Consensus Development Conference Statement
October 15-16, 1979

Confernce artwork, a stylized cell surrounded by virus particles and drug agents.

This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/.

This statement was originally published as: Amantadine: Does It Have a Role in the Prevention and Treatment of Influenza? NIH Consens Statement 1979 Oct 15-16;2(9):51-56.

For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Amantadine: Does It Have a Role in the Prevention and Treatment of Influenza? NIH Consens Statement Online 1979 Oct 15-16 [cited year month day];2(9):51-56. 

Introduction

A National Institutes of Health Consensus Development Conference on Amantadine: Does it have a Role in the Prevention and Treatment of Influenza? was held at NIH on October 15-16, 1979.

At NIH, consensus development conferences bring together biomedical research scientists, practicing physicians, consumers, and others as appropriate in an effort to reach general agreement on the safety and effectiveness of a medical technology. That technology may be a drug, device, or medical or surgical procedure.

Amantadine hydrochloride (Symmetrel*) is an antiviral compound which is currently indicated in the United States for the prevention and symptomatic management of the respiratory tract illness caused by influenza A virus strains. The antiviral activity of amantadine was reported 15 years ago and its efficacy in the prophylaxis of type A influenza was shown in clinical trials over 10 years ago.

Amantadine was approved in 1966 for use in the prevention of Asian (H2N2) influenza. However, this use of the drug has not received wide acceptance in the United States. The reluctance to use amantadine was due to several factors, including the inconvenience associated with the use of prophylactic drugs, concern about side effects and most important, the fact that it was originally approved for use only with Asian (H2N2) influenza. Shortly thereafter, A/Hong Kong/68 (H3N2) strains appeared and caused pandemic influenza. Because of restrictions placed in the initial approval, amantadine could not be recommended for use against Hong Kong influenza until further clinical trials had been completed, by which time the pandemic had passed.

The major use of amantadine over the past years has been in the treatment of Parkinson's disease. This has provided experience with long-term usage and side effects. By 1976, with the potential threat of swine influenza, sufficient data had been developed to justify changing the FDA license to include prophylactic and therapeutic use of amantadine against all strains of influenza A virus.

This Consensus Development Conference was called to review the information available on the use of amantadine hydrochloride in the prevention and treatment of disease caused by influenza A. The format utilized was the convening of a panel of individuals with various backgrounds but little or no personal involvement in research on amantadine hydrochloride. A group of experts with extensive knowledge and experience in the epidemiology of influenza, the evaluation of influenza vaccines, and the properties of amantadine hydrochloride presented and discussed the pros and cons of the several clinical uses of amantadine before the panel. The experts included scientists from the United Kingdom and Soviet Union, where there has been extensive experience with amantadine hydrochloride and its congener, rimantadine. The panel then met to consider five specific questions:

  1. What are the potential benefits of the prophylactic and therapeutic uses of amantadine hydrochloride for influenza A infections?
  2. Who should take amantadine hydrochloride and when should it be taken?
  3. What are the risks associated with the use of amantadine hydrochloride?
  4. Is there a role for the use of amantadine hydrochloride in combination with vaccines?
  5. Why has the medical profession not accepted amantadine hydrochloride in the prevention and treatment of influenza?
The following represents the consensus of the seven panel members.

 

It must be recognized that there are specific aspects in the report with which individual members may have some reservation or even frank disagreement, but the disagreements were not of a magnitude to warrant inclusion of a minority report.  

What Are Potential Benefits of Use of Amantadine Hydrochloride in the Treatment of Influenza Type A?

Numerous studies have shown amantadine hydrochloride to have an efficacy of approximately 70 percent in the prevention of influenza caused by type A strains. Consideration of potential benefits must take cognizance of this.

The use of amantadine hydrochloride as a prophylactic measure and in the treatment of influenza A has significant potential value in reducing the morbidity associated with this disease and its complications. It is anticipated that this will be of particular value among those with cardiopulmonary disease, especially the elderly who have more severe and life-threatening forms of disease and are more likely to have pneumonic complications. This applies especially to the million and a half aged persons in long-term care institutions. Under epidemic conditions, the prophylactic and therapeutic use of amantadine hydrochloride among those who care for them could help maintain essential services in such institutions.

Similar beneficial effects are anticipated from use of the drug in vulnerable patients exposed to influenza A in hospitals and those caring for them. Other high risk groups among whom beneficial results may be anticipated under epidemic conditions are essential public servants such as policemen, firemen, and military personnel, especially those who have not had influenza virus vaccine immunization.

A reduction in the mortality from influenza A and its complications is a desirable goal which will have to be verified by close observation of those undergoing treatment with amantadine hydrochloride.  

Who Should Take Amantadine and When Should It Be Taken?

The panel reviewed the manufacturer's approved recommendations, those suggested by experts, and the accumulated data. The panel agrees that amantadine has a role in both the prevention and treatment of influenza A. Amantadine is not effective against influenza B strains or against other respiratory viruses. It was felt that the indications could be ranked by priority. Those indications with a lower priority require a greater understanding between the physician and patient of the potential benefits, risks, and costs.

Prophylaxis

When amantadine hydrochloride is to be recommended, there must be both epidemiologic and virologic evidence of an outbreak of influenza A infection in the community or region. It should be recognized that influenza A outbreaks in communities extend over intervals of 4 to 6 weeks, not over periods of many months and that outbreak caused by other viral agents (e.g., parainfluenza virus) may precede or follow influenza and be confused with influenza in their clinical presentations. Groups with highest priorities for receipt of amantadine hydrochloride include:

  1. Unvaccinated children and adults at high risk of serious morbidity and mortality by virtue of underlying diseases which include pulmonary, cardiovascular, metabolic, neuromuscular or immuno-deficiency diseases. Note should be made that dosage regimens have not been well defined in patients with renal insufficiency; hence, its use in this group of patients should be cautious.
  2. Adults who have not been vaccinated with an appropriate contemporary influenza vaccine whose activities are essential to community function, e.g., policemen, firemen, selected hospital personnel. Such persons are in frequent contact with individuals who may have influenza and should be considered at higher risk of contracting influenza than the general population.
  3. Individuals in semi-closed institutional environments, especially older persons, who have not received the current influenza vaccine.

 

The groups for which the panel felt the benefit/risk considerations were less clear include all elderly patients (65 years or older) who have not received influenza vaccine and household contacts of an index case.

The use of amantadine hydrochloride for prophylaxis in hospital patients in the presence of a demonstrated outbreak should take into consideration local and particular risk factors and conditions; for example, the patient who is to undergo inhalation anesthesia may be at higher risk of serious complications.

The possible teratogenic risk of amantadine hydrochloride following administration to pregnant individuals is not fully known. The drug should be administered to pregnant women only after weighing the possible risks to the fetus versus benefits to the patient.

Therapy

To be therapeutically effective, amantadine hydrochloride must be administered as soon as possible and not later than 48 hours after onset of symptoms. Groups for which the panel felt therapy with amantadine hydrochloride should be strongly considered include:

  1. High risk patients as defined above.
  2. Patients in whom the physician makes the diagnosis of life-threatening primary influenza pneumonia or, children with life-threatening influenza-associated croup.
  3. Individuals whose positions are essential to community activities and for whom shortening of a symptomatic illness by 24 hours is judged important. It should be recognized that influenza is a mild disease in almost all otherwise healthy individuals and that treatment with amantadine hydrochloride will not be necessary in most such individuals. Initial evidence suggests that abnormalities in pulmonary function return to normal more rapidly in amantadine-treated patients than non-treated patients.
 What Are the Risks of the Use of Amantadine Hydrochloride in the Above-Described Fashions for the Prophylaxis and Treatment of Disease Caused By Influenza A Viruses?

The risks and problems that may develop from the use of amantadine hydrochloride pertain to both the individual recipient of the drug and to broader public health concerns:

Direct Side Effects of the Drug in Individual Patients

Numerous clinical trials involving over 11,000 subjects have been performed on amantadine prophylaxis for influenza A virus infections with careful evaluation of the side effects of the drug. Nervous system symptoms (insomnia, lightheadedness, nervousness, difficulty in concentration, or drowsiness) have been observed in up to 7 percent of individuals receiving amantadine (200 mg daily) in excess over control subjects receiving placebo. These effects tend to begin within several hours of receipt of a dose and are transient. If adverse symptoms do not develop in the first 48 hours after initiating prophylaxis or therapy, they are not likely to occur. If symptoms develop, they often subside during continuing drug administration. Mild impairment of intellectual acuteness and decreased motor function may occur and may influence a physician's decision whether to use such prophylaxis in the individual working at a very sensitive job requiring constant alertness. Other side effects occur at a low frequency and are of a less serious nature.

Chronic use of amantadine hydrochloride (for over 5 or 6 months), as in the treatment of Parkinson's disease, may be associated with the development of livido reticularis and peripheral edema; both resolve on omission of the drug. These findings do not appear to be a problem with the shorter courses of the drug that would be employed in the prophylaxis or treatment of influenza A infections. The use of amantadine hydrochloride in elderly subjects, based on extensive experience with patients with Parkinson's disease, does not appear to present other special problems or side effects. However, such patients merit further study for possible adverse reactions since they represent a group of patients with a higher likelihood of various coexisting organ dysfunctions which may contribute to drug toxicity.

The Potential for Drug Abuse

Thus far there have been no reports of abuse of amantadine hydrochloride by individuals attempting to alter their state of consciousness. Amantadine hydrochloride does not appear to provide prominent analgesia or euphoria, effects that might suggest the potential for misuse. Although available information would suggest that abuse of this drug is rather unlikely, some caution is still merited in view of the limited use of the drug until now.

Selection of Amantadine-Resistant Strains of Influenza A as a Result of Extensive Prophylactic and Therapeutic Use of This Drug

The spontaneous development of amantadine resistance among influenza A viruses in culture occurs at a relatively high frequency (about 1 x 10-4). Although amantadine-resistant variants have not as yet been isolated as the predominant virus from patients who have received the drug, the possible selection of such strains in the population under the pressure of extensive amantadine therapy must be considered. Inappropriate use of amantadine hydrochloride for prophylaxis and treatment of viral respiratory infections due to viruses other than influenza A or the widespread use of the drug beyond the special groups of patients indicated earlier may encourage the development of such resistance while not providing protection from influenza A for the most vulnerable patients. If such were to transpire, the current salutory prophylactic effect of the drug might be lost for the patients who truly need it, those patients at highest risk for fatal complications.  

Role for Combined Use of Amantadine Hydrochloride and Influenza Immunization

Immunization remains the primary method for prophylaxis against influenza. When amantadine hydrochloride is given for prophylaxis, it should be used as adjunctive therapy until the patient has received influenza vaccine and an immune response can be anticipated. Amantadine hydrochloride does not suppress the antibody response to inactivated influenza vaccine. If the patient had previously received vaccine containing antigen related to that of the current epidemic strain, an adequate antibody response can be anticipated in 70 to 80 percent of vaccines approximately 10 days after vaccine administration. Administration of amantadine hydrochloride can be discontinued at that time. Since vaccine efficacy is usually 70 to 80 percent, more prolonged administration of amantadine hydrochloride may provide an additional margin of protection for the elderly high-risk patient. If the patient had not received an antigenically similar vaccine in the past, administration of amantadine hydrochloride is continued for 4 to 6 weeks, assuming that influenza continues to occur in the community.

Immunocompromised individuals may not respond adequately to influenza vaccine. When the antibody status of such a patient is uncertain, amantadine prophylaxis may be indicated.  

Conclusions

 

  1. Under appropriate epidemiologic and clinical conditions, amantadine hydrochloride should be used in the prevention and treatment of influenza caused specifically by strains of influenza A.
  2. Amantadine hydrochloride should be considered complementary to active immunization with influenza vaccine in influenza control programs.
  3. The public and the medical profession should be made more aware of the need for and approaches to preventing influenza.
 

Unanswered Questions

During the discussion, the group recognized a number of areas in which the availability of further information would have rendered decisions easier. Such considerations, not necessarily listed in order of priority, include the following:

  • Procedures and facilities to enable rapid diagnosis of influenza A virus infection.
  • Additional studies of efficacy in elderly patients.
  • Additional studies in infants and children.
  • Better understanding of the pharmacology and pharmacokinetics of amantadine hydrochloride in all age groups, especially children and the elderly and in individuals with renal impairment.
  • The effect of amantadine hydrochloride on mortality due to influenza, especially primary influenza pneumonia.
  • Rimantadine as a congener which may be more effective and/or less toxic than amantadine hydrochloride.
  • Safety of amantadine hydrochloride in pregnancy.
  • Optimal regimens of dosage and duration of treatment.
  • Monitoring for the appearance of amantadine-resistant strain of influenza A virus.

Footnote


*Symmetrel is a du Pont registered U.S. trademark.

Consensus Development Panel

Jay P. Sanford, M.D. (Chairman)
Dean, School of Medicine
Uniformed Services University of Health Sciences
Bethesda, Maryland
Mrs. Laryl Lee Delker
Panel on Bacterial Vaccines with Standards of Potency
Moorestown, New Jersey
Robert H. Moser, M.D.
American College of Physicians
Philadelphia, Pennsylvania
John D. Nelson, M.D.
University of Texas
Southwestern Medical School
Dallas, Texas
Manuel Rodstein, M.D.
The Jewish Home and Hospital for the Aged
New York, New York
Karl Rolls, M.D.
Doctors Hospital Medical Complex
Sarasota, Florida
Morton N. Swartz, M.D.
Harvard Medical School
Cambridge, Massachusetts

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