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Amantadine Hydrochloride: Uses

Amantadine hydrochloride is used for symptomatic treatment and for prophylaxis of signs and symptoms of infection caused by various human and animal or avian strains of influenza A virus. While chemoprophylaxis with the drug should not be considered a substitute for annual vaccination with influenza virus vaccine, antiviral agents are critical adjuncts to influenza vaccine for the control and prevention of influenza.

Influenza Virus Infection, Treatment

When amantadine has been used in otherwise healthy adults and children for symptomatic treatment of uncomplicated influenza caused by susceptible influenza A virus and administered within 24-48 hours after the onset of symptoms, the drug has decreased viral shedding and reduced the degree and duration of fever, headache, and respiratory symptoms with a more rapid return to routine daily activities and improvement in airway function. It is not known whether amantadine is effective for the symptomatic treatment of these infections in patients whose symptoms have been present for more than 48 hours since most controlled studies evaluating efficacy of the drug only included patients whose symptoms had been present for 48 hours or less. Some clinicians state that they would still consider use of the drug during an influenza epidemic in patients whose symptoms have been present for longer than 48 hours.

Influenza Virus Infection

While amantadine and rimantadine generally are comparably effective in the treatment of influenza A infection, some evidence suggests that symptomatic improvement during the initial 24 hours of therapy with usual dosages of amantadine may be somewhat faster than that with rimantadine, probably because of pharmacokinetic differences between the drugs. In addition, although adverse effects of the drugs are similar, rimantadine may be associated with less frequent and/or severe nervous system effects.

Therefore, decisions regarding use of amantadine versus rimantadine for the treatment of influenza A infection should consider the patient's age, weight, and renal function; presence of other medical conditions; the potential for drug interactions; and the adverse effect profile and cost of the drug. Zanamivir or oseltamivir also can be used for treatment of influenza A infection; however, efficacy of these neuraminidase-inhibitor antivirals relative to amantadine or rimantadine remains to be more fully evaluated.

There have been no well-controlled studies to date to determine the efficacy of amantadine treatment in preventing serious complications of influenza A virus infection (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Most studies evaluating efficacy of amantadine for the treatment of influenza A infections have been performed in otherwise healthy adults and children with uncomplicated influenza; data are limited and inconclusive concerning efficacy of amantadine for treatment of influenza in individuals at high risk for serious influenza-related complications.

Resistant Strains of Influenza A Virus

Amantadine- and rimantadine-resistant strains of influenza A virus may appear in up to approximately 33% of patients receiving the drugs for treatment of influenza A infection. Individuals with influenza A infection who are receiving amantadine or rimantadine antiviral treatment may shed strains of the virus that are susceptible to the drugs early in the course of treatment; however, they also can shed resistant strains after 2-7 days of therapy. Immunocompromised patients may shed resistant strains for prolonged periods.

To minimize emergence of resistant strains, amantadine treatment should be discontinued as soon as clinically warranted, usually after 3-5 days or within 24-48 hours after the disappearance of signs and symptoms. Although most patients recover uneventfully even after resistant strains emerge (because of host immune responses), resistant strains are pathogenic and transmissible and can result in failures of drug prophylaxis in close contacts (e.g., family members, nursing home contacts). Individuals with influenza-like illness should be separated from and avoid contact with uninfected individuals as much as possible, regardless of whether they are receiving antiviral therapy.

Differential Diagnosis of Influenza and Influenza-like Illnesses

Early diagnosis of influenza infection can provide the option of using antiviral therapy and reduce unnecessary use of other anti-infective agents. The appropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. Some bacterial infections, including some that can lead to potentially severe or life-threatening complications, can produce symptoms similar to influenzainfection.In addition, bacterial infection can occur as a complication of influenza. The possibility of primary bacterial infection should be considered when making treatment decisions for patients with influenza-like illness, and clinicians evaluating such patients should consider a combination of epidemiologic, clinical, and, if indicated, laboratory and radiographic tests.

Influenza-like illness is a nonspecific respiratory illness characterized by fever, fatigue, cough, and other symptoms. Most cases are not caused by influenza, but by other viruses (e.g., rhinoviruses, respiratory syncytial virus [RSV], adenoviruses, parainfluenza viruses) or, less commonly, by bacteria (e.g., Legionella, Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae). In addition, several patients with inhalational anthrax that occurred in the US during September and October 2001 in the context of bioterrorism-related exposures to anthrax spores presented with symptoms of influenza-like illness. Therefore, the possibility of inhalational anthrax also should be considered when evaluating patients with influenza-like illness.

Adults or children can average 1-3 or 3-6 episodes of influenza-like illness, respectively, each year. Although influenza-like illness associated with influenza virus or RSV generally peaks during the winter; illness caused by rhinoviruses and parainfluenza viruses usually peaks during the fall and spring, and illness caused by adenoviruses occurs throughout the year. Respiratory illness caused by bacteria can occur throughout the year; however, illness caused by S. pneumoniae peaks during the winter and illness caused by Mycoplasma or Legionella is more common during the summer and fall.

Clinical Considerations

The presence of certain signs or symptoms may help to distinguish the various causes of influenza-like illness. Nasal congestion and rhinorrhea are features of most cases of influenza-like illnesses, but are infrequent in patients with inhalational anthrax.

Fever and/or chills, fatigue/malaise, cough (minimal or nonproductive), headache, myalgia, sore throat, and rhinorrhea are present in 64-94% of cases of laboratory-confirmed influenza. In patients with influenza-like illness from other viral or bacterial causes (except inhalational anthrax), these same symptoms are present in 62-94% of patients, although fever is present in only 40-73%. In these 2 groups of patients, nausea or vomiting occurs in 12%, abdominal pain in 22%, shortness of breath in 6%, and chest discomfort or pleuritic chest pain in 23-35%. In contrast, data from 10 patients with inhalational anthrax indicated that shortness of breath and chest discomfort or pleuritic chest pain occurred in 60-80%, nausea or vomiting in 80-90%, and abdominal pain in 30% of patients. In addition, 70% of these inhalational anthrax patients had profound, often drenching, sweats and all presented with fever or chills and fatigue/malaise, 90% with cough (minimal or nonproductive), 50% with headache, and 50-60% with myalgia, but only 20% presented with sore throat and only 10% had rhinorrhea.

Results of initial chest radiographs of 10 patients with inhalational anthrax indicated that 7 had mediastinal widening, 7 had infiltrates, and 8 had pleural effusion at the time of initial presentation; eventually pleural effusions were present in all of these patients.

Although most cases of influenza-like illness are not associated with radiographic findings of pneumonia, this can occur among the very young and in geriatric patients and patients with chronic lung disease. Influenza-associated pneumonia occurs in approximately 1-5% of adults, and in greater than 20% of influenza-infected geriatric adults. Influenza-associated pneumonia might be caused by the primary virus infection or, more commonly, by bacterial infection occurring coincident with or following influenza illness.

Diagnostic Tests

Several commercially available assays can be used for the rapid detection of influenza-like illnesses. Rapid tests for identification of influenza virus and RSV are available and, if used, should be done within the first 3-4 days of the illness when viral shedding is most likely. RSV antigen detection tests have a peak sensitivity of 75-95% in infants but do not have enough sensitivity to warrant their routine use among adults. Several available influenza rapid detection assays (e.g., Quidel Quickvue Influenza, ZymeTx Zstatflu) have a reported sensitivity and specificity range of 45-90% and 60-95%, respectively, and can easily be done in the clinician's office.

However, the clinical usefulness of these tests for the diagnosis of influenza in individual patients is limited because the sensitivity of the tests is relatively low.

These rapid influenza tests should not be done on every individual presenting with influenza-like illness, but (if used with viral cultures) can help determine whether influenza viruses are circulating among specific populations (e.g., nursing home residents, patients attending a clinic). The use of viral culture, in addition to rapid diagnostic tests, remains important because only cultures can provide information on the circulating influenza subtypes and strains.

Although there are no rapid screening tests to aid in diagnosis of inhalational anthrax in the early stages, blood cultures performed prior to initiation of anti-infective therapy can diagnostic. However, blood cultures should not be obtained routinely in patients with influenza-like illness who have no probable exposure to anthrax, but should be obtained in individuals in situations in which bacteremia is suspected.

Influenza Virus Infection, Prophylaxis

Results of numerous studies indicate that amantadine is about 70-90% effective in preventing influenza caused by type A strains. Clinical studies indicate that amantadine is as effective as rimantadine or influenza vaccination in preventing influenza A illness. The protective effect of amantadine or rimantadine and influenza vaccination may be additive. In contrast to results of studies evaluating efficacy when antiviral prophylaxis is given for a season or part of a season, results of studies evaluating antiviral prophylaxis with amantadine or rimantadine after a known exposure have not been consistent.

While postexposure prophylaxis with amantadine or rimantadine provided protection in families when the index case did not receive antiviral therapy, the drugs did not provide protection from influenza A infection in household contacts when amantadine or rimantadine was used to treat the index case, presumably because of spread of resistant virus within the household.

Annual vaccination with influenza virus vaccine, as recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is considered the primary means of preventing influenza and its complications. However, prophylaxis with an antiviral agent (e.g., amantadine, oseltamivir, rimantadine, zanamivir) is an important adjunct for the control and prevention of influenza.

Studies using amantadine or rimantadine for the prophylaxis of influenza A infection indicate that these drugs are about 70-90% effective in preventing illness from influenza A infection.

While amantadine and rimantadine are only effective in preventing influenza A infections, oseltamivir and zanamivir can be effective in preventing both influenza A and influenza B infections. Studies using oseltamivir or zanamivir for the prophylaxis of influenzainfection indicate that these drugs are about 79-84% effective in preventing febrile, laboratory-confirmed influenza A or B illness. Data are not available to date regarding the efficacy of any of these antiviral agents in preventing influenza in individuals who are severely immunocompromised.

Short-term prophylaxis with an antiviral agent (amantadine, oseltamivir, rimantadine, or zanamivir) may be indicated for high-risk individuals, household contacts of high-risk individuals, and health-care personnel who receive influenza virus vaccine after influenza activity begins. Antiviral prophylaxis during peak influenza activity may be considered for unvaccinated individuals who have frequent contact with high-risk individuals, including employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteers.

Antiviral prophylaxis also may be indicated when antigens contained in the current influenza virus vaccine do not closely match the viral strain, or when a poor antibody response to the vaccine is expected (e.g., in patients with severe immunodeficiency, including those with human immunodeficiency virus [HIV] infection).


Antiviral prophylaxis throughout the influenza season or during peak influenza activity may be considered for high-risk individuals when influenza virus vaccine is contraindicated (e.g., in individuals with a history of immediate hypersensitivity to egg protein or other ingredients in the vaccine) or when the vaccine is unavailable. The ACIP states that, unless contraindicated, antiviral prophylaxis can be offered to any individual who wishes to avoid influenza illness and that the decision whether or not to use such prophylaxis should be made on an individual basis.

Individuals considered at high risk for lower respiratory tract complications and death following influenza infection include those 65 years of age or older; residents of nursing homes and other chronic-care facilities that house individuals of any age with chronic medical conditions; children and adolescents (6 months to 18 years of age) receiving long-term salicylate therapy who may be at risk of developing Reye's syndrome after influenza infection; adults and children with chronic disorders of the cardiovascular or pulmonary systems (including asthma); and 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 drugs or HIV infection).

Although women who will be in the second or third trimester of pregnancy during the influenza season also are considered at high risk for influenza complications, safety of amantadine, oseltamivir, rimantadine, or zanamivir during pregnancy has not been established. Individuals at high risk, if they become ill with influenza, are more likely than the general population to require hospitalization, and hospitalization rates for these individuals may increase substantially during major influenza epidemics. Previously healthy children and younger adults also may require hospitalization for influenza-related complications, but the relative increase in their hospitalization rates during epidemics is lower than for individuals in the high-risk group.

Adjunctive Prophylaxis with Influenza Virus Vaccine

Individuals at high risk for influenza complications still can be vaccinated with influenza virus vaccine after an outbreak of influenza has begun in a community. However, the development of antibodies in adults can take as long as 2 weeks after vaccination.

Therefore, if influenza virus vaccine is administered after a local outbreak of influenza has begun, short-term antiviral prophylaxis should be considered for high-risk individuals. To provide protection until antibody responses to the vaccine develop, the antiviral agent usually is given for 2 weeks after vaccination. However, children younger than 9 years of age in this situation who are receiving influenza virus vaccine for the first time may require antiviral prophylaxis for up to 6 weeks following vaccination or until 2 weeks after the second dose of the vaccine.

Antiviral agents are used in the prevention and control of influenza outbreaks in hospitals or other institutions. When institutional outbreaks occur, antiviral prophylaxis should be administered to all residents, regardless of their vaccination status. If an outbreak is caused by a variant strain of virus that may not be controlled by the vaccine, the ACIP recommends that antiviral prophylaxis be considered for all employees, regardless of their vaccination status.

Antiviral prophylaxis may be indicated as an adjunct to influenza virus vaccine in individuals at high risk who are expected to have an inadequate antibody response to influenza virus vaccine, including HIV-infected individuals. The USPHS/IDSA recommends oseltamivir for prophylaxis of influenza A and B virus infection and rimantadine or amantadine for prophylaxis of influenza A infection.

HIV-infected Individuals

The ACIP, the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP), and the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA), currently recommend that annual vaccination be considered for all HIV-infected adults and children 6 months of age or older since these individuals may be at high risk of complications from influenza.

Influenza virus is not traditionally classified as an opportunistic pathogen, but many experts consider vaccination against the virus as logical in any HIV-infected individual (whether symptomatic or asymptomatic) because of the possible risks of respiratory infections in such patients and protective antibody levels are likely in many such vaccinees.Antiviral prophylaxis may be used in conjunction with, or as an alternative to, influenza virus vaccine in HIV-infected individuals who may have a poor antibody response to the vaccine and/or high risk of exposure to influenza A, especially during influenza epidemics or institutional outbreaks. The USPHS/IDSA recommends oseltamivir for prophylaxis of influenza A and B virus infection and rimantadine or amantadine for prophylaxis of influenza A infection.

Hematopoietic Stem Cell Transplant Recipients

Individuals who undergo hematopoietic stem cell transplant (HSCT) are at risk for a variety of opportunistic infections, including community-acquired respiratory viral infections (e.g., influenza, respiratory syncytial virus, parainfluenza virus, adenovirus). The CDC, the Infectious Diseases Society of America (IDSA), and the American Society of Blood and Marrow Transplantation (ASBMT) have established guidelines for preventing opportunistic infections in HSCT recipients.

These guidelines recommend lifelong annual vaccination with influenza virus vaccine in all HSCT recipients who are 6 months of age or older. However, because the vaccine is not likely to be beneficial and is not recommended during the first 6 months after HSCT, antiviral prophylaxis can be used if community or nosocomial influenza outbreaks occur during this time period. If influenza outbreaks occur and it has been 6-24 months after HSCT or it has been longer than 24 months after HSCT and the patient is still substantially immunocompromised (i.e., receiving immunosuppressive therapy, having a relapse of the underlying disease, graft-versus-host disease [GVHD]), the HSCT recipient should immediately receive influenza virus vaccine if they have not yet received their annual vaccination. In addition, during influenza A outbreaks, the HSCT recipient can receive antiviral chemoprophylaxis to provide protection until antibody responses to the vaccine develop.

To help prevent transmission of influenza A to a susceptible HSCT recipient, if influenza outbreaks occur and health-care workers, family members, or other close contacts of the HSCT recipient receive influenza virus vaccine, they also should receive a regimen of antiviral chemoprophylaxis to provide protection until a response to the vaccine is obtained. If a nosocomial outbreak occurs with an influenza A strain that is not contained in the available influenza virus vaccine, all healthy family members, close and household contacts, and health-care workers of HSCT recipients and candidates should receive antiviral prophylaxis until the end of the outbreak.

Although experience is limited to date regarding use of neuraminidase-inhibitor antivirals (oseltamivir, zanamivir) in HSCT recipients, these drugs can be offered to health-care workers, family members, or other close contacts for prophylaxis if amantadine or rimantadine cannot be tolerated, if the outbreak strain of influenza A is resistant to amantadine or rimantadine, or if the outbreak strain is influenza B.

Recommendations for prevention of influenza virus infection in HSCT recipients are the same for both allogeneic and autologous transplants. The guidelines for preventing opportunistic infections among HSCT recipients published by the CDC, IDSA, and ASBMT should be consulted for additional information on preventing opportunistic infections in these patients (including vaccinations) and for information on hospital infection control, strategies for safe living after transplantation, and hematopoietic stem cell safety.

Influenza, Outbreak Control in Institutions and Settings with Close-Proximity Living Conditions

Antiviral agents are used for the treatment and prophylaxis of influenza in hospitals and other institutions and are an important component of institutional outbreak control. In addition to use of antivirals, other outbreak control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, reoffering influenza vaccination to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients.

Most published reports on use of antiviral agents to control institutional outbreaks are based on studies where amantadine or rimantadine was used in influenza A outbreaks among nursing home residents. Limited information is available to date on use of oseltamivir or zanamivir for control of institutional outbreaks of influenza A or B.

When confirmed or suspected outbreaks of influenza occur in institutions that house individuals at high risk, antiviral prophylaxis should be initiated as early as possible to reduce the spread of the virus. Antiviral prophylaxis also can be considered for controlling influenza A outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings where individuals live in close proximity). Antiviral prophylaxis with rimantadine has been successful in controlling an influenza A outbreak aboard a large cruise ship.

Contingency planning for influenza outbreaks in institutions is needed to establish specific steps for rapid administration of antiviral agents when necessary, including preapproved medication orders or plans to obtain clinicians' orders on short notice. When institutional outbreaks occur, antiviral prophylaxis should be administered to all residents in the affected institution whether or not they received influenza vaccine the previous fall.

Prophylaxis for outbreak control should be continued for at least 2 weeks or until approximately 1 week after the end of the outbreak. To reduce the spread of the virus and to minimize disruption of patient care, antiviral prophylaxis can be offered to unvaccinated staff who provide care to high-risk patients. If the outbreak is caused by a variant strain of influenza A that may not be controlled by the vaccine, antiviral prophylaxis should be considered for all employees, regardless of their vaccination status.

To limit the potential transmission of drug-resistant influenza virus during institutional outbreaks, measures should be taken to prevent contact as much as possible between individuals receiving antiviral agents for prophylaxis and those receiving the drugs for treatment.

Influenza, Pandemic Control

Influenza viruses can cause pandemics, during which rates of illness and death from influenza-related complications can increase dramatically worldwide. Amantadine or rimantadine prophylaxis or treatment may be important first steps if an influenza pandemic occurs, especially if novel influenza A subtypes or animal or avian influenza strains that newly infect humans (e.g., avian type A [H5N1]) are involved since the currently available influenza virus vaccine would be unlikely to provide protection against these strains. The drugs may provide coverage against such strains until a new influenza vaccine can be formulated, produced, and distributed. Amantadine and rimantadine inhibit replication of virtually all naturally occurring human and animal strains of type A influenza virus.

While these antivirals would be useful in pandemic situations because of likely efficacy, other factors, including insufficient supplies, distribution limitations, and potential adverse effects (particularly for amantadine), could limit their usefulness, particularly for mass prophylaxis. In addition, it currently is unclear whether clinically important levels of resistant viral variants would emerge and distribute rapidly during extensive use of these antivirals in pandemic situations.

Current increases in the use of amantadine for the management of influenza in China, the likely origin of a future pandemic strain, contribute to concerns about potential resistant variants. It currently is not known what type and degree of selective drug pressure might cause extensive circulation of resistant variants in localized outbreaks or in the general community.

Currently, the principal usefulness of amantadine or rimantadine during a pandemic with type A influenza would appear to be for selective short-term prophylaxis until vaccine distribution and subsequent adequate antibody responses could be achieved and after known exposure (e.g., in household contacts and closed-population settings), and for the treatment of ill patients.

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