Influenza References
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Wintermeyer SM Nahata MC Rimantadine: a clinical perspective.
Ann Pharmacother (1995 Mar) 29(3):299-310 
OBJECTIVE: To provide a review of rimantadine, including its
  antiviral activity, pharmacokinetics, efficacy, adverse effects, drug
  interactions, and dosage and administration. Information on influenza
  A virus and clinical features of influenza disease are presented. 
  Comparative data on rimantadine and amantadine are described. DATA
  SOURCES: A MEDLINE search restricted to English-language literature
  published from 1966 through 1994 and an extensive review of journals
  was conducted. DATA EXTRACTION: The data on antiviral activity,
  pharmacokinetics, adverse effects, and drug interactions were
  obtained from various articles on rimantadine in open and controlled
  studies. Controlled double-blind studies were evaluated to assess the
  efficacy of rimantadine in prophylaxis and treatment of influenza A
  infection. DATA SYNTHESIS: Over 90% of a rimantadine dose was
  absorbed in 3-6 hours in healthy adults. Steady-state plasma
  concentrations have ranged from 0.10 to 2.60 micrograms/mL at doses
  of 3 mg/kg/d in infants to 100 mg twice daily in the elderly. Nasal
  fluid concentrations of rimantadine at steady-state were 1.5 times
  higher than plasma concentrations, which may explain the
  effectiveness of rimantadine despite a low plasma concentration. Over
  75% of a rimantadine dose was metabolized in the liver, and the
  parent compound and metabolites were almost completely eliminated by
  the kidneys. The elimination half-life ranged from 24.8 to 36.5
  hours, which allows once-daily dosing. Dosage adjustment is
  recommended for patients with severe renal impairment (creatinine
  clearance < or = 0.17 mL/s), severe hepatic dysfunction, or elderly
  nursing home patients. Drug-resistant strains of influenza A virus to
  rimantadine occurred in several studies with children and/or adults. 
  Clinical significance of drug-resistant strains has not been
  established. Rimantadine appeared to be effective in 85-90% of
  individuals for prevention of influenza A illness and in 50-65% for
  prevention of influenza A infection. Rimantadine reduced the time to
  a 50% reduction in symptoms by 1-3 days versus placebo. Differences
  in symptom reduction between rimantadine and placebo after the first
  3 days of treatment was not generally clinically significant. The
  most common adverse effects of rimantadine administration were
  associated with the central nervous system (CNS) and the
  gastrointestinal (GI) tract. CNS-related adverse effects occurred in
  3.2% of children younger than 10 years of age and 8.4% of adults. In
  elderly patients, the incidence of CNS-related adverse effects ranged
  from 4.9% at 100 mg/d to 12.5% at 200 mg/d. GI adverse effects
  occurred in 8.4% of children younger than 10 years of age, 3.1% of
  adults, and 2.9% at 100 mg/d and 17.0% at 200 mg/d in the elderly. 
  CONCLUSIONS: Rimantadine offers some desirable features for the
  treatment and prophylaxis of influenza A infection. It appears to be
  an attractive choice in elderly patients with a history of CNS
  adverse effects from amantadine and in patients with mild or moderate
  renal impairment. Although approved for twice-daily dosing,
  rimantadine has a pharmacokinetic profile that would allow once-daily
  dosing. It is effective for prophylaxis (not postexposure
  prophylaxis) and treatment of influenza A virus. It also has a low
  incidence of adverse effects. 
  
Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes MG, Soo W
Emergence and apparent transmission of rimantadine-resistant influenza A
virus in families.
N Engl J Med 1989 Dec 21;321(25):1696-702

To determine whether rimantadine can protect family members from acquiring
influenza A viral illness and to assess the possible selection of
drug-resistant strains of virus, we conducted a randomized, double-blind,
placebo-controlled study in three communities during two influenza seasons.
When influenza A occurred in a family, the members (including the index
patient) were given either rimantadine (adult oral dose, 200 mg per day) or
placebo for 10 days. The presence of illness was monitored by daily
recording of symptoms and temperature measurements; infection was determined
by isolation of the virus and by serologic studies. Among households with
documented influenza A infections, symptomatic illness occurred in one or
more contacts in 10 of 28 families treated with rimantadine and in 10 of 209
families treated with placebo. Asymptomatic secondary influenza A infections
were found in five families assigned to receive rimantadine and in four
families assigned to receive placebo. Rimantadine-resistant strains of
influenza A virus (H3N2 subtype) with mutations consisting of single amino
acid changes in the M2 protein (residue 27, 30, or 31) were recovered from
eight index patients and five contacts treated with rimantadine. There was
apparent transmission of drug-resistant strains of virus in six contacts
with secondary illnesses in five families. We conclude that when index
patients are treated concurrently, rimantadine is ineffective in protecting
household members from influenza A infection. If rimantadine is used for
both treatment and postexposure prophylaxis in families, rapid selection and
apparent transmission of drug-resistant influenza A viruses can occur.

Hayden FG, Sperber SJ, Belshe RB, Clover RD, Hay AJ, Pyke S
Recovery of drug-resistant influenza A virus during therapeutic use of
rimantadine.
Antimicrob Agents Chemother 1991 Sep;35(9):1741-7.]

The therapeutic activity of rimantadine and its relationship to the shedding
of drug-resistant influenza A virus were assessed in two randomized,
double-blind, placebo-controlled trials involving patients with
laboratory-documented influenza A virus (H3N2 subtype) illness of 2 days'
duration or less. In a family-based study, rimantadine treatment for 10 days
(24 children and adults) was associated with significant decreases in the
number of days to a 50% reduction in symptoms (mean difference, 2.5 days),
days of fever (1.6 days), and days of restricted activity (1.5 days)
compared with the results obtained with placebo-treated patients (32
children and adults). Drug-resistant virus was recovered from eight (33%) of
the rimantadine recipients on day 5. No differences in patient demographics
or illness severity at the time of enrollment in the study were apparent
between those who shed resistant virus and those who did not. Illness
resolution tended to be slower in those who shed resistant virus compared
with that in those who did not. In a study of adults treated for 5 days (six
treated with rimantadine, six treated with placebo), resistant virus was
recovered in three rimantadine recipients by day 3 of treatment. The
results indicate that drug-resistant influenza A virus (H3N2) can be recovered
from rimantadine-treated children and adults as early as 2 days after
starting treatment, but that rimantadine retains a net therapeutic benefit
compared with that of placebo.