Use of Antiviral Drugs for Influenza Recommended Guidelines for Practitioners Dr. Upton D. Allen University of Toronto Dr. Fred Y. Aoki University of Manitoba Dr. H. Grant Stiver University of British Columbia For the Canadian Pediatric Society and the Association for Medical Microbiology and Infectious Diseases Introduction and Background
Influenza A viruses and occasionally, influenza B strains, cause recurrent, almost annual epidemics in Canada, with significant morbidity, mortality, and economic loss 1.Widely accepted is the principle of immunization in minimizing the impact of influenza illness in individuals and populations, and the notion that antiviral drugs have a role in the management and control of influenza. However, our knowledge of best practices in immunization, such as the question of immunizing healthy children adults and pregnant women, continues to evolve as do our recommendations on the optimal use of antiviral drugs. While acknowledging that the latter area of practice continues to evolve, it was thought appropriate, nonetheless, to develop contemporary guidelines on the use of antiviral drugs for chemoprophylaxis and therapy, which are appropriate for the management of influenza in interpandemic periods. The recommendations that follow represent results of a joint effort supported by the Canadian Pediatric Society and the Association for Medical Microbiology and Infectious Diseases. The guidelines reflect the current state of knowledge regarding the use of influenza antivirals drugs, and may be modified as additional research data is forthcoming. II. Influenza Antiviral Drugs In Canada, currently licensed influenza antiviral agents are composed of two classes of drugs: the influenza A virus M2 proton channel blocker amantadine (Symmetrel™), and the influenza A and B virus neuraminidase inhibitors zanamivir (Relenza™) and oseltamivir (Tamiflu™). Rimantadine, an M2 ion channel blocker similar to amantadine but with less side effects, is licensed in the United States but not in Canada. Although a rationale for marketing rimantadine in Canada has recently been published 2, it is not currently approved for use so its possible role in influenza chemoprophylaxis and therapy will not be discussed further. Similarly, ribavirin administered to children ill with influenza as aerosol or oral tablets has been demonstrated to ameliorate symptoms and to be acceptably safe. However, as ribavirin is not licensed for influenza treatment or prophylaxis in Canada, it will also not be discussed further. The neuraminidase inhibitors are effective against recently emerging avian strains of influenza A H5N1 3-5, but virtually all of these highly virulent strains are resistant to amantadine 6. Formulations: Amantadine is formulated as 100 mg. Capsules, or the equivalent dose as 10 ml. of syrup. Oseltamivir comes in capsules of 75 mg or an oral suspension containing 12 mg/ml oseltamivir. Zanamivir is supplied in “Rotadisks” with 4 blisters containing 5 mg. of powder each. Antiviral drugs can be useful in the following settings: prophylaxis in a pandemic where an antigenic shift in the influenza A virus
has resulted in widespread influenza for which a vaccine is not yet available.
prophylaxis where a major antigenic drift or mutation has resulted in
circulation of an influenza strain not well matched to the currently available vaccine, e.g. drift from A/Sydney (H3N2)-like virus to A/Fujian (H3N2.
prophylaxis of high-risk patients who have received vaccine during an
outbreak but need time to develop an protective antibody response (2-3 weeks post-vaccination)
treatment of life-threatening influenza-like illness (ILI).
5. As treatment of persons with ILI who must be available for work-related or other
crucial responsibilities or whose comorbid conditions predispose them to a high risk of morbidity and mortality.
III. Prophylactic Efficacy
• Children The prophylactic efficacy of amantadine has been evaluated in four placebo-controlled trials in children > 8 years of age 7 (see Table 1.). Amantadine reduced the incidence of laboratory-confirmed influenza illness by 80% (median; range 69-92%). Zanamivir prophylactic efficacy has not been evaluated in controlled trials in children. However, children 5 to 17 years of age were included in a placebo-controlled trial of zanamivir for post-exposure prophylaxis of influenza in families 8. All families had 2 to 5 members including at least one child 5 to 17 years old. Zanamivir reduced the incidence of laboratory-confirmed illness from 18% (30/168 families) to 4% (6/169), a statistically significant difference. Tolerance was comparable between zanamivir and placebo therapy. Among asthmatics requiring regular use of medication, exacerbation occurred in 11% in the placebo group and 6% in the zanamivir groups 9. In a similar study of oseltamivir, post-exposure prophylaxis (75 mg o.d. x 7 days) reduced the incidence of laboratory-confirmed influenza in families from 23% (18/79 households treated with placebo) to 3.6% (3/84, treated with oseltamivir), a protective efficacy of 84% (p<0.001) 10. Each household consisted of 2 to 8 contacts > 12 years of age. Amantadine and oseltamivir are approved for influenza prophylaxis in children > 1 year and > 13 years of age, respectively.
Double-blind placebo-controlled trials of influenza antiviral drugs have demonstrated prophylactic efficacy ranging from 3%, when amantadine was used for prophylaxis of household contacts of persons being treated with amantadine, whereupon resistant virus
was transmitted 11, to 100% when the index case was not treated with amantadine 12 (Table 2). Amantadine has no effect on influenza B, due to differing conformation of the proton channel protein BM2. Both zanamivir and oseltamivir prevent influenza A and B , with an efficacy relative to placebo of 56 13 to 90% 14.
Table 1. Results of Selected Randomized Controlled Trials of Antiviral Drug Prophylaxis of Influenza
boarding school influenza outbreak A: n = 21 Control: n = 30
† This study was randomized but not blinded and had no placebo * Controls were not given placebo prophylaxis, but received oseltamivir treatment if developed infection
IV. Which prophylactic regimens are best?
There are no trials published that directly compare amantadine to the neuraminidase inhibitors (NAI’s), but the prophylactic efficacy of the two classes of agents is comparable. One should consider the potential side effects, cost, laboratory monitoring, and particularly the chance of virus resistance in choosing a regimen. The doses for prophylaxis and potential side effects are listed in Table 2. The emergence of influenza virus resistant to rimantadine (and therefore also amantadine) in households where an index case has been treated with M2 blockers, making rimantadine prophylaxis ineffective for family contacts 11,13, and residents of nursing homes 20, has been demonstrated. However, as noted in the 2004 recommendations of the CDC Advisory Committee on Immunization Practices 21 the effect of amantadine and rimantadine-resistance on the control of influenza has not been well studied. The Swedish recommendations published in 2003 report that amantadine has been withdrawn in Sweden in part because of the rapid emergence of resistance, as well as the “high frequency of central nervous system side effects” 22. With regard to the latter reason, rimantadine would likely be more tolerable, but neither of the ion channel blockers have any effect on influenza B. Furthermore, amantadine/rimantadine resistance has been steadily increasing worldwide 23, and H3N2 isolates from the 2005-06 season were 91% and 89% amantadine-resistant in the US 24 and Canada 25 respectively. Zanamivir is the recommended drug for treatment of influenza B in the Swedish recommendations, but this distinction is not made versus oseltamivir, in the CDC recommendations. Despite comparable efficacy in the trials listed in Table 3., Sweden has decided to recommend oseltamivir for prophylaxis over zanamivir, possibly because of rare reports of bronchospasm and “throat tightness” with zanamivir.
Table 2. Recommended dose regimens of amantadine, zanamivir and oseltamivir for prevention of influenza.
Amantadine Zanamivir Oseltamivir
Recommended dosage adjustments of amantadine according to creatinine clearance: based upon the current National Advisory Committee on Immunization (NACI), Canada Communicable Disease Report, 2005;31:1-32 Creatinine
Alternating daily doses of 100 and 200 mg Alternating dailydoses of 50 and 100 mg
100 mg thrice weekly 50 mg three times per week
Alternating weekly doses of 100 and 200 mg Alternating weekly doses of 50 and 100 mg
V. Treatment with antiviral drugs: Clinical Characteristics and Diagnosis of influenza: Proper diagnosis of influenza is important. The current influenza antivirals have no effect on other respiratory virus infections. Influenza illness in older children and adolescents is classically characterized by sudden onset of fever and chills accompanied by headache, malaise, myalgia, and cough that is non-productive 26. As the illness evolves, the respiratory tract signs become prominent with sore throat, nasal congestion, rhinitis, and a worsening cough. Influenza in younger children may be manifested as upper respiratory tract infection with a few additional symptoms or as a febrile illness with few respiratory symptoms. In infants, influenza may result in a clinical picture that mimics sepsis and can present as croup, bronchiolitis, and pneumonia. A well-recognized feature in some patients is acute myositis with calf tenderness and refusal to walk. This feature is particularly seen in children with influenza B infection. Other manifestations of influenza illness include Reye’s syndrome and central nervous system infection. Otitis media is a complication in 10% of children 27. In adults, the typical influenza syndrome is an acute onset fever with subsequent tracheobronchitis, although any upper respiratory infection syndrome can occur. Serious infection complications include bacterial pneumonia and rarely, primary influenza virus pneumonia. Treatment of influenza reduces the duration and severity of acute symptoms. Amantadine or rimantadine treatment has been associated, in as short a period as three days, with excretion of amantadine-resistant virus (despite a clinical response by the patient) which may infect close contacts 11. Emergence of resistance to the NAI oseltamivir has been reported in 18% of children being treated with this agent, 28 but there has been no report of human-to-human transmission or influenza illness due to these strains. Because clinically important resistance is rare with the NAI’s, they are the preferred drugs for treatment. Influenza antivirals should only be used for treatment when a patient demonstrates acute clinical symptoms compatible with influenza at a time when public health agencies report that influenza is prevalent in the community, or if at any time, influenza is specifically diagnosed by rapid tests. Zanamivir or oseltamivir should not be used if the duration of symptoms has been longer than 48 hours, as there are no data demonstrating effectiveness is negligible after this time. Diagnosing influenza illness by clinical criteria in adults is difficult and in children, even more problematical. Among non-immunized young healthy adults, the combination of a fever > 37.80C plus at least one respiratory symptom (sore throat, cough or nasal
symptoms) and one constitutional symptom (myalgia, headache, sweats, chills or fatigue) was confirmed to be influenza by laboratory testing in 60 to 71% of cases 29, 30. The presence of cough and fever > 37.80C had a positive predictive value for a laboratory- confirmed diagnosis of influenza of 86.8% although the negative predictive value is poor at 39.3% 31. Among immunized patients 60 years and older, the combination of fever, coughing and acute onset had a predictive value of 44% for a laboratory-confirmed diagnosis of influenza 32.The sensitivity and specificity of the clinical diagnosis of influenza in individuals at high risk of premature death and the development of complications of influenza due to older age or the presence of significant co-morbid medical conditions or prior immunization are not known. In children the clinical picture may be even less specific than in adults and they cannot articulate their symptoms as readily. Exclusive pediatric studies evaluating the sensitivity and specificity of a clinical diagnosis of influenza compared to a laboratory gold standard arelimited 33. In one study, fever, cough and rhinorrhea were the commonest clinical manifestations but they are all non-specific 34. Almost one third of pediatric patients seen in an emergency department during an epidemic had laboratory-confirmed influenza. Coexisting outbreaks of respiratory syncytial virus and influenza are not uncommon. Point of care or rapid laboratory tests to confirm the clinical diagnosis of influenza are sensitive (69-89%) and specific (83-99%) in children (because shed viruses in higher titer and for longer duration), but much less so in adults. They could be used to confirm the clinical diagnosis in children seen during an epidemic and add to the evidence supporting a decision to prescribe anti-influenza drugs and to not prescribe antibiotics. As well, they could be used to affirm that influenza is circulating in the community. The exact role for such tests remains unclear and will depend upon the peculiar economics of pediatric care in a region as well as the operating characteristics of the test. Treatment efficacy:
Clinical trials of the neuraminidase inhibitors in children have shown that acute symptoms are reduced by a median of 30 to 36 hours with zanamivir and oseltamivir respectively compared to placebo, otitis media is reduced by 44%, and antibiotic therapy is reduced by 25% 35 (Table 4).
In adults, randomized controlled trials of amantadine for early (within 24 hours of the onset of fever) treatment of influenza show a reduction in the severity of symptoms 36, 37. The more recent trials with zanamivir and oseltamivir started within 48 hours of the onset of symptoms (significant differences vs. placebo were found only in those equal or less than 36 hours for oseltamivir and equal or less
than 30 hours for zanamivir) demonstrate a reduction in symptoms of fever and cough from 1.5 to 3 days 29, 30, 38-40. The earlier the drugs are given after the onset of symptoms, the greater the reduction in duration of symptoms compared to placebo 41 (Table 5). Table 4.Randomized treatment trials of neuraminidase inhibitors involving children with influenza virus infections
Zanamivir 10 mg by oral Zanamivir 10 mg by oral Zanamivir 10 mg by oral Zanamivir 10 mg by oral Zanamivir 10 mg by oral Oseltamivir 2 mg/kg po
vs. 8.5% placebo. 5.5% of isolates resistant to oseltamivir.
Oseltamivir 2 mg/kg po
Table 5. Results of Selected Randomized Controlled Trials of Antiviral Drug Therapy of Influenza in Adults
VI. Use of influenza antivirals in pregnancy: There are no published trials of the use of either M2 proton channel blockers or NAI’s in pregnancy. The M2 blockers have both been shown to be teratogenic in animals in very high doses. If clinical circumstances warrant treatment or prophylaxis with an influenza antiviral agent in pregnant women, zanamivir is likely the better choice since it is administered by inhalation and systemic blood levels are comparatively much lower than oseltamivir. It is not known whether or not oseltamivir is excreted in human breast milk, and the decision to use it in lactating mothers should be made on a case by case basis. VII. Safety, Tolerance and Drug Interactions
Amantadine has some CNS stimulatory properties, and adults may complain of jitteriness, insomnia, and rarely nightmares. These may be more common (up to 15%) when the drug is used for several weeks for prophylaxis. Generally however, especially for the short time it is used for treatment (5 days), it is as well tolerated as placebo. Toxicity may be greater if there is accumulation in patients with impaired renal excretory mechanisms, and this applies particularly to the elderly. To avoid this it is recommended that elderly patients have serum creatinine levels measured at the beginning of treatment. Effective levels of amantadine are achieved in elderly patients given a reduced daily dose of 100 mg, rather than the usual 200 mg 45. In children, due to concerns regarding central nervous system toxicity caused by amantadine plus the fact that it is only active against influenza A, attention has been directed at developing the role of the neuraminidase inhibitors. Drug Interactions: Concomitant administration of triamterene and hydrochlorothiazide and trimethoprim-sulfamethoxazole caused central nervous system toxicity in adults, presumably due to interference with renal elimination of amantadine resulting in accumulation and toxicity. Neuraminidase inhibitors: Zanamivir: Zanamivir is administered as a powder by inhalation via a diskhaler. From 10 to 20% of the 10 mg inhaled dose is absorbed in adults, so systemic exposure is minimal. The drug is safe and well tolerated as evidenced by studies revealing no adverse effects after intravenous injection of 1200 mg/day to adult volunteers for 5 days. However, when administered as oral inhaled powder, practitioners are advised to beware of bronchospasm in zanamivir-treated patients. One other study of once daily inhaled zanamivir as prophylaxis of family members of index cases was unable to find an increased rate of asthma exacerbations in asthmatic contacts receiving zanamivir (6%) vs placebo (11%) 8. The other double-blind placebo-controlled trial of zanamivir treatment of influenza in patients 12 to 88 years of age (median 38 yrs) with asthma or chronic obstructive pulmonary disease did not find an increased incidence of bronchospasm in the zanamivir group 46. In fact the morning and evening peak expiratory flow rates were significantly increased in the zanamivir group 9. Despite this evidence there have been reports of acute bronchospasm in patients taking zanamivir, so that the Advisory Committee on Immunization Practices of the US Centers for Diseases Control and Prevention advised caution in using zanamivir for asthmatic and COPD patients and advised that the patient should have a short acting bronchodilator available during treatment 21. Drug Interactions: Interactions between zanamivir and other drugs co-administered systemically are neither likely nor expected due to the trivial absorption of zanamivir after oral inhalation. Oseltamivir:
The incidence of nausea or vomiting was increased by 3% over placebo in the therapeutic trials of oseltamivir, and by 3-12% in the prophylaxis trials, but rates of discontinuation were low and not different between the two groups, which consisted mostly of adults. Nausea or vomiting occurred early during therapy and usually then subsided despite continuation of the drug. No other side effects occurred significantly more frequently in oseltamivir than placebo recipients. Published pediatric data on the safety and efficacy of oseltamivir exist for children 1 year of age and older 44, 47. Pharmacokinetic data show that 2 mg/kg twice daily resulted in drug exposures within the range associated with tolerability and efficacy in adults who were administered approximately 1 mg/kg twice daily 47. A liquid formulation was shown in a randomized placebo controlled trial to be safe and well accepted by healthy children one to 12 years of age and children with asthma 6 to 12 years of age 44. In the placebo-controlled trial evaluating the therapeutic efficacy of oseltamivir in children 1 to 12 years of age, emesis occurred in 14.3% of children receiving oseltamivir 2 mg/kg/dose BID for 10 doses (max. 100 mg/dose) and 8.5% receiving placebo. Discontinuation rates due to adverse events were not different, being 1.8% and 1.1%, respectively 35. The safety and efficacy of oseltamivir in infants younger than 1 year of age have not been established. A caution was issued due to deaths observed in 7-day old mice receiving extremely high doses of the drug<4a>. These animals were fed a dose that was about 250 times the dose recommended for children. The concentrations of the pro-drug in the brain were 1500 times those of adult animals exposed to the same dose. Thus, it was felt that an immature blood–brain barrier may have caused the toxicity in these animals. Based on the ages of the animals and the stage of the development of their blood-brain barrier, the human equivalent was felt to be infants less than 1 year of age. In November 2005, there were reports of neuropsychiatric events and deaths in Japanese children receiving oseltamivir. The United States FDA has reviewed the available information and has concluded that the increased reports of neuropsychiatric events in Japanese children are most likely related to an increased awareness of influenza-associated encephalopathy, increased access to Tamiflu in that population, and a coincident period of intensive monitoring of adverse events<41b>. They were not able to establish a causal relationship between Tamiflu and the reported pediatric deaths. Drug Interactions: Interactions during coadministration of oseltamivir with other drugs are unlikely as it is eliminated largely unchanged into urine by glomerular filtration and renal tubular secretion by an anionic transporter and does not cause dose-related adverse effects in doses as high as VIII. Summary of Recommendations:
With respect to the role of antiviral drugs for the treatment or prevention of influenza infection, the Canadian Pediatric Society
and the Association of Medical Microbiology and Infectious Diseases Canada (AMMI) recommend the following: I. Drugs for the prevention and treatment of influenza:
Amantadine is approved and recommended for the prevention [evidence grade IB] and treatment [evidence grade IB) of only influenza A virus infection in individuals 1 year or older.
Zanamivir is approved and recommended for the treatment of influenza A and B virus infection in individuals greater than 7 years of age [evidence grade IA]. It may be used off-label for the prevention of influenza A and B virus infection in individuals greater than or equal to 5 years of age [evidence grade IA].
Oseltamivir is approved for the prevention [evidence grade IA] and treatment [evidence grade IA] of influenza A and B virus infection in individuals 13 years or older and older than 1 year, respectively. It may be used off-label for the prevention of influenza A and B virus infection in individuals greater than or equal to 1 year of age [evidence grade IA]. Based on current evidence it should not be used in infants less than 1 year of age [evidence grade IIID].
Prevention of influenza:
Antiviral drugs are recommended as a substitute for immunization to prevent influenza in the following situations:
When a vaccine is not available that is effective against strain(s) of influenza circulating in the community and exposure and the risk of illness is considered to persist throught the outbreak, amantadine, zanamivir or oseltamivir may be administered until vaccine becomes available or the outbreak has subsided, so called “seasonal prophylaxis” [evidence grade IB]. Data in Table 1 illustrate that the experience with these three drugs for seasonal prophylaxis is not uniform across all age groups.
Since no comparative trials have been conducted to support the selection of one agent from among the group,
the choice of drug to administered will depend upon other factors such as virus susceptibility (e.g. influenza A H5N1 is susceptible to NAI but not M2I drugs), ease of dosing (zanamivir = oseltamivir >> amantadine), tolerance (zanamivir > oseltamivir >> amantadine) and cost (amantadine << zanamivir = oseltamivir).
Prophylaxis may be continued until the outbreak has subsided (usually 2-6 weeks). Alternatively, it may be
discontinued if a vaccine has become available or if it is suspected that the individual has experienced (mild) influenza attenuated by chemoprophylaxis or less likely, has been shown to have been infected, based on laboratory testing which demonstrates that subclinical influenza has occurred due to the circulating strain, as demonstrated by culture, PCR of respiratory secretions or by the presence of hemagglutinin-inhibiting antibody.
When vaccine is contraindicated, seasonal chemoprophylaxis as discussed in (A) may be considered [evidence grade IIIC]. For example, when an individual has immediate-type hypersensitivity to egg protein, traces of which may be
present in vaccines prepared in embryonated chicken eggs, or to some other substance in the vaccine formulation, chemoprophylaxis is recommended. The choice of drug will require consideration, at least, of the factors listed above (Section II.A.).
The duration of prophylaxis may be as described above in II.A.
When an immediate protective effect is required chemoprophylaxis has been shown to be effective and well tolerated. Such a need may exist when i) an outbreak is diagnosed in a closed institutional setting or ii) in the family setting or iii) when influenza is causing illness in the community even as vaccine is being administered. i)
Prophylaxis in a closed institutional setting may be initiated when an outbreak is diagnosed [evidence grade IIB]. An outbreak may be diagnosed if at least two residents developing acute influenza-like illness within 72 hours of each other have laboratory-confirmed influenza illness which confirms that influenza is being transmitted. All three drugs have been used for outbreak contol in nursing homes. Zanamivir and oseltamivir may be preferable to amantadine [evidence grade IB].
Usually, chemoprophylaxis for outbreak control in an institution is administered for 10 days.
Prophylaxis may be discontinued if > 8 days have elapsed since the onset of the last case of influenza in the unit. If new cases continue to appear, prophylaxis will, by corollary, need to be continued so that this strategy could become in effect, seasonal prophylaxis.
When influenza occurs in the family setting, post-exposure chemoprophylaxis in unaffected members should be considered to reduce illness in the family [evidence grade IA].
Unaffected family members should be started on chemoprophylaxis as soon as possible after recognition
of influenza-like illness in the index case. All three drugs are recommended for post-exposure prophylaxisunless the virus is known to be resistant. Duration of prophylaxis is usually 7 to 10 days.
The index case may be treated with the recommended 5-day course of zanamivir or oseltamivir, but not
amantadine. Treatment of the index case with amantadine has resulted in failure of amantadine prophylaxis in other family members due to the rapid development of amantadine-resistant mutants in the treated index case.
Chemoprophylaxis may be utilized to protect individuals until vaccine-induced immunity develops [evidence grade IIIB]. When vaccine is co-administered that is expected to protect against a circulating strain causing illness in the community, chemoprophylaxis should be continued until vaccine-induced immunity is likely to have developed. The time for vaccine-induced immunity to develop may be 7 to 10 days if the virus strains in the vaccine are drift variants of strains that have been causing illness in one or more previous years such that some heterologous immunity is likely to exist that can be boosted by the current vaccine.
Where the vaccine contains a virus arising as a result of antigenic shift, (i.e. a pandemic strain), vaccine-
induced immunity may require two or more doses of vaccine. Chemoprophylaxis will need to be continued until it is probable that immunity has developed, as demonstrated by clinical trials, probably 2 to 3 weeks.
When high-risk individuals have been immunized but the vaccine strain(s) match poorly one or both of the hemagglutinin and/or neuraminidase antigens of the circulating strain, chemoprophylaxis is recommended [evidence grade IIIB].
The duration of prophylaxis will be as in II.A. above.
When individuals are not likely to respond to vaccine due to an immunocompromised state due to drugs or disease, chemoprophylaxis is recommended [evidence grade IIIB].
The duration of prophylaxis will be as in II.A. above.
Treatment of influenza illness:
In general, antiviral chemotherapy is recommended for individuals with severe illness and those most likely to develop complications of influenza or to die prematurely as a result of same.
When antiviral drugs are administered for treatment of influenza A or B infection, it is recommended that amantadine not be prescribed because of the high probability of the emergence of resistance [evidence grade IA], with possible treatment failure [evidence IB] and spread to others receiving amantadine for prophylaxis [evidence grade IA].
Since there have been no studies directly comparing the relative efficacies and safety of zanamivir and
oseltamivir, selecting one drug from among these agents will need to be based on such considerations as ability to orally inhale zanamivir or to tolerate its uncommon irritant effect on the tracheobronchial tree with resulting bronchospasm.
When zanamivir or oseltamivir are administered for treatment of influenza, they should be started as soon as possible after onset of symptoms [evidence grade IA] and in no case after 48 hours of symptoms (see next).
When the patient has been symptomatic for more than 48 hours, it is recommended that antiviral therapy not be prescribed [evidence grade IIIC].
For seriously ill patients, combination therapy with amantadine and an NAI may be considered [evidence grade IIIC].
E. For treatment of pregnant or breast-feeding women ill with influenza, it is noted that none of the drugs listed above can
be recommended as none has been evaluated for efficacy or safety in pregnant women or is approved for administration to them [evidence grade IIIC]. However, zanamivir is minimally bioavailable after oral administration. Thus, zanamivir administration to pregnant women is likely to cause minimal fetal exposure. Hence, from the point of view of safety, it may be the drug of choice for administration to pregnant women [evidence grade IIIC].
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DOENÇA METABÓLICA ÓSSEA DA PREMATURIDADE Miza Mª Barreto A. Vidigal Capítulo do livro Assistência ao Recém-Nascido , editado por Paulo R. Margotto, 2ª Edição DEFINIÇÃO Conjunto de condições que determinam alterações no processo de mineralização óssea levando a fragilidade do suporte estrutural deste e nos casos mais graves, pode ocasionar o aparecimento de fratu
“Practique español con nosotros” Lección 14: “Don Juan Tenorio” 1. Lea la siguiente introducción. El 31 de octubre, víspera de todos los santos, es la fecha en la que los católicos recuerdan a sus muertos. La celebración de la noche de Halloween pertenece a la cultura anglosajona y tiene su origen en las costumbres celtas. Son incontables los rituales que se c