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Summary of prescribing guidance for thetreatment and prophylaxis of influenza-likeillness: TREATMENT PHASE This guidance is intended to enable health protection units (HPUs) to address local queries about the treatment and prophylaxis of influenza A(H1N1). It is not a substitute for the Summary of Product Characteristics (SPC) and the Patient Information Leaflet (PIL) which must accompany the Further information is also available on the HPA website: www.hpa.org.uk Current guidelines are based on the Department of Health document Use of antiviral drugs in an influenza pandemic - scientific evidence base. Available from: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_077276 Note: NICE guidance on triggering prescription of antiviral medications does not apply during a flu pandemic. This guidance will be regularly reviewed and updated. Please refer to the HPA or Department of Health website.
TREATMENT OF SUSPECTED INFLUENZA A(H1N1)
Indications
drugs are not recommended for use in pregnancy unlessthe benefit to the mother justifies the theoretical risk to Adults and children over the age of one year the fetus. In the current circumstances the balance of Ideally treatment to be administered within 12-48 hours benefit to risk supports their use and they should be of onset of symptoms. Stop treatment if a negative provided for pregnant women. Indeed appropriate laboratory result is obtained. Current cases should be treatment of pregnant women with oseltamivir or defined as per the HPA case definition available from: zanamivir will help to reduce symptoms such as fever and Zanamivir is the recommended medicine, as it is inhaled Children under the age of one who have symptoms of and reaches low concentrations in the blood. However, if influenza should be treated with oseltamivir 2mg/kg a pregnant women has a contraindication to zanamivir, twice a day for 5 days. Children in this age group with or requires a medicine which is systemically active influenza symptoms will be assessed by a GP or other healthcare worker experienced in assessing children. Atthis assessment, the correct dose of antiviral medicine References:• Department of Health. Pandemic Influenza: guidance of preparing will be determined and any other medical management maternity services. 2008. Available from:www.dh.gov.uk/en/Publicationsandstatistics requirements will be identified. GPs will be available to /Publications/PublicationsPolicyAndGuidance/DH_091737.
• Department of Health. Recommendations on the use of antiviral medicines for review these children in the community, and will have low pregnant women, women who are breastfeeding and children under the age threshold for referring children to hospital clinics for further management decisions if severe or complicatedinfluenza, or adverse effects of treatment are suspected.
The UK Teratology Information Service (UK-TIS)The UK Teratology Information Service (UK-TIS, formerly Note: The HPA recommends advising clinicians to seek NTIS), which is a service commissioned by the HPA, have extra advice when prescribing for children under agreed to undertake the surveillance of pregnancy outcomes where women are prescribed oseltamivir or zanamivir.
Reference:• Department of Health. Recommendations on the use of antiviral medicines for Any woman who is pregnant and is confirmed as having pregnant women, women who are breastfeeding and children under the age of been exposed to an antiviral should be asked for herpermission for her contact details to be passed on to UK-TIS who can be contacted on 0844 892 0909.
As with many medicines, oseltamivir and zanamivir havenot been specifically tested in pregnancy and Informed consent to pass on contact details to UK-TIS breastfeeding and, therefore, are not licensed for this should be sought. UK-TIS have prepared a suitable script use. However, use in several hundred women during for seeking this information, the form of words pregnancy has not provided any evidence of harm to the fetus, and no harm has been shown in pregnant animalstreated with oseltamivir. In normal circumstances, these 'It is important to collect information on the effects of fluand its treatment on people in special groups, including Summary of prescribing guidance for thetreatment and prophylaxis of influenza-likeillness: TREATMENT PHASE those who are pregnant, as this helps us provide advice in the future. To allow us to do this, would you mind if we The recommended dose for children under one year of passed on your details and those of your GP to UK-TIS to age is 2mg/kg twice daily for 5 days. The Department of allow them to do this as part of their routine Health has provided the tables below regarding volumes to be administered in the under ones for different weight ranges. Further details about the UK-TIS service are available from: There are two different preparations which can be used www.hpa.org.uk/web/HPAweb&Page&HPAwebAutoListNa in this age group: one is a suspension manufactured by Roche, Tamiflu® suspension; and the other a solution ofoseltamivir, which will be prepared by designated We have provided an example checklist with available licensed hospital pharmacy manufacturing units. They are evidence on treatment for discussion with pregnant of differing concentrations and volumes; oseltamivir suspension has a strength of 12mg in 1 ml andoseltamivir solution has a strength of 15mg in 1ml; see Oseltamivir and its active metabolite, oseltamivircarboxylate, are excreted into human breast milk in very Note: The syringe provided in the Tamiflu® suspensions small amounts. Limited data suggest that clinical package should be discarded and replaced with a 3ml sequelae from maternal treatment would not be oral syringe, provided separately, to allow for There are no data on zanamivir use during lactation but Table 2 Department of Health recommended treatment doses of
based on limited bioavailability the systemic exposure of oseltamivir for children under the age of one year a breast fed infant from maternal treatment is expected Women who are breastfeeding who have symptoms of influenza should be treated with an antiviral medicine.
The preferred medicine is oseltamivir, as for other adults.
However if a woman’s baby is born and breastfeeding is started while the woman is taking zanamivir, she should complete the course of zanamivir, it is not necessary to References:• UK Medicines Information (www.ukmi.nhs.uk/) • Department of Health. Recommendations on the use of antiviral medicines for pregnant women, women who are breastfeeding and children under the age Administration and dosage schedule
For adults and children over the age of one year Oseltamivir capsules should be used as indicated in Table1 below: (1) This dose should be given TWICE a day for five days. Please dispense only ONE of thesealternative preparations.
(2) The HPA recommends advising clinicians to seek extra advice when prescribingfor children under 2 months old.
Table 1 Department of Health recommended treatment doses of oseltamivir for adults and children over the age of one year
30mg twice daily for five (5) days (ONE 30mg capsule to be taken twice a day for five days) 45mg twice daily for five (5) days (ONE 45mg capsule to be taken twice a day for five days) 60mg twice daily for five (5) days (TWO 30mg capsules (total of 60mg) to be taken twice a day for five days) 75mg twice daily for five (5) days (ONE 75mg capsule to be taken twice a day for five days) (1) Ideally dose should be calculated based upon the weight of the patient, however, during a pandemic this may not be practical and the use of the age based table above is appropriate.
(2) See appendices for accompanying vouchers and labels Summary of prescribing guidance for thetreatment and prophylaxis of influenza-likeillness: TREATMENT PHASE Renal Impairment or patients on renal Oseltamivir solution has a bitter taste and may require the addition of a small volume (less than 10ml) of a The advice of experts in renal medicine is that patients strongly flavoured sugary drink eg black current squash, who regularly attend a specialist renal clinic for to help very young children to tolerate the medicine. If management of renal failure should have their dose the medicine is added to a drink then the parents should considered by their usual renal team.
be told to make sure that the whole volume of the drinkis taken.
Zanamivir may be preferable in a patient with renalfailure as it is poorly systemically absorbed. Please also Note: The suspension and the solution are of differing concentrations and therefore different volumes by child’sweight are required for the two preparations. Always use Table 3 Department of Health recommended treatment dose of
the correct table to determine the volume for the oseltamivir for adults with renal impairment Recommended dose for oseltamivir treatment Table 4 Side effects of oseltamivir listed in the British
nausea, vomiting, abdominal pain, diarrhoea; See Renal Handbook and discuss with renal team See Renal Handbook and discuss with renal team hepatitis, arrhythmias, neuropsychiatric disorders Reference: SPC & Renal Handbook, 3rd edition. (in children and adolescents), visual disturbances, Formulations
Reference: British National Formulary, March 2009. Capsules30mg capsules (yellow), 10 cap pack45mg capsules (grey), 10 cap pack Table 5 Side effects of oseltamivir listed in the British
nausea, vomiting, abdominal pain, dyspepsia, The capsules should be administered as per Table 1. diarrhoea, headache, fatigue, insomnia, dizziness, If adults, adolescents or children are unable to swallow capsules they may receive appropriate doses of Tamiflu hepatitis, Stevens-Johnson syndrome, and toxic by opening capsules and pouring the contents of epidermal necrolysis, neuropsychiatric disorders capsules into a suitable, small amount (1 teaspoonmaximum) of sweetened food product such as regular or sugar-free chocolate syrup, honey (only for children twoyears or older), light brown or table sugar dissolved in Reference: British National Formulary for Children, March 2009. water, dessert toppings, sweetened condensed milk, (1) Any adverse effect should be reported using the yellow card system.
apple sauce or yogurt to mask the bitter taste. The mixture should be stirred and the entire contentsgiven to the patient. The mixture must be given immediately after its preparation. It is not necessary toadminister any undissolved white powder as this is Administration, dosage and
formulation
Sugar-free, tutti-frutti flavoured, oseltamivir (as TWO 5mg blisters to be inhaled (using the ‘Diskhaler’) phosphate) for reconstitution with water, 12mg/1ml the twice a day for five days (equivalent to 10mg twice a day Department of Health have advised that the suspension must be reserved for under 1 year olds only.
Caution: Asthma and chronic pulmonary disease (risk of bronchospasm); a short acting bronchodilator should be A solution of oseltamivir 15mg in one ml is being available. Avoid in severe asthma unless close monitoring prepared by designated licensed hospital pharmacy possible and appropriate facilities available to treat manufacturing units. The same 3 ml syringe as for the bronchospasm), uncontrolled chronic illness, other Tamiflu suspension will be provided for measuring the inhaled drugs should be administered before zanamivir. volume. The volume should be determined from thetable headed ‘oseltamivir solution 15 mg in one ml’. Reference: British National Formulary / British National Formulary for Children, March 2009.
Summary of prescribing guidance for thetreatment and prophylaxis of influenza-likeillness: TREATMENT PHASE Renal impairment or patients on renal Reference: UK Medicines Information (UKMi): www.ukmi.nhs.uk/ replacement therapiesZanamivir may be the preferred drug of choice in Note: Paediatric patients with severe renal impairment are not covered by this guidance. Seek specialist advice in all cases.
• Inhaled zanamivir results in approximately 10%-20% of the inhaled dose being absorbed.
Following inhalation, zanamivir is entirely excreted Table 6 Side effects of zanamivir listed in the BNF / BNFC
• The half life of zanamivir is prolonged in patients impairment, angioedema, urticaria, and rash; also reported, neuropsychiatric disorders (especially in • Given the importance of local concentrations, the low systemic exposure, and the previous tolerance of much impairment, angioedema, urticaria, and rash higher exposures, the manufacturers recommend that no dose adjustment is required in patients with Reference: British National Formulary / British National Formulary for Children, March 2009. • There is no published data about the use of zanamivir in patients undergoing renal replacement therapies,however for the above reasons, it has been suggested that the normal dose is used in these patients. PROPHYLAXIS OF INFLUENZA A (H1N1)
Indications
Adults and children over the age of one year novel pandemic virus strain, the preferred antiviral Currently the HPA algorithm should be followed to determine who needs prophylaxis, available from:www.hpa.org.uk Breastfeeding In the context of a novel influenza virus in a pandemic Note: Stop treatment if a negative laboratory result is situation the EMEA suggest the benefit of using antiviral medicines outweighs the risk, for both treatment and prophylaxis.
Under 1 year of ageThe balance of benefit and risk for using oseltamivir for If it is decided that a women who is breastfeeding the prophylaxis of influenza in children under one year requires prophylaxis because of family or other contact who are not currently suffering from influenza symptoms with a novel pandemic virus strain, the preferred antiviral is not clear. A decision on whether prophylaxis with medicine is oseltamivir. However if a woman’s baby is oseltamivir should be recommended should be taken by born and breastfeeding is started while the woman is an expert in the care of young children.
taking zanamivir, she should complete the course ofzanamivir: it is not necessary to switch to oseltamivir.
Reference:• Department of Health. Recommendations on the use of antiviral medicines for pregnant women, women who are breastfeeding and children under the age • Department of health. Recommendations on the use of antiviral medicines for pregnant women, women who are breastfeeding and children under the age of oneyear. 2009.
• EMEA. Guidance on use of antiviral medicines in the event of an influenza A/H1N1 In the context of a novel influenza virus in a pandemic pandemic. Available from: www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/27353509en.pdf situation the European Medicines Agency (EMEA) suggestthe benefit of using antiviral medicines outweighs therisk, for both treatment and prophylaxis.
If it is decided that a pregnant women requiresprophylaxis because of family or other contact with a Summary of prescribing guidance for thetreatment and prophylaxis of influenza-likeillness: TREATMENT PHASE Renal Impairment or patients on renal replacement therapies The advice of experts in renal medicine is that patientswho regularly attend a specialist renal clinic for Administration and dosage schedule
management of renal failure should have their doseconsidered by their usual renal team See Table 7 below. The Committee for Medicinal Products for Human Use (CHMP), EMEA has reviewed the evidence Department of Health recommended prophylaxis dose of oseltamivir for adults with renal impairment for under 1 year olds and noted that there is lessevidence to support the use of Tamiflu for the prevention of influenza. Therefore doctors should carefully consider the benefits and risks for each infant.
Reference:• EMEA. Guidance on use of antiviral medicines in the event of an influenza A/H1N1 See Renal Handbook and discuss with renal team pandemic: www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/27353509en.pdf See Renal Handbook and discuss with renal team Interim guidance on the use of oseltamivir Reference: SPC & Renal Handbook, 3rd edition.
(1) Paediatric patients with renal impairment are not covered by this guidance. Seek specialist The current Department of Health guidance on dosage of oseltamivir in secondary school age children (academic (2) Zanamivir may be preferable in a patient with renal failure as it is poorly systemicallyabsorbed. Please refer to zanamivir section.
years 7-11 / age 11-16 years) is covered by tworecommendations: Formulations
• If child is over 7 years and under 13 years of age (expected to be in the body weight range of 23-40kg) dose is 60mg once daily for 10 days. Side effects
Covered in treatment section above.
• If child is over 13 years (expected to be over 40kg body weight) dose is 75mg once daily for 10 days (adult dose). This may be amended in the case of large scale Administration, dosage and
prophylaxis for secondary schools in children aged 11 formulation
years and above; provided that 30mg capsules are notavailable, or, there is a need to enable simpler logistic Inhalation of powder, adult and child over 5 years.
TWO 5mg blisters to be inhaled (using the ‘Diskhaler’)once a day for ten days (equivalent to 10mg once a day • All children in secondary education (national academic year 7 and above) 75 mg once daily for 10 days provided that body weight is above 23kg. If body Renal impairment or patients on renal weight is 23kg, or less, then an individually calculated dose based upon weight and age should be used. No dose adjustment necessary. See treatment section above.
As this is interim guidance, whenever an HPU wishes touse this amended protocol they must contact the DeputyNational Incident Director (Medical) at the NECC toensure that it is still current and that the circumstanceswarrant its use.
Table 7 Department of Health recommended prophylaxis doses of oseltamivir for adults and children over the age of one year
30mg once daily for ten (10) days (ONE 30mg capsule to be taken once a day for ten days) 45mg once daily for ten (10) days (ONE 45mg capsule to be taken once a day for ten days) 60mg once daily for ten (10) days (TWO 30mg capsules (total 60mg) to be taken once a day for ten days) 75mg once daily for ten (10) days (ONE capsule to be taken once a day for ten days) (1) Ideally dose should be calculated based upon the weight of the patient, however, during a pandemic this may not be practical and the use of the age based table above is appropriate.
(2) See appendices for accompanying vouchers and labels.
Summary of prescribing guidance for thetreatment and prophylaxis of influenza-likeillness: TREATMENT PHASE • Department of Health. Use of antiviral drugs in an influenza pandemic - scientific evidence base.2006. Available from: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_077276 • Department of Health. Pandemic Influenza, Guidance of preparing maternity services. Available from: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_091737 • British National Formulary (BNF), March 2009.
• UK Medicines Information (UKMI) www.ukmi.nhs.uk/ • The electronic Medicines Comdpendium (eMC). Oseltamivir SPC. Available from: http://emc.medicines.org.uk/document.aspx?documentId=10446 • Renal Handbook, 3rd edition. Caroline Ashley and Aileen Currie, editors.
• Health Protection Agency algorithms. Available from: www.hpa.org.uk • RCPCH consensus statement available from: www.rcpch.ac.uk/Research/CE/Guidelines-frontpage/Guideline-Appraisals-by-Topic/practice-statements • EMEA. Guidance on use of antiviral medicines in the event of an influenza A/H1N1 pandemic. Available from: www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/27353509en.pdf • Draft briefing and guidance for adult renal units in the UK during an influenza pandemic. Prepared for the Renal Association of Clinical Affairs Board. 2007.
• Robson R, Buttimore A, Lynn K, et al. The pharmacokinetics and tolerability of oseltamivir suspension on haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 2006;21(9):2556-62 • Department of health. Recommendations on the use of antiviral medicines for pregnant women, women who are breastfeeding and children under the age of one year. 2009. Evidence relating to children aged under 1 Drug interactions in the treatment of HIV infection Background information for discussion with pregnant women Internal review of some of the original papers Oseltamivir is not licensed in children under 1 year.
However, Okamoto et al from Japan published a During influenza seasons it is recognised that children retrospective study of 103 children less than one year younger than 24 months are consistently at substantially higher risk of hospitalisation than are older children, andthe risk of hospitalisation attributable to influenza infection is highest in the youngest children.
www.fda.gov/medwatch/SAFETY/2003/tamiflu_deardoc.pdf) The Science and Research Department of the UK Royal College of Paediatrics & Child health have produced a The alert highlights the company’s concern following consensus statement on the use of oseltamivir in preclinical trials involving deaths in immature rats. infants under one year of age during a ‘flu pandemic The 7-day rats that died were associated with unusually which took account of expert opinion and information high exposure to both oseltamivir and oseltamivir available as of May 2009. Their full statement is phosphate. Further studies were carried out available on their website. Their summary The alert goes on to state that the clinical significance of Clinicians should weigh up the potential risks and these preclinical data to human infants is uncertain.
possibility of ineffective treatment versus the potential However, due to concerns over immature blood brain benefit of treatment in each case and ensure there has barriers in children under one year, Roche recommended been discussion with parents to enable them to make that Tamiflu not be administered to children less than an informed choice. If treatment with oseltamivir is considered for symptom relief in infants less than one year, the dose used in the published Japanese studies The Japanese group did not find any cases of fatality or (2 mg per kg twice daily) for five days would currently encephalopathy in 102 children (one lost to follow-up).
The authors did this study because of clinical concernsregarding influenza encephalopathy in this age group This is consistent with the advice given by the European and the fact that they would usually use oseltamivir to Medicines Agency on the 8th May 2009 that: In case of a pandemic, the Committee [for Medicinal The review by Whitley and Monto, 2006 refer to three Products for Human Use (CHMP)] agreed that there is clinical toxicology studies which had identified enough evidence to support the use of the Tamiflu neurotoxicity in newborn rats administered oseltamivir.
[oseltamivir] for the treatment in children younger They point out that the dosage used was higher that that than one year of age. The Committee noted that there used for humans and that the metabolism of oseltamivir is less evidence to support the use of Tamiflu for the prevention of influenza. Therefore doctors should carefully consider the benefits and risks for each infant. Should Tamiflu be prescribed to children under the age of one, the recommended dosage is 2 to 3 mg per kg body weight. 1. The RCPCH consensus statement available from: www.rcpch.ac.uk/Research/CE/Guidelines-frontpage/Guideline-Appraisals-by-Topic/practice-statements 2. EMEA, Guidance on use of antiviral medicines in the event of an influenza A/H1N1 pandemic, available from: www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/27353509en.pdf 3. Committee on Infectious Diseases. Prevention of Influenza: Recommendations for Influenza Immunization of Children, 2007–2008. Pediatrics 2008;121;e1016-e1031, 4. Richard J. Whitley, Arnold S. Monto. Prevention and Treatment of Influenza in High-Risk Groups: Children, Pregnant Women, Immunocompromised Hosts and Nursing Home Residents. 5. Okamoto, S, Kamiya, I, et al. Experience with Oseltamivir for Infants Younger Than 1 Year Old in Japan. The Pediatric Infectious Diseases Journal June 2005; Vol 24 (issue 6):575-5 6. Roche Pharmaceuticals. Alert letter December 2003. Available from: www.fda.gov/medwatch/SAFETY/2003/tamiflu-deardoc.pdf DRUG INTERACTION IN THE TREATMENT OF HIV INFECTION Note: This advice will be revised as more There are potential interactions between antiviraltreatment and anti-HIV therapy. This information is based on the best available knowledge of theoreticalinteractions and has been summarised by LiverpoolUniversity at www.hiv-druginteractions.org With the permission of Liverpool University theinformation below describes these interactions as theystand on the 19th May 2009. Oseltamivir• Not metabolised by, nor an inhibitor of CYP450 or • Oseltamivir is metabolised to oseltamivir carboxylate by hepatic esterases. The carboxylate undergoes renal excretion by glomerular filtration and tubular secretion.
• Transported by P-glycoprotein (P-gp), limiting Interaction Potential• No interaction anticipated at the level of hepatic metabolism. Oseltamivir has been linked tentatively with neuropsychiatric reactions and, if so, inhibition of brain P-gp by boosted protease inhibitors (PI) could increase risk of neurotoxicity. Although it is more likely that influenza itself is responsible for CNS symptoms,we suggest vigilance when oseltamivir and boosted PIs are coadministered.
• Need to consider potential for interaction at level of renal secretion (i.e. lamivudine, emtricitabine, tenofovir).
• Coadministration of probenecid (an inhibitor of renal secretion) increases oseltamivir carboxylate concentrations by ~2-fold (Wattanagoon Y, et al, 2009, Antimicrob Agents Chemother, 53: 945-952).
• Until there are further data on the magnitude of any interaction between oseltamivir and renally excreted Nucleoside Reverse Transcriptase Inhibitor (NRTI) we suggest caution in patients with any degree of renal impairment.
Zanamivir• Inhaled zanamivir results in 10-20% of the inhaled dose Interaction Potential• Does not undergo any appreciable metabolism • Does not inhibit or induce CYP450 enzymes • Renally cleared unchanged, but since systemic exposure is low, we consider there to be a very low potential forany interaction with renally cleared antiretrovirals.
BACKGROUND INFORMATION FOR DISCUSSION WITH
PREGNANT WOMEN
Please remember to refer to the most up to date • There are, however, a number of studies that have information on the Department of Health website, not found any increased risk of congenital anomalies in the relevant Royal Colleges, UKTIS and the EMEA. association with maternal influenza 6, 11-13 Maternal influenza has not been associated with an increased risk of spontaneous abortion and intrauterine death.
• An association has been reported between high fever-related maternal diseases (including influenza) Maternal Risk
and an increased risk of congenital anomalies in a case control study. 9, 14, 15 During the first trimester of • Pregnant women do not seem to be at an increased pregnancy the risk of congenital anomalies occuring risk of contracting influenza than the general may be reduced by the administration of antipyretics population. However, pregnant women, particularly in Fever associated with influenza can be reduced in the third trimester of pregnancy, appear to be at a pregnancy with the use of paracetamol; this antipyretic higher risk of developing influenza-associated is suitable for use in all stages of pregnancy.
pneumonia and cardio-respiratory complications. 1, 2 In keeping with this, the incidence of acutecardio-respiratory hospitalisations during influenza season increases throughout pregnancy, the highest incidence being during the third trimester. Refer to the pregnancy section above.
• An increase in influenza associated mortality among pregnant women was documented during the • The currently circulating influenza A(H1N1) virus influenza pandemics of 1918-1919 and 1957-1958, has been shown to be sensitive to the neuraminidase although a similar increase has not been noted during inhibitor antiviral medications zanamivir and oseltamivir, but is resistant to amantadine and rimantadine.
Risk to the fetus
• The neuraminidase inhibitors oseltamivir (Tamiflu®, oral) and zanamivir (Relenza®, inhaled) are effective • There are inconsistent data to suggest that maternal for prophylaxis and treatment of influenza.
influenza may be associated with an increased risk of some congenital anomalies, including oesophageal atresia,4 or anophthalmos/microphthalmos;5 an increased risk of anencephaly was also reported following epidemics of Asian influenza. 6, 7 8 • The Hungarian Case-Control Surveillance of Congenital Abnormalities reported an association between Maternal risk
maternal influenza during the second and third monthof pregnancy and congenital anomalies in the • Side effects as documented in the treatment offspring, including cleft lip or palate, neural tube defects, and cardiovascular abnormalities.9 The use ofantipyretics reduced the risk of congenital anomalies • Zanamivir is administered by inhalation and is suggesting that they were due to fever. Use of folic acid deposited at high concentrations throughout the supplements reduced or eliminated the apparent risk respiratory tract with less systemic absorption;18 for that associated with influenza during pregnancy.
reason it is the preferred drug for use in pregnant patients for treatment unless there is a clinical • A further case-control study involving 363 infants with neural tube defects (NTD) and 523 normal newborns indicated an increased risk of NTDs • However, due to its route of administration, associated with maternal influenza. In this study, risk zanamivir may be associated with adverse respiratory was enhanced when antipyretics were used.10 effects, such as bronchospasm and dyspnoea, which may be a concern in patients at risk of respiratory problems.
Risk to the fetus
• There are limited data available on the safety of oseltamivir and zanamivir in pregnancy, but the animalstudies and human exposure details that are available have not demonstrated harm. Risks of adverse fetal outcomes following influenza inpregnancy may be reduced by appropriate use of folicacid supplementation. Appropriate use of antipyretics(e.g. paracetamol) may also reduce risk the adversefoetal outcomes associated with fever. Adapted from Management of Pregnant Women during an influenza A(H1N1) Pandemic,UK Teratology Information Service. www.toxbase.org. May 2009.
1 Kort B. A., Cefalo R. C., Baker V. V. Fatal influenza A pneumonia in pregnancy. Am J Perinatol 1986, 3(3):179-182. 2. Neuzil K. M., Reed G. W., Mitchel E. F., Simonsen L., Griffin M. R. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998, 148(11): 3. Greenberg M, Jacobziner H, Pakter J. Maternal mortality in the epidemic of Asian influenza, New York City, 1957. Am J Obstet Gynecol 1958, 76:897-902. 4. Leck I. Incidence of malformations following influenza epidemics. Br J Prev Soc Med 1963, 17:70-80. 5. Busby A., Dolk H., Armstrong B. Eye anomalies: seasonal variation and maternal viral infections. Epidemiology 2005, 16(3):317-322. 6. Doll R., Hill A. B., Sakula J. Asian influenza in pregnancy and congenital defects. Br J Prev Soc Med 1960, 14:167-172. 7. Coffey V. P., Jessop W. J. Maternal influenza and congenital deformities: a prospective study. Lancet 1959, 2(7109):935-938. 8. Hakosalo J., Saxen L. Influenza epidemic and congenital defects. Lancet 1971, 2(7738):1346-1347. 9. Acs N., Banhidy F., Puho E., Czeizel A. E. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol 2005, 73(12):989-996. 10. Li Z., Ren A., Liu J., Pei L., Zhang L., Guo Z., Li Z. Maternal flu or fever, medication use, and neural tube defects: a population-based case-control study in Northern China. Birth Defects Res A Clin Mol Teratol 2007, 79(4):295-300. 11. Wilson M. G., Stein A. M. Teratogenic effects of asian influenza. A n extended study. Jama 1969, 210(2):336-337.
12. Walker W. M., Mc Kee Ap. Asian influenza in pregnancy; relationship to foetal anomalies. Obstet Gynecol 1959, 13(4):394-398. 13. Korones S. B., Todaro J., Roane J. A., Sever J. L. Maternal virus infection after the first trimester of pregnancy and status of offspring to 4 years of age in a predominantly Negro population. J Pediatr 1970, 77(2):245-251. 14. Acs N., Banhidy F., Horvath-Puho E., Czeizel A. E. Population-based case-control study of the common cold during pregnancy and congenital abnormalities. Eur J Epidemiol 2006, 15. Czeizel A. E., Puho E. H., Acs N., Banhidy F. High fever-related maternal diseases as possible causes of multiple congenital abnormalities: a population-based case-control study. Birth Defects Res A Clin Mol Teratol 2007, 79(7):544-551.
16. National Institute for Health and Clinical Excellence (NICE). NICE technology appraisal TA168 Amantadine, oseltamivir and zanamivir for the treatment of influenza. 2009. 17. National Institute for Health and Clinical Excellence (NICE). NICE technology appraisal TA158 Oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza. 2008. 18. The electronic Medicines Compendium (eMC). Relenza®. Available from: http://emc.medicines.org.uk. 19. Advisory Committee on Immunisation Practices (ACIP). Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. Available from: www.cdc.gov/mmwr/preview/mmwrhtml/rr57e717a1.htm SUPPORTIVE MEASURES
treatment schedules is a well recognised problem whichmay adversely affect patient compliance.
Paracetamol is indicated for the treatment of pyrexia and According to the manufacturer in adults, the most mild to moderate pain. Caution should be used in commonly reported adverse drug reactions (ADRs) were hepatic impairment, renal impairment and alcohol vomiting and nausea in the treatment studies, and nausea and headache in the prevention studies. The majority ofthese ADRs were reported on a single occasion on either Ibuprofen is indicated for pain and fever in children and the first or second treatment day and resolved available as syrup. Caution should be used in the elderly, spontaneously within 1-2 days. In children, the most allergic disorders (including history of hypersensitivity to commonly reported adverse drug reaction was vomiting. aspirin or any other NSAID-which includes those in whomattacks of asthma, angioedema, urticaria, or rhinitis have The manufacturer’s PIL for the 30/45/75mg capsules and been precipitated by aspirin or any other NSAID), during solution gives the following advice: The most common pregnancy and breastfeeding and in coagulation defects.
side effects of Tamiflu are nausea, vomiting, diarrhoea,stomach ache and headache. These side effects mostly Clearly this list is not exhaustive. Please refer to the occur only after the first dose of the medicine and will usually stop as treatment continues. The frequency ofthese effects is reduced if the medicinal product is Note: Owing to an association with Reye’s Syndrome, the CSM has advised that aspirin-containing preparationsshould not be given to children under 16 years, unlessspecifically indicated, e.g. for Kawasaki syndrome.
Aspirin and aspirin containing products are alsocontraindicated in breast feeding.
Reference: British National Formulary, March 2009.
Clinical management of patients with an influenza-likeillness during an influenza pandemic. Thorax, January 2007. Volume 62, supplement 1. Available from:http://thorax.bmj.com/content/vol62/suppl_1/ PIL:http://emc.medicines.org.uk/medicine/10474/PIL/Tamiflu+12mg+ml+powder+for+oral+suspension/http://emc.medicines.org.uk/medicine/20372/PIL/Tamiflu+30mg+and+45mg+Hard+Capsules/http://emc.medicines.org.uk/medicine/10467/PIL/Tamiflu+Capsules+75mg/ The occurrence of gastro-intestinal symptoms in association with the use of oseltamivir in prophylaxis and http://emc.medicines.org.uk/medicine/10446/SPC/Tamiflu+75mg+hard+capsule/ Gastrointestinal Adverse Drug Reactions (ADRs) in the oseltamivir treatment studies
and in the oseltamivir prophylaxis study in children published by the manufacturer
Percentage of Patients Experiencing the ADR Reference: Abstracted from the manufacturers data published on the electronic Medicines Compendium (eMC) accessed on 19 May 2009 athttp://emc.medicines.org.uk/document.aspx?documentId=10446.
Flu response centres (FRCs) have been established in each region of England to receive calls from health professionals regarding patients with flu-like illness and their contacts.
FRCs undertake the assessment of patients, arrange with Yorkshire and the Humber Flu Response Centre GPs and others for samples to be taken for laboratory diagnosis, identify and follow up contacts and arrange for prophylaxis to be given where appropriate.
South East - South Central Flu Response Centre Wording changed in Appendix 5 to more accurately reflectits contents: There are potential interactions between Version Control Statement 22/5/9. antiviral treatment and anti HIV therapy. This information is based on the best available knowledge of theoretical Name of UK-TIS (UK Teratology Information Service) interactions and has been summarised by Liverpool abbreviated consistently as UK-TIS rather than UK TIS.
University at www.hiv-druginteractions.org 2. Spelling standardised from foetus to fetus Spelling changed of Nucleoside Reverse Transcriptase 3. Additional paragraph added to Appendix 7 from the On page 7, in list of appendices, title of Appendix 5 Oseltamivir Summary of Product Characteristics reflecting changed from: Drug interactions with antiretrovirals to a change in their wording: According to the Drug interaction in the treatment of HIV infection.
manufacturer In adults, the most commonly reportedadverse drug reactions (ADRs) were vomiting and nausea Title of Appendix 4 changed from Pharmacy labels for in the treatment studies, and nausea and headache in oseltamivir capsules to Pharmacy Labels for the prevention studies. The majority of these ADRs were reported on a single occasion on either the first orsecond treatment day and resolved spontaneously within Title of Appendix 8 Summary of recommendations for 1-2 days. In children, the most commonly reported treatment/prophylaxis in all groups deleted as this adverse drug reaction was vomiting. The manufacturer’s PIL for the 30/45/75mg capsules and New Appendix 8 created with title of Version solution gives the following advice: The most common side effects of Tamiflu are nausea, vomiting, diarrhoea,stomach ache and headache. These side effects mostly 10 In Appendix 5 statement Refer to patient information occur only after the first dose of the medicine and will leaflet and or SPC made bold on request of manufacturer.
usually stop as treatment continues. The frequency ofthese effects is reduced if the medicinal product is taken 11. In Appendix 5 in sentence patient information leaflet and or SPC, patient information leaflet abbreviated to PIL forconsistency throughout document and wording changed PIL:http://emc.medicines.org.uk/medicine/10474/PIL/Tamiflu 12. Trade names removed from Page 4 and table on Page 6 to +12mg+ml+powder+for+oral+suspension/ ensure consistent generic pharmaceutical naming.
http://emc.medicines.org.uk/medicine/20372/PIL/Tamiflu+30mg+and+45mg+Hard+Capsules/ 13. Table on page 6 ammended with references to correct http://emc.medicines.org.uk/medicine/10467/PIL/Tamiflu table numbers for doses (Should read: Table 7-prophylaxis for adults and children over the age of 1, Table 8- prophylaxis for those with renal impairment) http://emc.medicines.org.uk/medicine/10446/SPC/Tamiflu+75mg+hard+capsule/ 14. Appendix 4, page 11 given new title: Pharmacy Labels for This replaces previous text: The official Summary ofProduct Characteristics for Tamiflu® clearly recognises nausea and vomiting as a “very common” side-effect in adults and in children and vomiting abdominal pain,diarrhoea and dyspepsia as common side effects, 1. Page 1, section 'Under 1 year of age', added the dose to supported by data from the clinical trials database. the treatment indication to read '. Children under the age The tables below shows the most frequently reported of one who have symptoms of influenza should be treated ADRs from clinical trials (abridged to show only with oseltamivir 2mg/kg twice a day for 5 days.’ 2. Page 2, section 'OSELTAMIVIR (Tamiflu(r)) TREATMENT', To control these side-effects the manufacturer subsection 'Under 1 year of age', sentence in first recommends that although Oseltamivir can be taken paragraph expanded to read '…The Department of Health without food, it is recommended that it is taken with has provided the tables below regarding volumes to be food to reduce the chance of nausea and administered in the under ones for different 3. Page 2, section 'OSELTAMIVIR (Tamiflu(r)) TREATMENT',subsection 'Under 1 year of age', second paragraph ammended to read '.There are two differentpreparations which can be used in this age group: one isa suspension manufactured by Roche, Tamiflu®suspension; and the other a solution of oseltamivir, whichwill be prepared by designated hospital pharmacylicensed manufacturing units. They are of differingconcentrations and volumes; oseltamivir suspension has astrength of 12mg in 1 ml and oseltamivir solution has astrength of 15mg in 1ml; see tables below.
4. Page 3, section 'Formulations', subsection 'Osletamivirsolution', paragraph ammended to read '. A solution ofoseltamivir 15mg in one ml is being prepared bydesignated licensed hospital pharmacy manufacturingunits.' and '. Oseltamivir solution has a bitter taste andmay require the addition of a small volume (less than10ml) of a strongly flavoured sugary drink e.g.
blackcurrant squash, to help very young children totolerate the medicine.
5. Section 'ZANAMAVIR (Relenza(r)) TREATMENT', subtitlechanged to read '.Adults and children over 5 years.' 6. Page 4, section 'Renal impairment or patients on renalreplacement therpaies', note ammended to read '.
Note: Paediatric patients with severe renal impairmentare not covered by this guidance. Seek specialist advice inall cases.' 7. Page 4, section 'Indications', subsection 'Under 1 yearof age', ammended to read '. A decision on whetherprophylaxis with oseltamivir should be recommendedshould be taken by an expert in the care of young children.' 8. Appendix 2, 'General practitioner/delegated healthcareprofessional authorisation voucher for adults and childrenaged 1 year and older' removed.
9. Appendix 3, 'General practitioner/delegated healthcareprofessional authorisation voucher for children aged lessthan 1 year' removed.
10. Appendix 4, 'PHARMACY LABELS FOR TREATMENTDOSING' removed.
11. Appendices 5-8 renumbered following removal ofappendixes 2 and 3.
12. Appendix 6, section 'Risk to the fetus', paragraph 5ammended for readability to '. During the first trimesterof pregnancy the risk of congenital anomalies occuringmay be reduced by the administration of antipyretics.’ 13. Added appendix, above version control statements,with description of the purpose of, and contact detailsfor flu response centres in England.
14. Change of name and removal of prescribing table toreflect end of containment phase.

Source: http://www.liverpool-lmc.org.uk/newsletters/200907/Att%2002%20HPA%20-%20Prescribing%20Treatment%20Phase.pdf