Tamiflu - Globally Endorsed In The Treatment And Prevention Of Influenza

Tamiflu®: Globally Endorsed in the Treatment and Prevention of Influenza.

Tamiflu® ( oseltamivir INN) is an orally administered anti-influenza drug of worldwide proven value in the in the treatment and prevention of Influenza A and Influenza B. Tamiflu® is a member of a small class of drugs called neuraminidase inhibitors which have largely superseded the older, less effective anti- influenza agents, the adamantanes (1,2,3,4).

Both Influenza A and Influenza B remain a major worldwide health concern with well documented seasonal epidemics and, in particular with Influenza A, pandemics. Which cause significant morbidity and mortality to hundreds of thousands, if not millions during pandemics, along with social and economic hardship and human misery (5, 6, 7). The constantly changing antigenic nature of the influenza virus has hampered effective vaccine production and vaccine scientists are often locked into a game of catch up with the virus’s changing immunological appearance. These factors in the context of our ever increasingly fluid world population mean Influenza remains a real and present world health threat (2, 5, 6, 7).

Tamiflu® was the product of a rational drug design project undertaken by C U Kim and his team at Gilead Sciences® and which was subsequently marketed by Roche®. Tamiflu is a pro-drug which is de-esterified within the liver to the free carboxylate. This bio-transformed drug is a competitive inhibitor of influenza neuraminidase, an enzyme essential for viral release and cellular dissemination, and so inhibits influenza viral reproduction (1, 7). Tamiflu® is the only orally administered neuraminidase inhibitor available to date; and this, along with its established efficacy, simple dosing schedules and safety profile has ensured it has remained an integral component of both national and international influenza control strategies and World Health Organisation public health directives(7, 8, 9, 10).

Reputable, well designed and independent clinical trials of Tamiflu have clearly established the significant benefit of Tamiflu® in the treatment of influenza in a wide variety of medical settings and patient groups including children and the medically vulnerable. Tamiflu® was shown to reduce symptom severity and duration, shorten recovery and convalescence times, reduce complication rates and reduce virus secretion in influenza infected patients (11, 13, 14, 15, 16, 17, 18, 19, 20). Tamiflu® was shown to be an effective prophylactic agent when administered to individual at risk of influenza infection in both community and residential settings and was well tolerated, even in patients where clinical circumstances dictated prolonged administration (11, 13, 16, 18, 19, 20).

Though Tamiflu® was never intended as a replacement for vaccination, however in the absence of an effective vaccine, limited vaccine availability and other instances of population vulnerability to influenza the use of Tamiflu®, notably in the current H1N1 Swine Flu pandemic and the H5N1 Avian Flu outbreaks, has ensured we have had an effective pharmaceutical defence in addition to other public health measures with which to combat the continuing national and world influenza threats. Where indicated, Tamiflu® can be co-administered with trivalent influenza vaccine without impairing vaccine response and providing antiviral cover while immunity develops in influenza at risk individuals (11, 21).

The World Health Organisation, the American Centre for Disease Control and European Medical agency, largely as a result of the current pandemic flu threat, have all revised their anti- influenza drug guidelines. And a central tenet of their policy is ensuring adequate supplies of Tamiflu® are readily available and the recommendation that adequate drug stocks be held in reserve worldwide. Additionally, drug safety and clinical trial data were scrutinised which resulted in the extension Tamiflu’s product licence to include children aged 1 year or greater along with pregnant and breastfeeding women (7, 8, 9, 10, 11).

In response to concerns about possible worldwide shortages of Tamiflu®, Roche®, the international product licence holder, has sublicensed the manufacture of Tamiflu to a number of pharmaceutical companies

throughout the globe to ensure sustainable, adequate production and supply of the drug in the event of further world influenza contingencies(22).

Roche®, based on its own production figures, estimates around 50 million people worldwide have been treated with Tamiflu. Influenza virus drug sensitivity monitoring has confirmed that current pandemic H1N1 and avian H5N1 strains remain sensitive to Tamiflu. Where practicable, in accordance with best practice guidelines, the prescription of anti-influenza drugs during seasonal influenza outbreaks should be guided by current local virus sensitivity data from the relevant authority (11).

Tamiflu® has been endorsed internationally as an effective and safe (7, 8, 9, 10, 11, 23, 24, 25, 26, 27, 28) anti-influenza agent with significant utility in both the treatment and prevention of Influenza A and Influenza B infection; this in the absence of a superior comparator, its ease of administration and simple dosing schedules have made Tamiflu® the drug of choice in the management and containment of Influenza throughout the world (11).

Tamiflu® (oseltamivir phosphate ) Prescribing Data

Tamiflu® is presented as capsules containing 30mg (light yellow hard gel caps), 45mg (grey hard gel caps) or 75mg (grey/light yellow hard gel caps) of oseltamivir as the phosphate salt for oral administration. Roche and dosage

are printed on each capsule in blue ink. Capsules are available as blister packages of 10 capsules. Tamiflu® is also available in bottles as a powder for reconstitution to an oral suspension, which when reconstituted with water as directed contains 12mg/mL of oseltamivir base. Not to be stored at ambient temperatures above 30°C.

Indications

Tamiflu® is indicated for the treatment and prevention of infections due to influenza Viruses of type A and B in adults and children one year of age or older.

Dosage Treatment of Influenza in Adults and Adolescents aged 13 years or older: The recommended dose of Tamiflu® is 75mg twice daily for five days. Treatment should be commenced within 48hrs of onset of symptoms. Capsules may be taken with food

Prophylaxis of Influenza in Adults and Adolescents aged 13 years or older: The recommended dose of Tamiflu® is 75mg once daily for at least

ten days. Treatment should commence within 48hrs of exposure. Safety and efficacy have been demonstrated for up to 6 weeks. The period of has protection as been determined to be as long as the dosing is continued. Capsules may be taken with food.

Treatment of Influenza in Paediatric Patients: The recommended dose of Tamiflu for children aged 1 yr or older is shown in Table 1. Tamiflu oral suspension may be used in patients unable to swallow a capsule. Table 1: Oral Dose of Tamiflu® for the Treatment of Influenza in Paediatric Patients by Weight Body Weight

Body Weight

(kg)

(lbs)

≤15kg

>15kg to 23kg >23kg to

≤33lbs

>33lbs to 51lbs >51lbs to

Recommend

No. Of

No. Of

ed Dose for

Bottles of

Tamiflu®

5 Days

Tamiflu®

Capsules

Susp

Required for

Needed for

a 5 Day

dose 5 Day

Regimen

Regimen 1

10 Tamiflu®

30mg twice daily

Caps

45mg twice

(30mg) 10 Tamiflu®

2

daily

Caps

60mg twice

(45mg) 20 Tamiflu®

2

40kg

88lbs >40kg

>88lbs

daily

Caps

75mg twice

(30mg) 10 Tamiflu®

3

daily

Caps (75mg)

Prophylaxis of Influenza in Paediatric Patients: The recommended dose of Tamiflu® for children aged 1 year or older is shown in Table 2. Tamiflu® oral suspension may be used in patients unable to swallow a capsule. Table 2: Oral Dose of Tamiflu® for Prophylaxis of Influenza in Paediatric Patients by Weight. Body Weight

Body Weight

(kg)

(lbs)

≤15kg

≤33lbs

Recommend

No. Of

No. Of

ed Dose for

Bottles of

Tamiflu®

10 days

Tamiflu®

Capsules

Susp

Required for

Needed for

a 10 Day

a 10 Day

Regimen

Regimen 1

10 Tamiflu®

30mg once daily

>15kg to 23kg

>33lbs to 51lbs

45mg once daily

Caps 2

(30mg) 10 Tamiflu® Caps

>23kg to 40kg

>51lbs to 88lbs

>40kg

60 mg once

2

daily >88lbs

75 mg once daily

(45mg) 20 Tamiflu® Caps

3

(30mg) 10 Tamiflu® Caps (75mg)

Special Precautions and Dosage Instructions

Pregnancy and Nursing Mothers: To date research suggests that any risk associated with the use of Tamiflu® during pregnancy or nursing mothers to be extremely low. However, the use of Tamiflu® in these clinical instances is indicated only if the potential benefit justifies any potential risk to the foetus or breast-fed infant (11, 23).

Hepatic Impairment: No dose adjustment is recommended for patients for patients with mild to moderate hepatic impairment (11). Renal Impairment: Dose adjustment is recommended for patients with creatinine clearance between 10 and 30 mL/min. For the treatment of influenza the dose should be reduced to 75mg once daily for five days. For the prophylaxis of influenza the dose of Tamiflu® should be reduced to 75mg

every other day or 30mg of Tamiflu® once daily. No recommended dosing regimens are available for patients undergoing routine haemodialysis and continuous peritoneal dialysis with end stage renal disease (11).

Adverse Events

Tamiflu® is well tolerated in the vast majority of patients, opinion which has been supported by evidence from numerous clinical trials and extensive post marketing drug surveillance ( 11, 24, 25, 26, 27, 28). The most commonly reported adverse events to Tamiflu® occurring in around 1-2% of patients have been gastrointestinal, with diarrhoea and vomiting being the most prevalent. This is frequently mild in nature and there is evidence to suggest it can be mitigated by dosing Tamiflu® at mealtimes. Other more infrequent adverse events associated with the administration of Tamiflu® have included allergic type reactions including skin rashes and tissue oedema. Very rarely, Tamiflu® administration, particularly in young children, may be associated with adverse neurological reactions ranging from mild mood disturbances to very atypical behavioural changes. These have been in most instances self limiting and evidence of causality has not been established(11, 25, 26, 27, 28).

Contraindications The administration of Tamiflu is contraindicated in patients with a known hypersensitivity to oseltamivir or any other component of Tamiflu’s formulation.

References •

Law W, Chen X, Kim CU: Discovery and development of GS 4104 (oseltamivir, Tamiflu®): an orally influenza neuraminidase inhibitor. Curr Med Chem. 2000 Jun; 7 (6): 663-72.

•

Ward Penelope, Small Ian, Smith James, Suter P, Dutkowski R: Oseltamivir (Tamiflu®) and its potential for use in the event of an influenza pandemic. Journal of Antimicrobial Chemotherapy (2005) 55, Suppl. S1, i5-i21.

•

Rungrotmongkol T, Intharathep P, Malaisree M, Nunthaboot N, Kaiyawet N, Sompornpisut P, Payungporn S, Poovorawan Y, Hannongbua S: Susceptability of antiviral drugs against 2009 influenza A (H5N1) virus. Biochem Biophys Res Commun. 2009 Jul 31; 385(3): 390-4. Epub 2009 May 20.

•

http://www.rocheexchange.com/influenza/productinformation/tamiflu

•

Zambon MC: Epidemiology and pathogenesis of influenza. J Antimicrb Chemother. 1999 Nov; Supp B 3-9.

•

Influenza A and Influenza B virus infection. The Merk Manual.

•

http://www.telegraph.co.uk/health/swine-flu/5509060/World-flupandemics-a-timeline.html

•

http://www.who.int/csr/disease/swineflu/notes/h1n1_use_antivirals_200 90820/en/

•

http://www.emea.europa.eu/pdfs/human/vwp/21430106en.pdf

•

http://www.cdc.gov/flu/professionals/antivirals/dosage.htm

•

http://www.rocheexchange.com/influenza/productinformation/tamiflu

•

Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, Nicholson K: Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation. Health Technol Assess. 2009 Feb; 13(11): iii, ix-xii, 1-246.

•

Khazeni N, Bravata DM, Holty JE, Uyeki TM, Stave CD, Gould MK: Safety and Efficacy of Extended-Duration Antiviral Chemoprophylaxis Against Pandemic and Seasonal Influenza. Ann Intern Med. 2009 Aug 3. [Epub ahead of print].

•

Piedra PA, Schulman KL, Blumentals WA: Effects of oseltamivir on influenza related complications in children with chronic medical conditions. Paediatrics. 2009 Jul; 124(1): 170-8.

•

White NJ, Webster RG, Govorkova EA, Uyeki TM: What is the optimal therapy for patients with H5N1 influenza. PLos med. 2009 Jun 23; 6(6): e1000091. Epub 2009 Jun 23.

•

Schirmer P, Holodniy M: Oseltamivir for treatment and prophylaxis of influenza infection. Expert Opin Drug Saf. 2009 May; 8(3): 357-71.

•

Orzeck EA, Shi N, Blumentals WA: Oseltamivir and the risk of influenza-related complications and hospitalizations in patients with diabetes.

•

Matheson NJ, Harnden AR, Parera R, Sheikh A, Symmonds-Abrahams M: Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev. 2007 Jan 24; (1): CD002744.

•

Hayden FG, Pavia AT: Antiviral management of seasonal and pandemic influenza. J Infec Dis, 2006 Nov 1; 194 Suppl 2: S119-26.

•

Milrose, SC http://goldpharma.com/search/Tamiflu/lang/ENGLISH/

•

Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG: Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analysis of randomised controlled trials. BMJ. 2003 Jun 7; 326(7401): 1235.

•

Antiviral drugs in influenza: an adjunct to vaccination in some situations. Prescrire Int 2006 Feb; 15(81): 21-30.

•

http://articles.latimes.com/2005/dec/13/business/fi-briefs13.

•

Tanaka T, Nakajima K, Murashima A, Garcia-Bournissen F, Koren G, Ito S: Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ. 2009 Jul 7; 181(12): 55-8. Epub 2009 Jun 15.

•

Wallensten A, Oliver T, Lewis D, Harrison S: Compliance and side effects of prophylactic oseltamivir treatment in a school South West England. Euro Surveill. 2009 Jul 30; 14(30): 19285.

•

Casscells SW, Granger E, Kress AM, Linton A: The association between oseltamivir use and adverse neuropsychiatric outcomes among TRICARE beneficiaries, ages 1 through 21 years diagnosed with influenza. Int J Adolesc Med Health. 2009 Jan-Mar; 21(1): 79-89.

•

Toovey S, Rayner C, Prinssen E, Chu T, Donner B, Thakrar B, Dutkowski R, Hoffman G et al: Assessment of neuropsychiatric events in influenza patients treated with oseltamivir: a comprehensive review.

•

Blumentals WA, Song X: The safety of oseltamivir in patients with influenza: analysis of healthcare claims data from six influenza seasons. MedGenMed. 2007 Oct 30;9(4):23.

•

Dutkowski R, Thakrar B, Froehlich E, Suter P, Ward P: Safety and Pharmacology of oseltamivir in clinical use. Drug Saf. 2003; 26(11): 7867-801.