Oseltamivir 75 MG Oral Capsule
DRUG INTERACTIONS
7 Live attenuated influenza vaccine, intranasal ( 7 ): Do not administer until 48 hours following cessation of TAMIFLU.
Do not administer TAMIFLU until 2 weeks following administration of the live attenuated influenza vaccine, unless medically indicated.
Influenza Vaccines The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated.
However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of TAMIFLU, unless medically indicated.
The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus.
Trivalent inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU.
Overall Drug Interaction Profile for Oseltamivir Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely.
Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver.
Drug interactions involving competition for esterases have not been extensively reported in literature.
Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement interactions is low.
In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases.
Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs, the elimination characteristics of oseltamivir carboxylate (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways.
Coadministration of probenecid results in an approximate two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney.
However, due to the safety margin of oseltamivir carboxylate, no dose adjustments are required when coadministering with probenecid.
No pharmacokinetic interactions have been observed when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), or warfarin.
OVERDOSAGE
10 At present, there has been no experience with overdose.
Single doses of up to 1000 mg of TAMIFLU have been associated with nausea and/or vomiting.
DESCRIPTION
11 TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 6 mg/mL oseltamivir base.
In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone K30, croscarmellose sodium, and sodium stearyl fumarate.
The 30 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and red iron oxide.
The 45 mg capsule shell contains gelatin, titanium dioxide, and black iron oxide.
The 75 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide.
Each capsule is printed with blue ink, which includes FD&C Blue No.
2 as the colorant.
In addition to the active ingredient, the powder for oral suspension contains sorbitol, monosodium citrate, xanthan gum, titanium dioxide, tutti-frutti flavoring, sodium benzoate, and saccharin sodium.
Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1).
The chemical formula is C 16 H 28 N 2 O 4 (free base).
The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt.
The structural formula is as follows: Chemical Structure
CLINICAL STUDIES
14 14.1 Treatment of Influenza Adult Subjects Two placebo-controlled double-blind clinical trials were conducted: one in the U.S.
and one outside the U.S.
Subjects were eligible for these trials if they had fever >100ºF, accompanied by at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache) and influenza virus was known to be circulating in the community.
In addition, all subjects enrolled in the trials were allowed to take fever-reducing medications.
Of 1355 subjects enrolled in these two trials, 849 (63%) subjects were influenza-infected (age range 18 to 65 years; median age 34 years; 52% male; 90% Caucasian; 31% smokers).
Of the 849 influenza-infected subjects, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of unknown type.
TAMIFLU was started within 40 hours of onset of symptoms.
Subjects participating in the trials were required to self-assess the influenza-associated symptoms as “none,” “mild,” “moderate,” or “severe.” Time to improvement was calculated from the time of treatment initiation to the time when all symptoms (nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were assessed as “none” or “mild.” In both studies, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1.3 day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to subjects receiving placebo.
Subgroup analyses of these studies by gender showed no differences in the treatment effect of TAMIFLU in men and women.
In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of 150 mg TAMIFLU twice daily for 5 days.
Geriatric Subjects Three double-blind placebo-controlled treatment trials were conducted in subjects ≥65 years of age in three consecutive seasons.
The enrollment criteria were similar to that of adult trials with the exception of fever being defined as >97.5°F.
Of 741 subjects enrolled, 476 (65%) subjects were influenza-infected.
Of the 476 influenza-infected subjects, 95% were infected with influenza type A and 5% with influenza type B.
In the pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1-day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to those receiving placebo (p=NS).
However, the magnitude of treatment effect varied between studies.
Pediatric Subjects One double-blind placebo-controlled treatment trial was conducted in pediatric subjects aged 1 to 12 years (median age 5 years), who had fever (>100°F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community.
Of 698 subjects enrolled in this trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian).
Of the 452 influenza-infected subjects, 67% were infected with influenza A and 33% with influenza B.
The primary endpoint in this study was the time to freedom from illness, a composite endpoint that required 4 individual conditions to be met.
These were: alleviation of cough, alleviation of coryza, resolution of fever, and parental opinion of a return to normal health and activity.
TAMIFLU treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by 1.5 days compared to placebo.
Subgroup analyses of this study by gender showed no differences in the treatment effect of TAMIFLU in male and female pediatric subjects.
14.2 Prophylaxis of Influenza Adult Subjects The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and a postexposure prophylaxis study in households.
The primary efficacy parameter for all these studies was the incidence of laboratory-confirmed clinical influenza.
Laboratory-confirmed clinical influenza was defined as oral temperature ≥99.0°F/37.2°C plus at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a four-fold increase in virus antibody titers from baseline.
In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 13 to 65 years), TAMIFLU 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory-confirmed clinical influenza from 5% (25/519) for the placebo group to 1% (6/520) for the TAMIFLU group.
In a seasonal prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU 75 mg once daily taken for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4% (12/272) for the placebo group to <1% (1/276) for the TAMIFLU group.
About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders.
In a study of postexposure prophylaxis in household contacts (aged ≥13 years) of an index case, TAMIFLU 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days reduced the incidence of laboratory-confirmed clinical influenza from 12% (24/200) in the placebo group to 1% (2/205) for the TAMIFLU group.
Index cases did not receive TAMIFLU in the study.
Pediatric Subjects The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in a randomized, open-label, postexposure prophylaxis study in households that included children aged 1 to 12 years, both as index cases and as family contacts.
All index cases in this study received treatment.
The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the household.
Laboratory-confirmed clinical influenza was defined as oral temperature ≥100°F/37.8°C plus cough and/or coryza recorded within 48 hours, plus either a positive virus isolation or a four-fold or greater increase in virus antibody titers from baseline or at illness visits.
Among household contacts 1 to 12 years of age not already shedding virus at baseline, TAMIFLU for oral suspension 30 mg to 60 mg taken once daily for 10 days reduced the incidence of laboratory-confirmed clinical influenza from 17% (18/106) in the group not receiving prophylaxis to 3% (3/95) in the group receiving prophylaxis.
Immunocompromised Subjects A double-blind, placebo-controlled study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects (including 18 pediatric subjects 1 to 12 years of age) who had received solid organ (n=388; liver, kidney, liver and kidney) or hematopoietic stem cell transplants (n=87).
Median time since transplant for solid organ transplant recipients was 1105 days for the placebo group and 1379 days for the oseltamivir group.
Median time since transplant for hematopoietic stem cell transplant recipients was 424 days for the placebo group and 367 days for the oseltamivir group.
Approximately 40% of subjects received influenza vaccine prior to entering the study.
The primary efficacy endpoint for this study was the incidence of confirmed, clinical influenza, defined as oral temperature >99.0 ° F/37.2 ° C plus cough and/or coryza, all recorded within 24 hours, plus either a positive virus culture or a four-fold increase in virus antibody titers from baseline.
The incidence of confirmed clinical influenza was 3% (7/238) in the group not receiving TAMIFLU compared with 2% (5/237) in the group receiving TAMIFLU; this difference was not statistically significant.
A secondary analysis was performed using the same clinical symptoms and RT-PCR for laboratory confirmation of influenza.
Among subjects who were not already shedding virus at baseline, the incidence of RT-PCR-confirmed clinical influenza was 3% (7/231) in the group not receiving TAMIFLU and <1% (1/232) in the group receiving TAMIFLU.
HOW SUPPLIED
16 /STORAGE AND HANDLING TAMIFLU Capsules 45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules.
“ROCHE” is printed in blue ink on the grey body and “45 mg” is printed in blue ink on the grey cap.
Available in blister packages of 10 (NDC 54868-6083-0).
75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin capsules.
“ROCHE” is printed in blue ink on the grey body and “75 mg” is printed in blue ink on the light yellow cap.
Available in blister packages of 10 (NDC 54868-4476-0).
Storage Store the capsules at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
TAMIFLU for Oral Suspension Supplied as a white powder blend in a glass bottle.
After constitution, the powder blend produces a white tutti-frutti–flavored oral suspension.
After constitution with 55 mL of water, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL).
Each bottle is supplied with a bottle adapter and a 10 mL oral dispenser (NDC 54868-6315-0).
Storage Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
Store constituted suspension under refrigeration for up to 17 days at 2° to 8°C (36° to 46°F).
Do not freeze.
Alternatively, store constituted suspension for up to 10 days at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
RECENT MAJOR CHANGES
Dosage and Administration ( 2.1 , 2.2 , 2.3 , 2.7 , 2.8 ) 3/2011
GERIATRIC USE
8.5 Geriatric Use Of the total number of subjects in clinical studies of TAMIFLU for the treatment of influenza, 19% were 65 and over, while 7% were 75 and over.
Of the total number of patients in clinical studies of TAMIFLU for the prophylaxis of influenza, 25% were 65 and over, while 18% were 75 and over.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.
The safety of TAMIFLU in geriatric subjects has been established in clinical studies that enrolled 741 subjects (374 received placebo and 362 received TAMIFLU).
Some seasonal variability was noted in the clinical efficacy outcomes [see Clinical Studies (14.1) ] .
Safety and efficacy have been demonstrated in elderly residents of nursing homes who took TAMIFLU for up to 42 days for the prevention of influenza.
Many of these individuals had cardiac and/or respiratory disease, and most had received vaccine that season [see Clinical Studies (14.2) ] .
DOSAGE FORMS AND STRENGTHS
3 Capsules: 30 mg, 45 mg, 75 mg 30-mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard gelatin capsules.
“ROCHE” is printed in blue ink on the light yellow body and “30 mg” is printed in blue ink on the light yellow cap.
45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules.
“ROCHE” is printed in blue ink on the grey body and “45 mg” is printed in blue ink on the grey cap.
75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin capsules.
“ROCHE” is printed in blue ink on the grey body and “75 mg” is printed in blue ink on the light yellow cap.
For Oral Suspension: 6 mg/mL (final concentration when constituted) White powder blend for constitution to a white tutti-frutti–flavored suspension.
After constitution, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL).
Capsules: 30 mg, 45 mg, 75 mg ( 3 ) Powder for oral suspension: 360 mg oseltamivir base (constituted to a final concentration of 6 mg/mL) ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Oseltamivir is an antiviral drug [see Clinical Pharmacology (12.4) ].
INDICATIONS AND USAGE
1 TAMIFLU is an influenza neuraminidase inhibitor indicated for: Treatment of influenza in patients 1 year and older who have been symptomatic for no more than 2 days.
( 1.1 ) Prophylaxis of influenza in patients 1 year and older.
( 1.2 ) Important Limitations of Use : Efficacy not established in patients who begin therapy after 48 hours of symptoms.
( 1.3 ) Not a substitute for annual influenza vaccination.
( 1.3 ) No evidence of efficacy for illness from agents other than influenza viruses types A and B.
( 1.3 ) Consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use.
( 1.3 ) 1.1 Treatment of Influenza TAMIFLU is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days.
1.2 Prophylaxis of Influenza TAMIFLU is indicated for the prophylaxis of influenza in patients 1 year and older.
1.3 Limitations of Use The following points should be considered before initiating treatment or prophylaxis with TAMIFLU: Efficacy of TAMIFLU in patients who begin treatment after 48 hours of symptoms has not been established.
TAMIFLU is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.
There is no evidence for efficacy of TAMIFLU in any illness caused by agents other than influenza viruses types A and B.
Influenza viruses change over time.
Emergence of resistance mutations could decrease drug effectiveness.
Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs.
Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use TAMIFLU.
PEDIATRIC USE
8.4 Pediatric Use The safety and efficacy of TAMIFLU in pediatric patients younger than 1 year of age have not been studied.
TAMIFLU is not indicated for either treatment or prophylaxis of influenza in pediatric patients younger than 1 year of age because of the unknown clinical significance of nonclinical animal toxicology data for human infants [see Nonclinical Toxicology (13.2) ] .
PREGNANCY
8.1 Pregnancy Pregnancy Category C There are insufficient human data upon which to base an evaluation of risk of TAMIFLU to the pregnant woman or developing fetus.
Studies for effects on embryo-fetal development were conducted in rats (50, 250, and 1500 mg/kg/day) and rabbits (50, 150, and 500 mg/kg/day) by the oral route.
Relative exposures at these doses were, respectively, 2, 13, and 100 times human exposure in the rat and 4, 8, and 50 times human exposure in the rabbit.
Pharmacokinetic studies indicated that fetal exposure was seen in both species.
In the rat study, minimal maternal toxicity was reported in the 1500 mg/kg/day group.
In the rabbit study, slight and marked maternal toxicities were observed, respectively, in the 150 and 500 mg/kg/day groups.
There was a dose-dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in the exposed offspring in these studies.
However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied.
Because animal reproductive studies may not be predictive of human response and there are no adequate and well-controlled studies in pregnant women, TAMIFLU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
NUSRING MOTHERS
8.3 Nursing Mothers In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk.
It is not known whether oseltamivir or oseltamivir carboxylate is excreted in human milk.
TAMIFLU should, therefore, be used only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Serious skin/hypersensitivity reactions: Discontinue TAMIFLU and initiate appropriate treatment if allergic-like reactions occur or are suspected.
( 5.1 ) Neuropsychiatric events: Patients with influenza, including those receiving TAMIFLU, particularly pediatric patients, may be at an increased risk of confusion or abnormal behavior early in their illness.
Monitor for signs of abnormal behavior.
( 5.2 ) 5.1 Serious Skin/Hypersensitivity Reactions Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with TAMIFLU.
TAMIFLU should be stopped and appropriate treatment instituted if an allergic-like reaction occurs or is suspected.
5.2 Neuropsychiatric Events Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes.
These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.
There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU.
Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on TAMIFLU usage data.
These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution.
The contribution of TAMIFLU to these events has not been established.
Closely monitor patients with influenza for signs of abnormal behavior.
If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing treatment for each patient.
5.3 Bacterial Infections Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza.
TAMIFLU has not been shown to prevent such complications.
5.4 Limitations of Populations Studied Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease has not been established.
No difference in the incidence of complications was observed between the treatment and placebo groups in this population.
No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.
Efficacy of TAMIFLU for treatment or prophylaxis of influenza has not been established in immunocompromised patients.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (Patient Information) 17.1 Information for Patients Patients and/or caregivers should be advised of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions and should stop TAMIFLU and seek immediate medical attention if an allergic-like reaction occurs or is suspected.
Patients and/or caregivers should be advised of the risk of neuropsychiatric events in patients with influenza and should contact their physician if they experience signs of abnormal behavior while receiving TAMIFLU.
Their physician will determine if TAMIFLU treatment should be continued.
Instruct patients to begin treatment with TAMIFLU as soon as possible from the first appearance of flu symptoms.
Similarly, prevention should begin as soon as possible after exposure, at the recommendation of a physician.
Instruct patients to take any missed doses as soon as they remember, except if it is near the next scheduled dose (within 2 hours), and then continue to take TAMIFLU at the usual times.
TAMIFLU is not a substitute for a flu vaccination.
Patients should continue receiving an annual flu vaccination according to guidelines on immunization practices.
A bottle of TAMIFLU for oral suspension contains approximately 11 g sorbitol.
One dose of 75 mg TAMIFLU for oral suspension delivers 2 g sorbitol.
For patients with hereditary fructose intolerance, this is above the daily maximum limit of sorbitol and may cause dyspepsia and diarrhea.
DOSAGE AND ADMINISTRATION
2 Treatment of influenza ( 2.2 ) Adults and adolescents (13 years and older): 75 mg twice daily for 5 days Pediatric patients (1 year and older): Based on weight twice daily for 5 days Renally impaired patients (creatinine clearance 10-30 mL/min): Reduce to 75 mg once daily for 5 days ( 2.4 ) Prophylaxis of influenza ( 2.3 ) Adults and adolescents (13 years and older): 75 mg once daily for at least 10 days – Community outbreak: 75 mg once daily for up to 6 weeks Pediatric patients (1 year and older): Based on weight once daily for 10 days – Community outbreak: Based on weight once daily for up to 6 weeks Renally impaired patients (creatinine clearance 10-30 mL/min): Reduce to 75 mg once every other day or 30 mg once daily ( 2.4 ) 2.1 Dosing for Treatment and Prophylaxis of Influenza TAMIFLU may be taken with or without food [see Clinical Pharmacology (12.3) ] .
However, when taken with food, tolerability may be enhanced in some patients.
The recommended oral treatment and prophylaxis dose of TAMIFLU for patients 1 year of age and older is shown in Table 1 .
Table 1 Treatment and Prophylaxis Dosing of Oral TAMIFLU for Influenza For Patients 1 Year of Age and Older Based on Body Weight Weight (kg) Weight (lbs) Treatment Dosing for 5 days Prophylaxis Dosing for 10 days Volume of Oral Suspension (6 mg/mL) for each Dose Number of Bottles of Oral Suspension to Dispense Number of Capsules and Strength to Dispense 15 kg or less 33 lbs or less 30 mg twice daily 30 mg once daily 5 mL 1 bottle 10 Capsules 30 mg 16 kg thru 23 kg 34 lbs thru 51 lbs 45 mg twice daily 45 mg once daily 7.5 mL 2 bottles 10 Capsules 45 mg 24 kg thru 40 kg 52 lbs thru 88 lbs 60 mg twice daily 60 mg once daily 10 mL 2 bottles 20 Capsules 30 mg 41 kg or more 89 lbs or more 75 mg twice daily 75 mg once daily 12.5 mL 3 bottles 10 Capsules 75 mg 2.2 Standard Dosage – Treatment of Influenza Adults and Adolescents The recommended oral dose of TAMIFLU for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily for 5 days.
Treatment should begin within 2 days of onset of symptoms of influenza.
TAMIFLU for oral suspension may be used by patients who cannot swallow a capsule (see Table 1 ).
Pediatric Patients TAMIFLU is not indicated for treatment of influenza in pediatric patients younger than 1 year.
The recommended oral dose of TAMIFLU for pediatric patients 1 year and older is shown in Table 1 .
For pediatric patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation.
If the oral suspension product is not available, TAMIFLU capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar (dissolved in water).
If the appropriate strengths of TAMIFLU capsules are not available to mix with sweetened liquids and the oral suspension product is not available, then a pharmacist may compound an emergency supply of oral suspension from TAMIFLU 75 mg capsules [see Dosage and Administration (2.8) ] .
2.3 Standard Dosage – Prophylaxis of Influenza Adults and Adolescents The recommended oral dose of TAMIFLU for prophylaxis of influenza in adults and adolescents 13 years and older following close contact with an infected individual is 75 mg once daily for at least 10 days.
Therapy should begin within 2 days of exposure.
The recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once daily.
Safety and efficacy have been demonstrated for up to 6 weeks in immunocompetent patients.
The duration of protection lasts for as long as dosing is continued.
Safety has been demonstrated for up to 12 weeks in immunocompromised patients.
TAMIFLU for oral suspension may also be used by patients who cannot swallow a capsule (see Table 1 ).
Pediatric Patients The safety and efficacy of TAMIFLU for prophylaxis of influenza in pediatric patients younger than 1 year of age have not been established.
The recommended oral dose of TAMIFLU for pediatric patients 1 year and older following close contact with an infected individual is shown in Table 1 .
For pediatric patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation.
If the oral suspension product is not available, TAMIFLU capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar (dissolved in water).
If the appropriate strengths of TAMIFLU capsules are not available to mix with sweetened liquids and the oral suspension product is not available, then a pharmacist may compound an emergency supply of oral suspension from TAMIFLU 75 mg capsules [see Dosage and Administration (2.8) ] .
Prophylaxis in pediatric patients following close contact with an infected individual is recommended for 10 days.
Therapy should begin within 2 days of exposure.
For prophylaxis in pediatric patients during a community outbreak of influenza, dosing may be continued for up to 6 weeks.
2.4 Renal Impairment Data are available on plasma concentrations of oseltamivir carboxylate following various dosing schedules in patients with renal impairment [see Clinical Pharmacology (12.3) ] .
Treatment of Influenza Dose adjustment is recommended for adult patients with creatinine clearance between 10 and 30 mL/min receiving TAMIFLU for the treatment of influenza.
In these patients it is recommended that the dose be reduced to 75 mg of TAMIFLU once daily for 5 days.
No recommended dosing regimens are available for patients with end-stage renal disease undergoing routine hemodialysis or continuous peritoneal dialysis treatment.
Prophylaxis of Influenza For the prophylaxis of influenza, dose adjustment is recommended for adult patients with creatinine clearance between 10 and 30 mL/min receiving TAMIFLU.
In these patients it is recommended that the dose be reduced to 75 mg of TAMIFLU every other day or 30 mg TAMIFLU every day.
No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.
2.5 Hepatic Impairment No dose adjustment is recommended for patients with mild or moderate hepatic impairment (Child-Pugh score ≤9) [see Clinical Pharmacology (12.3) ] .
2.6 Geriatric Patients No dose adjustment is required for geriatric patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ] .
2.7 Preparation of TAMIFLU for Oral Suspension It is recommended that TAMIFLU for oral suspension be constituted by the pharmacist prior to dispensing to the patient: a) Tap the closed bottle several times to loosen the powder.
b) Measure 55 mL of water in a graduated cylinder.
c) Add the total amount of water for constitution to the bottle and shake the closed bottle well for 15 seconds.
d) Remove the child-resistant cap and push bottle adapter into the neck of the bottle.
e) Close bottle with child-resistant cap tightly.
This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.
Label the bottle with instructions to Shake Well before each use.
The constituted TAMIFLU for oral suspension (6 mg/mL) should be used within 17 days of preparation when stored under refrigeration or within 10 days if stored at controlled room temperature; the pharmacist should write the date of expiration of the constituted suspension on a pharmacy label.
The patient package insert and oral dispenser should be dispensed to the patient.
2.8 Emergency Compounding of an Oral Suspension from 75 mg TAMIFLU Capsules (Final Concentration 6 mg/mL) The following directions are provided for use only during emergency situations.
These directions are not intended to be used if the FDA-approved, commercially manufactured TAMIFLU for oral suspension is readily available from wholesalers or the manufacturer.
Compounding an oral suspension with this procedure will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.
Commercially manufactured TAMIFLU for oral suspension (6 mg/mL) is the preferred product for pediatric and adult patients who have difficulty swallowing capsules or where lower doses are needed.
In the event that TAMIFLU for oral suspension is not available, the pharmacist may compound a suspension (6 mg/mL) from TAMIFLU capsules 75 mg using one of these vehicles: Cherry Syrup (Humco ® ), Ora-Sweet ® SF (sugar-free) (Paddock Laboratories), or simple syrup.
Other vehicles have not been studied.
This compounded suspension should not be used for convenience or when the FDA-approved TAMIFLU for oral suspension is commercially available.
First, calculate the total volume of an oral suspension needed to be compounded and dispensed for each patient.
The total volume required is determined by the weight of the patient (see Table 2 ).
Table 2 Volume of an Oral Suspension (6 mg/mL) Needed to be Compounded Based Upon the Patient’s Body Weight Weight (kg) Weight (lbs) Total Volume to Compound per Patient (mL) 15 kg or less 33 lbs or less 75 mL 16 thru 23 kg 34 thru 51 lbs 100 mL 24 thru 40 kg 52 thru 88 lbs 125 mL 41 kg or more 89 lbs or more 150 mL Second, determine the number of capsules and the amount of water and vehicle (Cherry Syrup, Ora-Sweet ® SF, or simple syrup) that are needed to prepare the total volume (determined from Table 2 : 75 mL, 100 mL, 125 mL, or 150 mL) of compounded oral suspension (6 mg/mL) (see Table 3 ).
Table 3 Number of TAMIFLU 75 mg Capsules and Amount of Vehicle (Cherry Syrup, Ora-Sweet ® SF, or Simple Syrup) Needed to Prepare the Total Volume of a Compounded Oral Suspension (6 mg/mL) Total Volume of Compounded Oral Suspension to be Prepared 75 mL 100 mL 125 mL 150 mL Number of TAMIFLU 75 mg Capsules 6 capsules (450 mg oseltamivir) 8 capsules (600 mg oseltamivir) 10 capsules (750 mg oseltamivir) 12 capsules (900 mg oseltamivir) Amount of Water 5 mL 7 mL 8 mL 10 mL Volume of Vehicle Cherry Syrup (Humco ® ) OR Ora-Sweet ® SF (Paddock Laboratories) OR simple syrup 69 mL 91 mL 115 mL 137 mL Third, follow the procedure below for compounding the oral suspension (6 mg/mL) from TAMIFLU capsules 75 mg: Place the specified amount of water into a polyethyleneterephthalate (PET) or glass bottle (see Table 3 ).
Carefully separate the capsule body and cap and pour the contents of the required number of TAMIFLU 75 mg capsules into the PET or glass bottle.
Gently swirl the suspension to ensure adequate wetting of the TAMIFLU powder for at least 2 minutes.
Slowly add the specified amount of vehicle to the bottle.
Close the bottle using a child-resistant cap and shake well for 30 seconds to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension.
(Note: The active drug, oseltamivir phosphate, readily dissolves in the specified vehicles.
The suspension is caused by inert ingredients of TAMIFLU capsules which are insoluble in these vehicles.) Put an ancillary label on the bottle indicating “Shake Well Before Use.” Instruct the parent or caregiver that any unused suspension remaining in the bottle following completion of therapy must be discarded by either affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions.
Place an appropriate expiration date on the label according to storage conditions below.
Storage of the Emergency Compounded Suspension Refrigeration: Stable for 5 weeks (35 days) when stored in a refrigerator at 2° to 8°C (36° to 46°F).
Room Temperature: Stable for five days (5 days) when stored at room temperature, 25°C (77°F).
Note: The storage conditions are based on stability studies of compounded oral suspensions, using the above mentioned vehicles, which were placed in glass and polyethyleneterephthalate (PET) bottles.
Stability studies have not been conducted with other vehicles or bottle types.
Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, and drug name and any other required information to be in compliance with all State and Federal Pharmacy Regulations.
Dosing of the Compounded Suspension (6 mg/mL) Refer to Table 1 for the proper dosing instructions for the pharmacy label.