Tamiflu

Tamiflu information, interactions and side effects, 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-amino3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C16H28N2O4 (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:

tamiflu

INDICATIONS

Treatment Of Influenza

TAMIFLU is indicated for the treatment of acute, uncomplicated illness due to influenza infection in patients 2 weeks of age and older who have been symptomatic for no more than 2 days.

Prophylaxis Of Influenza

TAMIFLU is indicated for the prophylaxis of influenza in patients 1 year and older.

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 substitutions 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.

DOSAGE AND ADMINISTRATION

Dosing For Treatment And Prophylaxis Of Influenza

Treatment with TAMIFLU should begin within 2 days of onset of symptoms of influenza or following close contact with an infected individual.

TAMIFLU may be taken with or without food. However, when taken with food, tolerability may be enhanced in some patients.

For 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.

Treatment Of Influenza

Adults and Adolescents (13 years of age and older)

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. TAMIFLU for oral suspension may be used by patients who cannot swallow a capsule (12.5 mL of TAMIFLU for oral suspension [6 mg/mL] delivers 75 mg).

Pediatric Patients (2 weeks to 12 years of age)

The recommended oral dose of TAMIFLU for treatment of influenza in pediatric patients 1 to 12 years of age is shown in Table 1.

The recommended oral dose of TAMIFLU for treatment of influenza in pediatric patients 2 weeks to less than 1 year of age is 3 mg/kg twice daily for 5 days (shown in Table 1).

Prophylaxis Of Influenza

Adults and Adolescents (13 years of age and older)

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. 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 (12.5 mL of TAMIFLU for oral suspension [6 mg/mL] delivers 75 mg).

Pediatric Patients (1 to 12 years of age)

The recommended oral dose of TAMIFLU for prophylaxis of influenza in pediatric patients 1 to 12 years of age based on body weight is shown in Table 1. Prophylaxis in pediatric patients following close contact with an infected individual is recommended for 10 days. For prophylaxis in pediatric patients during a community outbreak of influenza, dosing may be continued for up to 6 weeks.

The safety and efficacy of TAMIFLU for prophylaxis of influenza have not been established in infants less than 1 year of age.

Table 1 : Treatment (twice daily dosing for 5 days) and Prophylaxis (once daily dosing for 10 days) Dosing of Oral TAMIFLU for Influenza in Pediatric Patients

 

Weight (kg) 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†
Patients from 2 Weeks to less than 1 Year of Age
Any weight 3 mg/kg twice daily Not applicable‡ 0.5 mL/kg§ 1 bottle Not applicable
Patients 1 to 12 Years of Age Based on Body Weight
15 kg or less 30 mg twice daily 30 mg once daily 5 mL 1 bottle 10 Capsules 30 mg
15.1 kg thru 23 kg 45 mg twice daily 45 mg once daily 7.5 mL 2 bottles 10 Capsules 45 mg
23.1 kg thru 40 kg 60 mg twice daily 60 mg once daily 10 mL 2 bottles 20 Capsules 30 mg
40.1 kg or more 75 mg twice daily 75 mg once daily 12.5 mL 3 bottles 10 Capsules 75 mg
* An oral dosing dispensing device that measures the appropriate volume in mL should be utilized with the oral suspension.
† Oral Suspension is the preferred formulation for patients who cannot swallow capsules.
‡ TAMIFLU is not approved for prophylaxis of patients less than 1 year of age.
§ For patients less than 1 year of age, provide an appropriate dosing device that can accurately measure and administer small volumes.

 

Renal Impairment

Data are available on plasma concentrations of oseltamivir carboxylate following various dosing schedules in patients with renal impairment.

Treatment of Influenza

Dose adjustment is recommended for adult patients with creatinine clearance between 10 and 60 mL/min and patients with end-stage renal disease (ESRD) undergoing hemodialysis or continuous peritoneal dialysis receiving TAMIFLU for the treatment of influenza. TAMIFLU is not recommended for patients with ESRD not undergoing dialysis. The recommended doses are detailed in Table 2 below.

Table 2 : Recommended Dose Adjustments for Treatment of Influenza in Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

 

Renal Impairment/Creatinine Clearance Recommended Treatment Regimen*
Mild Creatinine Clearance > 60-90 mL/min 75 mg twice daily for 5 days
Moderate Creatinine Clearance > 30-60 mL/min 30 mg twice daily for 5 days
Severe Creatinine Clearance > 10-30 mL/min 30 mg once daily for 5 days
ESRD Patients on Hemodialysis Creatinine Clearance ≤ 10 mL/min 30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days†
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ Creatinine Clearance ≤ 10 mL/min A single 30 mg dose administered immediately after a dialysis exchange
* Capsules or suspension can be used for 30 mg dosing.
† Assuming three hemodialysis sessions are performed in the 5-day period. Treatment can be initiated immediately if influenza symptoms develop during the 48 hours between hemodialysis sessions; however, the post-hemodialysis dose should still be administered independently of time of administration of the initial dose.
‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

 

Prophylaxis of Influenza

For the prophylaxis of influenza, dose adjustment is recommended for adult patients with creatinine clearance between 10 and 60 mL/min and patients with end-stage renal disease (ESRD) undergoing hemodialysis or continuous peritoneal dialysis receiving TAMIFLU. The duration of prophylaxis is the same as recommended for patients with normal renal function. TAMIFLU is not recommended for patients with ESRD not undergoing dialysis. The recommended doses are detailed in Table 3 below.

Table 3 : Recommended Dose Adjustments for Prophylaxis of Influenza in Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

 

Renal Impairment/Creatinine Clearance Recommended Prophylaxis Regimen*
Mild Creatinine Clearance > 60-90 mL/min 75 mg once daily
Moderate Creatinine Clearance > 30-60 mL/min 30 mg once daily
Severe Creatinine Clearance > 10-30 mL/min 30 mg every other day
ESRD Patients on Hemodialysis Creatinine Clearance ≤ 10 mL/min 30 mg after alternate hemodialysis cycles†
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ Creatinine Clearance ≤ 10 mL/min 30 mg once weekly immediately after dialysis exchange
* Capsules or suspension can be used for 30 mg dosing.
† An initial dose can be administered prior to the start of dialysis.
‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

 

Hepatic Impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (Child-Pugh score ≤ 9).

Geriatric Patients

No dose adjustment is required for geriatric patients.

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:

  1. Tap the closed bottle several times to loosen the powder.
  2. Measure 55 mL of water in a graduated cylinder.
  3. Add the total amount of water for constitution to the bottle.
  4. Close bottle with child-resistant cap tightly and shake the closed bottle well for 15 seconds.

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 should be dispensed to the patient. Pharmacists should ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Pharmacists should counsel patients on how to utilize an oral dosing dispenser and correctly measure the oral suspension as prescribed (see Table 1).

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, determine the dose of TAMIFLU for the patients then determine total volume of an oral suspension needed to be compounded based on Table 4.

Table 4 : Volume of an Oral Suspension (6 mg/mL) Needed to be Compounded Based Upon the Patient’s TAMIFLU Dose

 

TAMIFLU Dose* Total Volume to Compound per Patient (mL)
15 mg or less 37.5 mL
30 mg 75 mL
45 mg 100 mL
60 mg 125 mL
75 mg 150 mL
* If the TAMIFLU dose is between the doses listed, the total volume of oral suspension to compound should default to the next greater dose listed.

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 4: 37.5 mL, 75 mL, 100 mL, 125 mL, or 150 mL) of compounded oral suspension (6 mg/mL) (see Table 5).

Table 5 : 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 37.5 mL 75 mL 100 mL 125 mL 150 mL
Number of TAMIFLU 75 mg Capsules* 3 capsules (225 mg oseltamivir) 6 capsules (450 mg oseltamivir) 8 capsules (600 mg oseltamivir) 10 capsules (750 mg oseltamivir) 12 capsules (900 mg oseltamivir)
Amount of Water 2.5 mL 5 mL 7 mL 8 mL 10 mL
Volume of Vehicle Cherry Syrup (Humco®) OR Ora-Sweet® SF (Paddock Laboratories) OR simple syrup 34.5 mL 69 mL 91 mL 115 mL 137 mL
*Includes overage to ensure all doses can be delivered

Third, follow the procedure below for compounding the oral suspension (6 mg/mL) from TAMIFLU capsules 75 mg:

  1. Place the specified amount of water into a polyethyleneterephthalate (PET) or glass bottle (see Table 5).
  2. 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.
  3. Gently swirl the suspension to ensure adequate wetting of the TAMIFLU powder for at least 2 minutes.
  4. Slowly add the specified amount of vehicle to the bottle.
  5. 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.)
  6. Put an ancillary label on the bottle indicating “Shake Well Before Use.”
  7. 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.
  8. 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 Dosage and Administration sections 2.2, 2.3, 2.4 and Table 1 for the proper dosing instructions for the pharmacy label.

Dosage Forms And Strengths

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).

HOW SUPPLIED

Storage And Handling

TAMIFLU Capsules

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. Available in blister packages of 10 (NDC 0004-0802-85).

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 0004-0801-85).

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 0004-0800-85).

Storage

Store the capsules at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

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). (NDC 0004-0822-05).

Storage

Store dry powder at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

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).

SIDE EFFECTS

The following serious adverse reactions are discussed below and elsewhere in the labeling:

  • Serious skin and hypersensitivity reactions
  • Neuropsychiatric events

The most common adverse reactions are nausea and vomiting.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Treatment Studies in Adult and Adolescent Subjects (13 years of age and older)

A total of 1171 subjects who participated in adult controlled clinical trials for the treatment of influenza were treated with TAMIFLU. The most frequently reported adverse events in these studies were nausea and vomiting. These events were generally of mild to moderate severity and usually occurred on the first 2 days of administration. Less than 1% of subjects discontinued prematurely from clinical trials due to nausea and vomiting.

Adverse events that occurred with an incidence of 1% or greater in 1440 subjects taking placebo or TAMIFLU 75 mg twice daily in adult treatment studies are shown in Table 6. This summary includes 945 healthy young adults and 495 “at risk” subjects (elderly patients and patients with chronic cardiac or respiratory disease). Those events reported numerically more frequently in subjects taking TAMIFLU compared with placebo were nausea, vomiting, bronchitis, insomnia, and vertigo.

Prophylaxis Studies in Adult and Adolescent Subjects (13 years of age and older)

A total of 4187 subjects (adolescents, healthy adults, and elderly) participated in prophylaxis studies, of whom 1790 received the recommended dose of 75 mg once daily for up to 6 weeks. Adverse events were qualitatively very similar to those seen in the treatment studies, despite a longer duration of dosing (see Table 6). Events reported more frequently in subjects receiving TAMIFLU compared to subjects receiving placebo in prophylaxis studies, and more commonly than in treatment studies, were aches and pains, rhinorrhea, dyspepsia and upper respiratory tract infections. However, the difference in incidence between TAMIFLU and placebo for these events was less than 1%. There were no clinically relevant differences in the safety profile of the 942 elderly subjects who received TAMIFLU or placebo, compared with the younger population.

Table 6 : Most Frequent Adverse Events in Studies in Naturally Acquired Influenza in Subjects 13 Years of Age and Older

 

Adverse Event* Treatment Prophylaxis
Placebo
N=716
TAMIFLU 75 mg twice daily
N=724
Placebo/ No Prophylaxis†
N=1688
TAMIFLU 75 mg once daily
N=1790
Nausea (without vomiting) 40 (6%) 72 (10%) 56(3%) 129 (7%)
Vomiting 21 (3%) 68 (9%) 16 (1%) 39 (2%)
Diarrhea 70 (10%) 48 (7%) 40 (2%) 50 (3%)
Bronchitis 15 (2%) 17 (2%) 22 (1%) 15 (1%)
Abdominal pain 16 (2%) 16 (2%) 25 (1%) 37 (2%)
Dizziness 25 (3%) 15 (2%) 21 (1%) 24 (1%)
Headache 14 (2%) 13 (2%) 306 (18%) 326 (18%)
Cough 12 (2%) 9 (1%) 119 (7%) 94 (5%)
Insomnia 6 (1%) 8 (1%) 15 (1%) 22 (1%)
Vertigo 4 (1%) 7 (1%) 4 ( < 1%) 4 ( < 1%)
Fatigue 7 (1%) 7 (1%) 163 (10%) 139 (8%)
* Adverse events included are all events reported in the treatment studies with frequency ≥ 1% in the TAMIFLU 75 mg twice daily group.
† The majority of subjects received placebo; 254 subjects from a randomized, open-label postexposure prophylaxis study in households did not receive placebo or prophylaxis therapy.

Additional adverse events occurring in less than 1% of patients receiving TAMIFLU for treatment included unstable angina, anemia, pseudomembranous colitis, humerus fracture, pneumonia, pyrexia, and peritonsillar abscess.

Treatment Studies in Pediatric Subjects (1 to 12 years of age)

A total of 1032 pediatric subjects aged 1 to 12 years (including 698 otherwise healthy pediatric subjects aged 1 to 12 years and 334 asthmatic pediatric subjects aged 6 to 12 years) participated in controlled clinical trials of TAMIFLU given for the treatment of influenza. A total of 515 pediatric subjects received treatment with TAMIFLU for oral suspension.

Adverse events occurring in 1% or greater of pediatric subjects receiving TAMIFLU treatment are listed in Table 7. The most frequently reported adverse event was vomiting. Other events reported more frequently by pediatric subjects treated with TAMIFLU included abdominal pain, epistaxis, ear disorder, and conjunctivitis. These events generally occurred once and resolved despite continued dosing resulting in discontinuation of drug in 8 out of 515 (2%) cases.

The adverse event profile in adolescents is similar to that described for adult subjects and pediatric subjects aged 1 to 12 years.

Prophylaxis Studies in Pediatric Subjects (1 to 12 years of age)

Pediatric subjects aged 1 to 12 years participated in a postexposure prophylaxis study in households, both as index cases (n=134) and as contacts (n=222). Gastrointestinal events were the most frequent, particularly vomiting. In a separate 6-week, uncontrolled, pediatric seasonal prophylaxis study (n=49), the adverse events noted were consistent with those previously observed (see Table 7).

Table 7 : Most Frequent Adverse Events Occurring in Children Aged 1 to 12 Years in Studies in Naturally Acquired Influenza

 

Adverse Event1 Treatment Trials* Household Prophylaxis Trialf
Placebo
N=517
TAMIFLU 2 mg/kg twice daily
N=515
No Prophylaxis§
N=87
Prophylaxis with TAMIFLU once daily§
N=99
Vomiting 48(9%) 77(15%) 2(2%) 10(10%)
Diarrhea 55(11%) 49(10%) 1(1%)
Otitis media 58(11%) 45(9%) 2(2%) 2(2%)
Abdominal pain 20(4%) 24(5%) 3(3%)
Asthma (including aggravated) 19(4%) 18(3%) 1(1%) 1(1%)
Nausea 22(4%) 17(3%) 1(1%) 4(4%)
Epistaxis 13(3%) 16(3%) 1(1%)
Pneumonia 17(3%) 10(2%) 2(2%)
Ear disorder 6(1%) 9(2%)
Sinusitis 13(3%) 9(2%)
Bronchitis 11(2%) 8(2%) 2(2%)
Conjunctivitis 2( < 1%) 5(1%)
Dermatitis 10(2%) 5(1%)
Lymphadenopathy 8(2%) 5(1%)
Tympanic membrane disorder 6(1%) 5(1%)
* Pooled data from trials of TAMIFLU treatment of naturally acquired influenza.
† A randomized, open-label study of household transmission in which household contacts received either prophylaxis or no prophylaxis but treatment if they became ill. Only contacts who received prophylaxis or who remained on no prophylaxis are included in this table.
‡ Adverse events included in Table 7 are all events reported in the treatment studies with frequency ≥ 1% in the TAMIFLU 75 mg twice daily group.
§ Unit dose = age-based dosing of 30 mg, 45 mg, or 60 mg

 

Treatment Studies in Pediatric Subjects (2 weeks to less than 1 year of age)

Assessment of adverse reactions is based on two open label studies that included safety data on 135 influenza-infected subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post conceptional age) exposed to TAMIFLU at doses ranging from 2 to 3.5 mg/kg twice daily for 5 days. The safety profile was similar across the age range studied, with vomiting, diarrhea and diaper rash being the most frequently reported adverse reactions. The safety profile observed in subjects 2 weeks to less than 1 year of age was consistent with the established safety profile of adults and pediatric subjects older than 1 year of age.

Prophylaxis Study in Immunocompromised Subjects

In a 12-week seasonal prophylaxis study in 475 immunocompromised subjects, including 18 pediatric subjects 1 to 12 years of age, the safety profile in the 238 subjects receiving TAMIFLU was consistent with that previously observed in other TAMIFLU prophylaxis clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of TAMIFLU. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to TAMIFLU exposure.

Body as a Whole: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia

Dermatologic: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme

Digestive: Hepatitis, liver function tests abnormal

Cardiac: Arrhythmia

Gastrointestinal disorders: Gastrointestinal bleeding, hemorrhagic colitis

Neurologic: Seizure

Metabolic: Aggravation of diabetes

Psychiatric: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions.

DRUG INTERACTIONS

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.

PRECAUTIONS

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.

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.

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.

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.

Safety and efficacy of TAMIFLU for treatment of influenza in pediatric patients less than 2 weeks of age have not been established. Safety and efficacy of TAMIFLU for prophylaxis of influenza have not been established for pediatric patients less than 1 year of age.

Patient Counseling Information

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In 2-year carcinogenicity studies in mice and rats given daily oral doses of the prodrug oseltamivir phosphate up to 400 mg/kg and 500 mg/kg, respectively, the prodrug and the active form oseltamivir carboxylate induced no statistically significant increases in tumors over controls. The mean maximum daily exposures to the prodrug in mice and rats were approximately 130- and 320-fold, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons. The respective safety margins of the exposures to the active oseltamivir carboxylate were 15- and 50-fold.

Oseltamivir was found to be non-mutagenic in the Ames test and the human lymphocyte chromosome assay with and without enzymatic activation and negative in the mouse micronucleus test. It was found to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. Oseltamivir carboxylate was non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay with and without enzymatic activation and negative in the SHE cell transformation test.

In a fertility and early embryonic development study in rats, doses of oseltamivir at 50, 250, and 1500 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 6 of pregnancy. Males were dosed for 4 weeks before mating, during mating, and for 2 weeks after mating. There were no effects on fertility, mating performance or early embryonic development at any dose level. The highest dose was approximately 100 times the human systemic exposure (AUC0-24h) of oseltamivir carboxylate.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with TAMIFLU in pregnant women. Available published epidemiological data suggest that TAMIFLU, taken in any trimester, is not associated with an increased risk of birth defects. However, these studies individually are limited by small sample sizes, use of different comparison groups, and some lacked information on dose, which preclude a definitive assessment of the risk. In animal studies, there was a dose-dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in offspring of rats and rabbits exposed at maternally toxic doses 100 and 50 times human exposures, respectively. TAMIFLU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, still births, birth defects, preterm delivery, low birth weight and small for gestational age.

Data

Human Data Published prospective and retrospective observational studies of approximately 1500 women exposed to oseltamivir during pregnancy including approximately 400 women exposed in the first trimester suggest that the observed rate of congenital malformations was not increased above the rate in the general comparison population, regardless of when therapy was administered during the gestational period. However, individually, none of these studies had adequate sample sizes and some lacked information on dose which preclude a definitive assessment of the risk.

Animal Data 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, based on AUC. Pharmacokinetic studies indicated that there was fetal exposure 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. At the maternally toxic doses, statistically significant increases in the incidence rates of a variety of minor skeletal abnormalities and variants were observed in the exposed offspring. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied.

Nursing Mothers

Risk Summary

Based on limited published data, oseltamivir and oseltamivir carboxylate are present in human milk at low levels considered unlikely to lead to toxicity in the breastfed infant. Exercise caution when TAMIFLU is administered to a nursing woman.

Pediatric Use

Safety and efficacy of TAMIFLU for treatment of influenza in pediatric patients less than 2 weeks of age have not been established. Safety and efficacy of TAMIFLU for prophylaxis of influenza have not been established for pediatric patients less than 1 year of age.

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 subjects 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.

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.

Renal Impairment

Dose adjustment is recommended for patients with a serum creatinine clearance between 10 and 60 mL/min and for patients with end-stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal dialysis treatment.

Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. The safety and pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

OVERDOSE

Reports of overdoses with TAMIFLU have been received from clinical trials and during postmarketing experience. In the majority of cases reporting overdose, no adverse events were reported. Adverse events reported following overdose were similar in nature to those observed with therapeutic doses of TAMIFLU.

CONTRAINDICATIONS

TAMIFLU is contraindicated in patients with known serious hypersensitivity to oseltamivir or any component of the product. Severe allergic reactions have included anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme.

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