Tamiflu

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of TAMIFLU for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily (one 75 mg capsule or 12.5 mL of oral suspension twice daily) for 5 days.

Storage

Store the capsules at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature].

Reports of overdoses with TAMIFLU have been received from clinical trials and during postmarketing experience. In the majority of cases reporting overdose, no adverse reactions were reported. Adverse reactions reported following overdose were similar in nature to those observed with therapeutic doses of TAMIFLU [see Adverse Reactions (6)].

TAMIFLU (oseltamivir phosphate), an influenza neuraminidase inhibitor (NAI), is available as:

• Capsules containing 30 mg, 45 mg, or 75 mg of oseltamivir for oral use, in the form of oseltamivir phosphate, and
• A powder for oral suspension, which when constituted with water as directed contains 6 mg per mL oseltamivir base.

In addition to the active ingredient, each capsule contains croscarmellose sodium, povidone K30, pregelatinized starch, sodium stearyl fumarate and talc. The 30 mg capsule shell contains gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The 45 mg capsule shell contains black iron oxide, gelatin, and titanium dioxide. The 75 mg capsule shell contains black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow 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 monosodium citrate, saccharin sodium, sodium benzoate, sorbitol, titanium dioxide, tutti-frutti flavoring, and xanthan gum.

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 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 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 [see Warnings and Precautions (5.1)].

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

• Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1)]
• Neuropsychiatric events [see Warnings and Precautions (5.2)]

Live attenuated influenza vaccine (LAIV), intranasal:

Avoid administration of LAIV within 2 weeks before or 48 hours after TAMIFLU use, unless medically indicated. (7)

Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal function which may increase the risk of TAMIFLU-associated adverse reactions. Therefore, dosage adjustment is recommended for patients with a serum creatinine clearance between 10 and 60 mL/minute and for patients with end-stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal dialysis treatment [see Dosage and Administration (2.4)]. TAMIFLU is not recommended for patients with ESRD not undergoing dialysis [see Indications and Usage (1.3) and Clinical Pharmacology (12.3)].

• 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.
• 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 [see Microbiology (12.4)].
• TAMIFLU is not recommended for patients with end-stage renal disease not undergoing dialysis [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

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 [see Clinical Pharmacology (12.3)].

TAMIFLU is an influenza neuraminidase inhibitor (NAI) indicated for:

• Treatment of acute, uncomplicated influenza A and B in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours. (1.1)
• Prophylaxis of influenza A and B in patients 1 year and older. (1.2)

Limitations of Use:

• Not a substitute for annual influenza vaccination. (1.3)
• Consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use. (1.3)
• Not recommended for patients with end-stage renal disease not undergoing dialysis. (1.3)

Oseltamivir is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].

TAMIFLU is indicated for the treatment of acute, uncomplicated illness due to influenza A and B infection in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours.

• Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme: 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)

Treatment of influenza

• Adults and adolescents (13 years and older): 75 mg twice daily for 5 days (2.2)
• Pediatric patients 1 to 12 years of age: Based on weight twice daily for 5 days (2.2)
• Pediatric patients 2 weeks to less than 1 year of age: 3mg/kg twice daily for 5 days (2.2)
• Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg twice daily for 5 days (2.4)
• Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once daily for 5 days (2.4)
• ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days (2.4)
• ESRD patients on CAPD: Reduce to a single 30 mg dose immediately (2.4)

Prophylaxis of influenza

• Adults and adolescents (13 years and older): 75 mg once daily for at least 10 days (2.3)
  • -
    Community outbreak: 75 mg once daily for up to 6 weeks (2.3)
• Pediatric patients 1 to 12 years of age: Based on weight once daily for 10 days (2.3)
  • -
    Community outbreak: Based on weight once daily for up to 6 weeks (2.3)
• Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg once daily (2.4)
• Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once every other day (2.4)
• ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after alternate hemodialysis cycles for the recommended duration of prophylaxis (2.4)
• ESRD patients on CAPD: Reduce to 30 mg immediately and then 30 mg once weekly for the recommended duration of prophylaxis (2.4)

There have been postmarketing reports of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU [see Adverse Reactions (6.2)]. 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. 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. Closely monitor TAMIFLU-treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing TAMIFLU for each patient.

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

TAMIFLU Capsules:

• 30-mg (30 mg free base equivalent of the phosphate salt): light yellow, hard gelatin, with "ROCHE" printed in blue ink on the light yellow body and "30 mg" printed in blue ink on the light yellow cap.
• 45-mg (45 mg free base equivalent of the phosphate salt): grey, hard gelatin, with "ROCHE" printed in blue ink on the grey body and "45 mg" printed in blue ink on the grey cap.
• 75-mg (75 mg free base equivalent of the phosphate salt): grey/light yellow, hard gelatin, with "ROCHE" is printed in blue ink on the grey body and "75 mg" printed in blue ink on the light yellow cap.

TAMIFLU for Oral Suspension: 6 mg per mL (final concentration when constituted)

• White powder blend for constitution.

The following adverse reactions have been identified during post-approval 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.

General disorders and administration site conditions: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia

Skin and subcutaneous tissue disorders: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme [see Warnings and Precautions (5.1)]

Gastrointestinal Disorders: Gastrointestinal bleeding, hemorrhagic colitis

Cardiac Disorders: Arrhythmia

Hepatobiliary Disorders: Hepatitis, abnormal liver function tests

Nervous System Disorders: Seizure

Metabolism and Nutrition Disorders: Aggravation of diabetes

Psychiatric Disorders: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions [see Warnings and Precautions (5.2)]

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.

Efficacy of TAMIFLU for the treatment or prophylaxis of influenza has not been established in immunocompromised patients [see Clinical Studies (14.2)]. Safety of TAMIFLU has been demonstrated for up to 12 weeks for prophylaxis of influenza in immunocompromised patients [see Adverse Reactions (6.1)].

There is no evidence for efficacy of TAMIFLU in any illness caused by pathogens other than influenza viruses. 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. Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Administer TAMIFLU for the treatment of influenza in patients 2 weeks of age or older [see Dosage and Administration (2.2)] or for prophylaxis of influenza in patients 1 year and older [see Dosage and Administration (2.3)] using:

• TAMIFLU capsules or
• TAMIFLU for oral suspension (supplied as a powder). This is the preferred formulation (6 mg per mL) for patients who cannot swallow capsules. Prior to use, the supplied TAMIFLU powder must be constituted with water by the pharmacist to produce the oral suspension [see Dosage and Administration (2.5)].

The capsules and oral suspension may be taken with or without food; however, tolerability may be enhanced if TAMIFLU is taken with food.

Adjust the TAMIFLU dosage in patients with moderate or severe renal impairment [see Dosage and Administration (2.4)].

For patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation. When TAMIFLU for oral suspension is not available from wholesaler or the manufacturer, 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). During emergency situations and when neither the oral suspension or the age-appropriate strengths of TAMIFLU capsules to mix with sweetened liquids are available, then a pharmacist may prepare an emergency supply of oral suspension from TAMIFLU 75 mg capsules [see Dosage and Administration (2.6)].

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. Stop TAMIFLU and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of TAMIFLU is contraindicated in patients with known serious hypersensitivity to TAMIFLU [see Contraindications (4) and Adverse Reactions (6.2)].

Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease was evaluated in one randomized, placebo-controlled clinical trial. Efficacy in this population, as measured by time to alleviation of all symptoms, was not established, but no new safety signals were identified [see Clinical Studies (14.1) ].

No clinical trial data are available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.

Table 2 displays the dosage recommendations for the treatment and prophylaxis of influenza in adults with various stages of renal impairment (estimated creatinine clearance of less than or equal to 90 mL per minute). Dosage modifications are recommended in adults with an estimated creatinine clearance less than or equal to 60 mL per minute [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3)].

NDC 0004-0822-05

Tamiflu ^®

(oseltamivir phosphate)

for Oral Suspension

6 mg/mL

Each mL contains 6 mg

oseltamivir base after

constitution.

60 mL (usable volume

after constitution)

Rx only

Genentech

10240835

Initiate treatment with TAMIFLU within 48 hours of influenza symptom onset.

Initiate post-exposure prophylaxis with TAMIFLU within 48 hours following close contact with an infected individual. Initiate seasonal prophylaxis with TAMIFLU during a community outbreak.

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 recommended 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 in this study was approximately 115 times the human systemic exposure (AUC_0-24h) of oseltamivir carboxylate that occurs after administration of the maximum recommended human dose.

NDC 0004-0802-85

Tamiflu ^®

(oseltamivir phosphate) Capsules

30 mg

Each capsule contains oseltamivir phosphate equivalent to 30 mg

oseltamivir (free base).

Rx only

10 Capsules

Genentech

10175386

NDC 0004-0801-85

Tamiflu ^®

(oseltamivir phosphate) Capsules

45 mg

Each capsule contains oseltamivir phosphate equivalent to 45 mg

oseltamivir (free base).

Rx only

10 Capsules

Genentech

10175387

NDC 0004-0800-85

Tamiflu^®

(oseltamivir phosphate) Capsules

75 mg

Each capsule contains oseltamivir phosphate equivalent to 75 mg

oseltamivir (free base).

Rx only

10 Capsules

Genentech

11026905

Prior to dispensing to the patient, constitute TAMIFLU for oral suspension (supplied as powder):

• a)
  Tap the closed bottle containing the supplied TAMIFLU white powder 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.
• d)
  Close bottle with child-resistant cap tightly and shake the closed bottle well for 15 seconds.
• e)
  Label the bottle with instructions to "Shake Well Before Use".
• f)
  The constituted oral suspension contains 360 mg of oseltamivir base per 60 mL of volume (6 mg per mL) and is white, tutti-frutti–flavored). Use the constituted oral suspension within 17 days of preparation when stored under refrigeration, 2º to 8ºC (36º to 46ºF), or within 10 days if stored at controlled room temperature, 25ºC (77ºF). Write the expiration date of the constituted oral suspension on the bottle label.
• g)
  Ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize the oral dosing dispenser and correctly measure the oral suspension as prescribed (see Tables 1 and 2).

No dose adjustments are needed for either oseltamivir or the concomitant drug when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), rimantadine, amantadine, or warfarin [see Clinical Pharmacology (12.3)].

The following directions are provided for use only during emergency situations and when FDA-approved, commercially manufactured TAMIFLU for oral suspension is not available from wholesalers or the manufacturer.

The following emergency preparation instructions will provide one patient with enough TAMIFLU for a 5-day course of treatment of influenza or a 10-day course of prophylaxis of influenza:

Fructose can be harmful to patients with hereditary fructose intolerance. One dose of 75 mg TAMIFLU for oral suspension delivers 2 grams of sorbitol. This is above the daily maximum limit of sorbitol for patients with hereditary fructose intolerance and may cause dyspepsia and diarrhea.

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of TAMIFLU for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily (one 75 mg capsule or 12.5 mL of oral suspension twice daily) for 5 days.

Storage

Store the capsules at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature].

Reports of overdoses with TAMIFLU have been received from clinical trials and during postmarketing experience. In the majority of cases reporting overdose, no adverse reactions were reported. Adverse reactions reported following overdose were similar in nature to those observed with therapeutic doses of TAMIFLU [see Adverse Reactions (6)].

TAMIFLU (oseltamivir phosphate), an influenza neuraminidase inhibitor (NAI), is available as:

• Capsules containing 30 mg, 45 mg, or 75 mg of oseltamivir for oral use, in the form of oseltamivir phosphate, and
• A powder for oral suspension, which when constituted with water as directed contains 6 mg per mL oseltamivir base.

In addition to the active ingredient, each capsule contains croscarmellose sodium, povidone K30, pregelatinized starch, sodium stearyl fumarate and talc. The 30 mg capsule shell contains gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The 45 mg capsule shell contains black iron oxide, gelatin, and titanium dioxide. The 75 mg capsule shell contains black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow 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 monosodium citrate, saccharin sodium, sodium benzoate, sorbitol, titanium dioxide, tutti-frutti flavoring, and xanthan gum.

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 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 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 [see Warnings and Precautions (5.1)].

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

• Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1)]
• Neuropsychiatric events [see Warnings and Precautions (5.2)]

Live attenuated influenza vaccine (LAIV), intranasal:

Avoid administration of LAIV within 2 weeks before or 48 hours after TAMIFLU use, unless medically indicated. (7)

Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal function which may increase the risk of TAMIFLU-associated adverse reactions. Therefore, dosage adjustment is recommended for patients with a serum creatinine clearance between 10 and 60 mL/minute and for patients with end-stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal dialysis treatment [see Dosage and Administration (2.4)]. TAMIFLU is not recommended for patients with ESRD not undergoing dialysis [see Indications and Usage (1.3) and Clinical Pharmacology (12.3)].

• 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.
• 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 [see Microbiology (12.4)].
• TAMIFLU is not recommended for patients with end-stage renal disease not undergoing dialysis [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

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 [see Clinical Pharmacology (12.3)].

TAMIFLU is an influenza neuraminidase inhibitor (NAI) indicated for:

• Treatment of acute, uncomplicated influenza A and B in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours. (1.1)
• Prophylaxis of influenza A and B in patients 1 year and older. (1.2)

Limitations of Use:

• Not a substitute for annual influenza vaccination. (1.3)
• Consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use. (1.3)
• Not recommended for patients with end-stage renal disease not undergoing dialysis. (1.3)

Oseltamivir is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].

TAMIFLU is indicated for the treatment of acute, uncomplicated illness due to influenza A and B infection in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours.

• Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme: 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)

Treatment of influenza

• Adults and adolescents (13 years and older): 75 mg twice daily for 5 days (2.2)
• Pediatric patients 1 to 12 years of age: Based on weight twice daily for 5 days (2.2)
• Pediatric patients 2 weeks to less than 1 year of age: 3mg/kg twice daily for 5 days (2.2)
• Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg twice daily for 5 days (2.4)
• Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once daily for 5 days (2.4)
• ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days (2.4)
• ESRD patients on CAPD: Reduce to a single 30 mg dose immediately (2.4)

Prophylaxis of influenza

• Adults and adolescents (13 years and older): 75 mg once daily for at least 10 days (2.3)
  • -
    Community outbreak: 75 mg once daily for up to 6 weeks (2.3)
• Pediatric patients 1 to 12 years of age: Based on weight once daily for 10 days (2.3)
  • -
    Community outbreak: Based on weight once daily for up to 6 weeks (2.3)
• Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg once daily (2.4)
• Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once every other day (2.4)
• ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after alternate hemodialysis cycles for the recommended duration of prophylaxis (2.4)
• ESRD patients on CAPD: Reduce to 30 mg immediately and then 30 mg once weekly for the recommended duration of prophylaxis (2.4)

There have been postmarketing reports of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU [see Adverse Reactions (6.2)]. 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. 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. Closely monitor TAMIFLU-treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing TAMIFLU for each patient.

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

TAMIFLU Capsules:

• 30-mg (30 mg free base equivalent of the phosphate salt): light yellow, hard gelatin, with "ROCHE" printed in blue ink on the light yellow body and "30 mg" printed in blue ink on the light yellow cap.
• 45-mg (45 mg free base equivalent of the phosphate salt): grey, hard gelatin, with "ROCHE" printed in blue ink on the grey body and "45 mg" printed in blue ink on the grey cap.
• 75-mg (75 mg free base equivalent of the phosphate salt): grey/light yellow, hard gelatin, with "ROCHE" is printed in blue ink on the grey body and "75 mg" printed in blue ink on the light yellow cap.

TAMIFLU for Oral Suspension: 6 mg per mL (final concentration when constituted)

• White powder blend for constitution.

The following adverse reactions have been identified during post-approval 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.

General disorders and administration site conditions: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia

Skin and subcutaneous tissue disorders: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme [see Warnings and Precautions (5.1)]

Gastrointestinal Disorders: Gastrointestinal bleeding, hemorrhagic colitis

Cardiac Disorders: Arrhythmia

Hepatobiliary Disorders: Hepatitis, abnormal liver function tests

Nervous System Disorders: Seizure

Metabolism and Nutrition Disorders: Aggravation of diabetes

Psychiatric Disorders: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions [see Warnings and Precautions (5.2)]

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.

Efficacy of TAMIFLU for the treatment or prophylaxis of influenza has not been established in immunocompromised patients [see Clinical Studies (14.2)]. Safety of TAMIFLU has been demonstrated for up to 12 weeks for prophylaxis of influenza in immunocompromised patients [see Adverse Reactions (6.1)].

There is no evidence for efficacy of TAMIFLU in any illness caused by pathogens other than influenza viruses. 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. Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Administer TAMIFLU for the treatment of influenza in patients 2 weeks of age or older [see Dosage and Administration (2.2)] or for prophylaxis of influenza in patients 1 year and older [see Dosage and Administration (2.3)] using:

• TAMIFLU capsules or
• TAMIFLU for oral suspension (supplied as a powder). This is the preferred formulation (6 mg per mL) for patients who cannot swallow capsules. Prior to use, the supplied TAMIFLU powder must be constituted with water by the pharmacist to produce the oral suspension [see Dosage and Administration (2.5)].

The capsules and oral suspension may be taken with or without food; however, tolerability may be enhanced if TAMIFLU is taken with food.

Adjust the TAMIFLU dosage in patients with moderate or severe renal impairment [see Dosage and Administration (2.4)].

For patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation. When TAMIFLU for oral suspension is not available from wholesaler or the manufacturer, 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). During emergency situations and when neither the oral suspension or the age-appropriate strengths of TAMIFLU capsules to mix with sweetened liquids are available, then a pharmacist may prepare an emergency supply of oral suspension from TAMIFLU 75 mg capsules [see Dosage and Administration (2.6)].

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. Stop TAMIFLU and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of TAMIFLU is contraindicated in patients with known serious hypersensitivity to TAMIFLU [see Contraindications (4) and Adverse Reactions (6.2)].

Efficacy of TAMIFLU in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease was evaluated in one randomized, placebo-controlled clinical trial. Efficacy in this population, as measured by time to alleviation of all symptoms, was not established, but no new safety signals were identified [see Clinical Studies (14.1) ].

No clinical trial data are available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.

Table 2 displays the dosage recommendations for the treatment and prophylaxis of influenza in adults with various stages of renal impairment (estimated creatinine clearance of less than or equal to 90 mL per minute). Dosage modifications are recommended in adults with an estimated creatinine clearance less than or equal to 60 mL per minute [see Use in Specific Population (8.6) and Clinical Pharmacology (12.3)].

NDC 0004-0822-05

Tamiflu ^®

(oseltamivir phosphate)

for Oral Suspension

6 mg/mL

Each mL contains 6 mg

oseltamivir base after

constitution.

60 mL (usable volume

after constitution)

Rx only

Genentech

10240835

Initiate treatment with TAMIFLU within 48 hours of influenza symptom onset.

Initiate post-exposure prophylaxis with TAMIFLU within 48 hours following close contact with an infected individual. Initiate seasonal prophylaxis with TAMIFLU during a community outbreak.

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 recommended 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 in this study was approximately 115 times the human systemic exposure (AUC_0-24h) of oseltamivir carboxylate that occurs after administration of the maximum recommended human dose.

NDC 0004-0802-85

Tamiflu ^®

(oseltamivir phosphate) Capsules

30 mg

Each capsule contains oseltamivir phosphate equivalent to 30 mg

oseltamivir (free base).

Rx only

10 Capsules

Genentech

10175386

NDC 0004-0801-85

Tamiflu ^®

(oseltamivir phosphate) Capsules

45 mg

Each capsule contains oseltamivir phosphate equivalent to 45 mg

oseltamivir (free base).

Rx only

10 Capsules

Genentech

10175387

NDC 0004-0800-85

Tamiflu^®

(oseltamivir phosphate) Capsules

75 mg

Each capsule contains oseltamivir phosphate equivalent to 75 mg

oseltamivir (free base).

Rx only

10 Capsules

Genentech

11026905

Prior to dispensing to the patient, constitute TAMIFLU for oral suspension (supplied as powder):

• a)
  Tap the closed bottle containing the supplied TAMIFLU white powder 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.
• d)
  Close bottle with child-resistant cap tightly and shake the closed bottle well for 15 seconds.
• e)
  Label the bottle with instructions to "Shake Well Before Use".
• f)
  The constituted oral suspension contains 360 mg of oseltamivir base per 60 mL of volume (6 mg per mL) and is white, tutti-frutti–flavored). Use the constituted oral suspension within 17 days of preparation when stored under refrigeration, 2º to 8ºC (36º to 46ºF), or within 10 days if stored at controlled room temperature, 25ºC (77ºF). Write the expiration date of the constituted oral suspension on the bottle label.
• g)
  Ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize the oral dosing dispenser and correctly measure the oral suspension as prescribed (see Tables 1 and 2).

No dose adjustments are needed for either oseltamivir or the concomitant drug when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), rimantadine, amantadine, or warfarin [see Clinical Pharmacology (12.3)].

The following directions are provided for use only during emergency situations and when FDA-approved, commercially manufactured TAMIFLU for oral suspension is not available from wholesalers or the manufacturer.

The following emergency preparation instructions will provide one patient with enough TAMIFLU for a 5-day course of treatment of influenza or a 10-day course of prophylaxis of influenza:

Fructose can be harmful to patients with hereditary fructose intolerance. One dose of 75 mg TAMIFLU for oral suspension delivers 2 grams of sorbitol. This is above the daily maximum limit of sorbitol for patients with hereditary fructose intolerance and may cause dyspepsia and diarrhea.