Oseltamivir Phosphate

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Oseltamivir Phosphate Prescribing Information

Oseltamivir phosphate capsules are 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 Treatment of Influenza

Oseltamivir phosphate capsules are 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.

• Prophylaxis of influenza A and B in patients 1 year and older.

1.2 Prophylaxis of Influenza

Oseltamivir phosphate capsules are indicated for the prophylaxis of influenza A and B in patients 1 year and older.

Limitations of Use:

• Not a substitute for annual influenza vaccination.

1.3 Limitations of Use

Oseltamivir phosphate capsules are 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 oseltamivir phosphate capsules
[see Microbiology (12.4)].
Oseltamivir phosphate capsules, are 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)].

• Consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use.

1.3 Limitations of Use

Oseltamivir phosphate capsules are 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 oseltamivir phosphate capsules
[see Microbiology (12.4)].
Oseltamivir phosphate capsules, are 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)].

• Not recommended for patients with end-stage renal disease not undergoing dialysis.

1.3 Limitations of Use

Oseltamivir phosphate capsules are 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 oseltamivir phosphate capsules
[see Microbiology (12.4)].
Oseltamivir phosphate capsules, are 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)].

Treatment of influenza

2.2 Recommended Dosage for Treatment of Influenza

Initiate treatment with oseltamivir phosphate capsules within 48 hours of influenza symptom onset.

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of oseltamivir phosphate capsules 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.

Pediatric Patients (2 weeks of age through 12 years of age)

Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in pediatric patients 2 weeks of age through 12 years of age and provides information about prescribing the capsule or the formulation for oral suspension.

Adults and adolescents (13 years and older): 75 mg twice daily for 5 days (
2.2 Recommended Dosage for Treatment of Influenza
Initiate treatment with oseltamivir phosphate capsules within 48 hours of influenza symptom onset.

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of oseltamivir phosphate capsules 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.

Pediatric Patients (2 weeks of age through 12 years of age)

Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in pediatric patients 2 weeks of age through 12 years of age and provides information about prescribing the capsule or the formulation for oral suspension.

)
Pediatric patients 1 to 12 years of age: Based on weight twice daily for 5 days (
2.2 Recommended Dosage for Treatment of Influenza
Initiate treatment with oseltamivir phosphate capsules within 48 hours of influenza symptom onset.

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of oseltamivir phosphate capsules 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.

Pediatric Patients (2 weeks of age through 12 years of age)

Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in pediatric patients 2 weeks of age through 12 years of age and provides information about prescribing the capsule or the formulation for oral suspension.

)
Pediatric patients 2 weeks to less than 1 year of age: 3 mg/kg twice daily for 5 days (
2.2 Recommended Dosage for Treatment of Influenza
Initiate treatment with oseltamivir phosphate capsules within 48 hours of influenza symptom onset.

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of oseltamivir phosphate capsules 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.

Pediatric Patients (2 weeks of age through 12 years of age)

Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in pediatric patients 2 weeks of age through 12 years of age and provides information about prescribing the capsule or the formulation for oral suspension.

)

Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg twice daily for 5 days

2.4 Dosage in Patients with Renal Impairment

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)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

† The recommended duration for post-exposure prophylaxis is at least 10 days and the recommended duration for community outbreak (seasonal/pre-exposure) prophylaxis is up to 6 weeks (or up to 12 weeks in immunocompromised patients).

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once daily for 5 days

2.4 Dosage in Patients with Renal Impairment

[see Use in Specific Population (8.6)and Clinical Pharmacology (12.3)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

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 Dosage in Patients with Renal Impairment

[see Use in Specific Population (8.6)and Clinical Pharmacology (12.3)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

ESRD patients on CAPD: Reduce to a single 30 mg dose immediately

2.4 Dosage in Patients with Renal Impairment

[see Use in Specific Population (8.6)and Clinical Pharmacology (12.3)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

Prophylaxis of influenza

Adults and adolescents (13 years and older): 75 mg once daily for at least 10 days (

2.3 Recommended Dosage for Prophylaxis of Influenza

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

Adults and Adolescents (13 years of age and older)

The recommended dosage of oseltamivir phosphate capsules for prophylaxis of influenza in adults and adolescents 13 years and older is 75 mg orally once daily (one 75 mg capsule or 12.5 mL of oral suspension once daily) for at least 10 days following close contact with an infected individual and up to 6 weeks during a community outbreak. In immunocompromised patients, oseltamivir phosphate capsules may be continued for up to 12 weeks

[see Use in Specific Populations (8.9)].

The duration of protection lasts for as long as oseltamivir phosphate capsules dosing is continued.

Pediatric Patients (1 year to 12 years of age)

Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for prophylaxis of influenza in pediatric patients 1 year to 12 years of age based on body weight and provides information about prescribing the capsule or the formulation for oral suspension. Prophylaxis in pediatric patients is recommended for 10 days following close contact with an infected individual and up to 6 weeks during a community outbreak

[see Use in Specific Populations (8.4)

and

Clinical Studies (14.2)].

Table 1 Oseltamivir phosphate Dosage Recommendations in Pediatric Patients for

Treatment

and

Prophylaxis

of Influenza

Weight	Treatment Dosage for 5 days	Prophylaxis Dosage for 10 days*	Volume of Oral Suspension (6 mg/mL) for each Dose^†	Number of Bottles of Oral Suspension to Dispense	Number of Capsules to Dispense (Strength)^‡
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 to 23 kg	45 mg twice daily	45 mg once daily	7.5 mL	2 bottle	10 capsules (45 mg)
23.1 kg to 40 kg	60 mg twice daily	60 mg once daily	10 mL	2 bottle	20 capsules (30 mg)
40.1 kg to more	75 mg twice daily	75 mg once daily	12.5 mL	3 bottle	10 capsules (75 mg)

* The recommended duration for post-exposure prophylaxis is 10 days and the recommended duration for community outbreak (seasonal/pre-exposure) prophylaxis is up to 6 weeks (or up to 12 weeks in immunocompromised patients). The amount supplied (e.g., number of bottles or capsules) for seasonal prophylaxis may be greater than for post-exposure prophylaxis.

^†Use an oral dosing dispensing device that measures the appropriate volume in mL with the oral suspension.

^‡Oseltamivir phosphate for oral suspension is the preferred formulation for patients who cannot swallow capsules.

^§For patients less than 1 year of age, provide an appropriate dosing device that can accurately measure and administer small volumes.

)

Community outbreak: 75 mg once daily for up to 6 weeks (

2.3 Recommended Dosage for Prophylaxis of Influenza

Adults and Adolescents (13 years of age and older)

[see Use in Specific Populations (8.9)].

The duration of protection lasts for as long as oseltamivir phosphate capsules dosing is continued.

Pediatric Patients (1 year to 12 years of age)

[see Use in Specific Populations (8.4)

and

Clinical Studies (14.2)].

Table 1 Oseltamivir phosphate Dosage Recommendations in Pediatric Patients for

Treatment

and

Prophylaxis

of Influenza

Weight	Treatment Dosage for 5 days	Prophylaxis Dosage for 10 days*	Volume of Oral Suspension (6 mg/mL) for each Dose^†	Number of Bottles of Oral Suspension to Dispense	Number of Capsules to Dispense (Strength)^‡
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 to 23 kg	45 mg twice daily	45 mg once daily	7.5 mL	2 bottle	10 capsules (45 mg)
23.1 kg to 40 kg	60 mg twice daily	60 mg once daily	10 mL	2 bottle	20 capsules (30 mg)
40.1 kg to more	75 mg twice daily	75 mg once daily	12.5 mL	3 bottle	10 capsules (75 mg)

)

Pediatric patients 1 to 12 years of age: Based on weight once daily for 10 days (

2.3 Recommended Dosage for Prophylaxis of Influenza

Adults and Adolescents (13 years of age and older)

[see Use in Specific Populations (8.9)].

The duration of protection lasts for as long as oseltamivir phosphate capsules dosing is continued.

Pediatric Patients (1 year to 12 years of age)

[see Use in Specific Populations (8.4)

and

Clinical Studies (14.2)].

Table 1 Oseltamivir phosphate Dosage Recommendations in Pediatric Patients for

Treatment

and

Prophylaxis

of Influenza

Weight	Treatment Dosage for 5 days	Prophylaxis Dosage for 10 days*	Volume of Oral Suspension (6 mg/mL) for each Dose^†	Number of Bottles of Oral Suspension to Dispense	Number of Capsules to Dispense (Strength)^‡
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 to 23 kg	45 mg twice daily	45 mg once daily	7.5 mL	2 bottle	10 capsules (45 mg)
23.1 kg to 40 kg	60 mg twice daily	60 mg once daily	10 mL	2 bottle	20 capsules (30 mg)
40.1 kg to more	75 mg twice daily	75 mg once daily	12.5 mL	3 bottle	10 capsules (75 mg)

)

Community outbreak: Based on weight once daily for up to 6weeks (

2.3 Recommended Dosage for Prophylaxis of Influenza

Adults and Adolescents (13 years of age and older)

[see Use in Specific Populations (8.9)].

The duration of protection lasts for as long as oseltamivir phosphate capsules dosing is continued.

Pediatric Patients (1 year to 12 years of age)

[see Use in Specific Populations (8.4)

and

Clinical Studies (14.2)].

Table 1 Oseltamivir phosphate Dosage Recommendations in Pediatric Patients for

Treatment

and

Prophylaxis

of Influenza

Weight	Treatment Dosage for 5 days	Prophylaxis Dosage for 10 days*	Volume of Oral Suspension (6 mg/mL) for each Dose^†	Number of Bottles of Oral Suspension to Dispense	Number of Capsules to Dispense (Strength)^‡
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 to 23 kg	45 mg twice daily	45 mg once daily	7.5 mL	2 bottle	10 capsules (45 mg)
23.1 kg to 40 kg	60 mg twice daily	60 mg once daily	10 mL	2 bottle	20 capsules (30 mg)
40.1 kg to more	75 mg twice daily	75 mg once daily	12.5 mL	3 bottle	10 capsules (75 mg)

)

Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg once daily

2.4 Dosage in Patients with Renal Impairment

[see Use in Specific Population (8.6)and Clinical Pharmacology (12.3)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once every other day

2.4 Dosage in Patients with Renal Impairment

[see Use in Specific Population (8.6)and Clinical Pharmacology (12.3)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

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 Dosage in Patients with Renal Impairment

[see Use in Specific Population (8.6)and Clinical Pharmacology (12.3)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

ESRD patients on CAPD: Reduce to 30 mg immediately and then 30 mg once weekly for the recommended duration of prophylaxis

2.4 Dosage in Patients with Renal Impairment

[see Use in Specific Population (8.6)and Clinical Pharmacology (12.3)].

Table 2 Recommended Dosage Modifications for

Treatment

and

Prophylaxis

of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Renal Impairment (Creatinine Clearance)	Recommended Treatment Regimen*	Recommended Prophylaxis Regimen*†
Mild (>60-90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30-60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10-30 mL/minute)	30 mg once daily for 5 days	30 mg every other day
ESRD Patients on Hemodialysis (≤10 mL/minute)	30 mg immediately and then 30 mg after every hemodialysis cycle (treatment duration not to exceed 5 days)	30 mg immediately and then 30 mg after alternate hemodialysis cycles
ESRD Patients on Continuous Ambulatory Peritoneal Dialysis‡ (≤10 mL/minute)	A single 30 mg dose administered immediately	30 mg immediately and then 30 mg once weekly
ESRD Patients not on Dialysis	oseltamivir phosphate capsule is not recommended	oseltamivir phosphate capsule is not recommended

* Capsules can be used for 30 mg dosing.

‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.

Oseltamivir phosphate capsules, USP:

30-mg (30 mg free base equivalent of the phosphate salt): Size "4" hard gelatin capsules with light yellow opaque colour body with black colour band, imprinted with "M" and light yellow opaque colour cap imprinted with "30 mg".
45-mg (45 mg free base equivalent of the phosphate salt): Size "4" hard gelatin capsules with grey opaque colour body with black colour band, imprinted with '' M " and grey opaque colour cap imprinted with "45mg".
75-mg (75 mg free base equivalent of the phosphate salt): Size "2" hard gelatin capsules with grey opaque colour body with black colour band, imprinted with "M" and light yellow opaque colour cap imprinted with "75 mg".

Risk Summary

There are no adequate and well-controlled studies with oseltamivir phosphate in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Available published epidemiological data suggest that oseltamivir phosphate, 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

[

12.3 Pharmacokinetics

Absorption and Bioavailability

Oseltamivir is absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted predominantly by hepatic esterases to oseltamivir carboxylate. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate and less than 5% of the oral dose reaches the systemic circulation as oseltamivir (see Table 6).

Table 6 Mean (% CV) Pharmacokinetic Parameters of Oseltamivir and Oseltamivir Carboxylate Following Multiple Dosing of 75 mg Capsules Twice Daily (n=20)

Parameter	Oseltamivir	Oseltamivir Carboxylate
C_max(ng/mL)	65 (26)	348 (18)
AUC_0-12h(ng·h/mL)	112 (25)	2719 (20)

Plasma concentrations of oseltamivir carboxylate are proportional to doses up to 500 mg given twice daily (about 6.7 times the maximum recommended oseltamivir phosphate dosage)

[see Dosage and Administration (2)].

Coadministration with food had no significant effect on the peak plasma concentration (551 ng/mL under fasted conditions and 441 ng/mL under fed conditions) and the area under the plasma concentration time curve (6218 ng·h/mL under fasted conditions and 6069 ng·h/mL under fed conditions) of oseltamivir carboxylate.

Distribution

The volume of distribution (V_ss) of oseltamivir carboxylate, following intravenous administration in 24 subjects (Oseltamivir phosphate is not available as an IV formulation), ranged between 23 and 26 liters.

The binding of oseltamivir carboxylate to human plasma protein is low (3%). The binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions.

Elimination

Absorbed oseltamivir is primarily (>90%) eliminated by conversion to the active metabolite, oseltamivir carboxylate. Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration. Oseltamivir carboxylate is not further metabolized and is eliminated unchanged in urine. Plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration.

Metabolism

Oseltamivir is extensively converted to the active metabolite, oseltamivir carboxylate, by esterases located predominantly in the liver. Oseltamivir carboxylate is not further metabolized. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms.

Excretion

Oseltamivir carboxylate is eliminated entirely (>99%) by renal excretion. Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5 L/h), indicating that tubular secretion (via organic anion transporter) occurs in addition to glomerular filtration. Less than 20% of an oral radiolabeled dose is eliminated in feces.

Specific Populations

Renal Impairment

Administration of 100 mg of oseltamivir phosphate twice daily (about 1.3 times the maximum recommended dosage) for 5 days to subjects with various degrees of renal impairment showed that exposure to oseltamivir carboxylate is inversely proportional to declining renal function.

Population-derived pharmacokinetic parameters were determined for patients with varying degrees of renal function including ESRD patients on hemodialysis. Median simulated exposures of oseltamivir carboxylate for recommended treatment and prophylaxis regimens are provided in Table 7. The pharmacokinetics of oseltamivir have not been studied in ESRD patients not undergoing dialysis

[see Indications and Usage (1.3),

and

Use in Specific Populations (8.6)].

Table 7 Simulated Median Treatment Exposure Metrics of Oseltamivir Carboxylate in Patients with Normal Renal Function, with Renal Impairment and ESRD Patients on Hemodialysis

Renal Function/Impairment	Normal Creatinine Clearance 90-140 mL/min (n=57)	Mild Creatinine Clearance 60-90 mL/min (n=45)	Moderate Creatinine Clearance 30-60 mL/min (n=13)	Severe Creatinine Clearance 10-30 mL/min (n=11)	ESRD Creatinine Clearance <10 mL/min on Hemodialysis (n=24)
Recommended Treatment Regimens
PK exposure parameter	75 mg twice daily	75 mg twice daily	30 mg twice daily	30 mg once daily	30 mg every HD cycle
C_min(ng/mL)	145	253	180	219	221
C_max(ng/mL)	298	464	306	477	1170
AUC₄₈(ng.h/mL)^*	11224	18476	12008	16818	23200
Recommended Prophylaxix Regimens
PK exposure parameter	75 mg once daily	75 mg once daily	30 mg once daily	30 mg every other day	30 mg alternate HD cycle
C_min(ng/mL)	39	62	57	70	42
C_max(ng/mL)	213	311	209	377	903
AUC₄₈(ng.hr/mL)^*	5294	8336	6262	9317	11200

*AUC normalized to 48 hours

In continuous ambulatory peritoneal dialysis (CAPD) patients, the peak concentration of oseltamivir carboxylate following a single 30 mg dose of oseltamivir or once weekly oseltamivir was approximately 3 fold higher than in patients with normal renal function who received 75 mg twice daily. The plasma concentration of oseltamivir carboxylate on Day 5 (147 ng/mL) following a single 30 mg dose in CAPD patients is similar to the predicted C_min(160 ng/mL) in patients with normal renal function following 75 mg twice daily. Administration of 30 mg once weekly to CAPD patients resulted in plasma concentrations of oseltamivir carboxylate at the 168-hour blood sample of 63 ng/mL, which were comparable to the C_minin patients with normal renal function receiving the approved regimen of 75 mg once daily (40 ng/mL).

Hepatic Impairment

In clinical studies, oseltamivir carboxylate exposure was not altered in subjects with mild or moderate hepatic impairment

[see

Use in Specific Populations (8.7)

Pregnant Women

A pooled population pharmacokinetic analysis indicates that the oseltamivir phosphate dosage regimen resulted in lower exposure to the active metabolite in pregnant women (n=59) compared to non-pregnant women (n=33). However, this predicted exposure is expected to have activity against susceptible influenza virus strains and there are insufficient pharmacokinetics and safety data to recommend a dose adjustment for pregnant women

[see

Use in Specific Populations (8.1)

Pediatric Subjects (1 year to 12 years of age)

The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in a single-dose pharmacokinetic study in pediatric subjects aged 5 to 16 years (n=18) and in a small number of pediatric subjects aged 3 to 12 years (n=5) enrolled in a clinical trial. Younger pediatric subjects cleared both the prodrug and the active metabolite faster than adult subjects resulting in a lower exposure for a given mg/kg dose. For oseltamivir carboxylate, apparent total clearance decreases linearly with increasing age (up to 12 years). The pharmacokinetics of oseltamivir in pediatric subjects over 12 years of age are similar to those in adult subjects

[see

Use in Specific Populations (8.4

)].

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

The pharmacokinetics of oseltamivir and oseltamivir carboxylate have been evaluated in two open-label studies of pediatric subjects less than one year of age (n=122) infected with influenza. Apparent clearance of the active metabolite decreases with decreasing age in subjects less than 1 year of age; however the oseltamivir and oseltamivir carboxylate exposure following a 3 mg/kg dose in subjects under 1 year of age is expected to be within the observed exposures in adults and adolescents receiving 75 mg twice daily and 150 mg twice daily

[see

Use in Specific Populations (8.4)

Geriatric Patients

Exposure to oseltamivir carboxylate at steady-state was 25 to 35% higher in geriatric subjects (age range 65 to 78 years) compared to young adults given comparable doses of oseltamivir. Half-lives observed in the geriatric subjects were similar to those seen in young adults. Based on drug exposure and tolerability, dose adjustments are not required for geriatric patients for either treatment or prophylaxis

[see

Use in Specific Populations (8.5)

Drug Interaction Studies

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.

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 clinically relevant pharmacokinetic interactions have been observed when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), rimantadine, amantadine, or warfarin.

In animal reproduction studies with oseltamivir, no adverse developmental effects were observed at clinically relevant exposures

(see Data).

The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2-4% and 15-20%, respectively.

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 more than 5,000 women exposed to oseltamivir phosphate during pregnancy, including more than 1,000 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

Oseltamivir was administered orally during organogenesis to pregnant rats (at 50, 250, or 1500 mg/kg/day on gestation days 6 to 17) and rabbits (at 50, 150, or 500 mg/kg/day on gestation days 6 to 18). In rats, embryo‐fetal effects consisting of an increased incidence of minor skeletal malformations were observed at a maternally toxic dose (1500 mg/kg/day), resulting in systemic drug exposures (based on AUC for oseltamivir carboxylate) 190 times human exposures at the maximum recommended human dose (MRHD) of oseltamivir phosphate (75 mg twice a day). In the rabbit study, embryo-fetal effects consisting of an increased incidence of minor skeletal abnormalities and variants were observed at maternally toxic doses (≥150 mg/kg/day) resulting in systemic exposures (based on AUC for oseltamivir carboxylate) ≥8 times human exposures at the MRHD of oseltamivir phosphate.

In prenatal and postnatal development studies in rats, oseltamivir was administered orally (at 50, 250, 500, or 1500 mg/kg/day) from organogenesis through late gestation, delivery, and lactation (gestation day 6 to postpartum/lactation day 20). Prolonged parturition duration and reduced offspring viability were observed at a maternally toxic dose (1500 mg/kg/day). No adverse maternal or offspring effects were observed at doses ≤500 mg/kg/day, resulting in systemic drug exposures (based on AUC for oseltamivir carboxylate) 44 times human exposures at the MRHD of oseltamivir phosphate.

Oseltamivir phosphate 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

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 oseltamivir phosphate. Stop oseltamivir phosphate and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of oseltamivir phosphate is contraindicated in patients with known serious hypersensitivity to oseltamivir phosphate

[see Contraindications (4)

and

Adverse Reactions (6.2)].

Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme: Discontinue oseltamivir phosphate and initiate appropriate treatment if allergic-like reactions occur or are suspected.
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 oseltamivir phosphate. Stop oseltamivir phosphate and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of oseltamivir phosphate is contraindicated in patients with known serious hypersensitivity to oseltamivir phosphate
[see Contraindications (4)
and
Adverse Reactions (6.2)].
Neuropsychiatric events: Patients with influenza, including those receiving oseltamivir phosphate 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 Neuropsychiatric Events

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 oseltamivir phosphate
[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 oseltamivir phosphate usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir phosphate 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 oseltamivir phosphate -treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing oseltamivir phosphate for each patient.

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