Oseltamivir Phosphate: Package Insert and Label Information

OSELTAMIVIR PHOSPHATE — oseltamivir phosphate powder, for suspension
Lupin Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Treatment of Influenza

Oseltamivir phosphate for oral suspension 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.

1.2 Prophylaxis of Influenza

Oseltamivir phosphate for oral suspension is indicated for the prophylaxis of influenza A and B in patients 1 year and older.

1.3 Limitations of Use

• Oseltamivir phosphate for oral suspension 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 oseltamivir phosphate for oral suspension [see Microbiology (12.4)].
• Oseltamivir phosphate for oral suspension 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)].

2 DOSAGE AND ADMINISTRATION

2.1 Dosage and Administration Overview

Administer oseltamivir phosphate for oral suspension 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:

● Oseltamivir phosphate 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 oseltamivir phosphate for oral suspension powder must be constituted with water by the pharmacist to produce the oral suspension [see Dosage and Administration (2.5)].

An oral suspension may be taken with or without food; however, tolerability may be enhanced if oseltamivir phosphate for oral suspension is taken with food.

Adjust the oseltamivir phosphate for oral suspension dosage in patients with moderate or severe renal impairment [see Dosage and Administration (2.4)].

For patients who cannot swallow capsules, oseltamivir phosphate for oral suspension is the preferred formulation. When oseltamivir phosphate for oral suspension is not available from wholesaler or the manufacturer, oseltamivir phosphate 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 oseltamivir phosphate capsules to mix with sweetened liquids are available, then a pharmacist may prepare an emergency supply of oral suspension from oseltamivir phosphate 75 mg capsules [see Dosage and Administration (2.6)].

2.2 Recommended Dosage for Treatment of Influenza

Initiate treatment with oseltamivir phosphate for oral suspension within 48 hours of influenza symptom onset.

Adults and Adolescents (13 Years of Age and Older)

The recommended oral dosage of oseltamivir phosphate for oral suspension 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 for oral suspension 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.

2.3 Recommended Dosage for Prophylaxis of Influenza

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

Adults and Adolescents (13 Years of Age and Older)

The recommended dosage of oseltamivir phosphate for oral suspension 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 for oral suspension 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 for oral suspension dosing is continued.

Pediatric Patients (1 Year to 12 Years of Age)

Table 1 displays the recommended oral dosage of oseltamivir phosphate for oral suspension for prophylaxis of influenza in pediatric patients 1 year to 12 years of age based on body weight and provides information about prescribing 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

* 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.
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)‡
Pat ients 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
Pat ients 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 bottles	10 capsules (45 mg)
23.1 kg to 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)

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 Populations (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

* Oral suspension can be used for 30 mg dosing. † Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients.
R enal Impairment ( C reatinine Clearance)	R ecommended Treatment Regimen *	R ecommended Prophylaxis Regimen*†
Mild (>60 to 90 mL/minute)	75 mg twice daily for 5 days	75 mg once daily
Moderate (>30 to 60 mL/minute)	30 mg twice daily for 5 days	30 mg once daily
Severe (>10 to 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 is not recommended	Oseltamivir phosphate is not recommended

2.5 Preparation and Storage of Constituted Oseltamivir Phosphate Oral Suspension

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

1. Tap the closed bottle containing the supplied oseltamivir phosphate for oral suspension white to light brown powder 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.
5. Label the bottle with instructions to “Shake Well Before Use”.
6. The constituted oral suspension contains 360 mg of oseltamivir base per 60 mL of volume (6 mg per mL) and is white to light brown, tutti-frutti–flavored). Use the constituted oral suspension within 17 days of preparation when stored under refrigeration, 2° to 8°C (36° to 46°F), or within 10 days if stored at controlled room temperature, 25°C (77°F). Write the expiration date of the constituted oral suspension on the bottle label.
7. 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).

2.6 Emergency Preparation of Oral Suspension from 75 mg Oseltamivir Phosphate Capsules

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

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

Step #1: Determine the dosage of oseltamivir phosphate for the patient [see Dosage and Administration (2.2, 2.3, and 2.4)] then determine the total volume of oral suspension needed to be prepared (see Table 3).

Table 3 Emergency Preparation: Volume of Prepared Oral Suspension (6 mg per mL) Based Upon Oseltamivir Phosphate Dose

* If the oseltamivir phosphate dose is between the doses listed, use the greater listed dose to determine the total volume of prepared oral suspension.
Oseltamivir Phosphate Dose *	Total Volume to Prepare p e r Patient
15 mg or less	37.5 mL
30 mg	75 mL
45 mg	100 mL
60 mg	125 mL
75 mg	150 mL

Step #2: Preparation must be performed with only one of the following vehicles (other vehicles have not been studied): Cherry Syrup (Humco^®), Ora-Sweet^® SF (sugar-free) (Paddock Laboratories), or simple syrup. Determine the number of capsules and the amount of water and vehicle needed to prepare the total volume (see Table 3) of prepared oral suspension (6 mg per mL) for a complete treatment or prophylaxis course (see Table 4).

Table 4 Emergency Preparation: Number of Oseltamivir Phosphate 75 mg Capsules and Amount of Water and Vehicle Needed to Prepare the Total Volume of a Prepared Oral Suspension (6 mg per mL)

* Includes overage to ensure all doses can be delivered
T otal Volume of Prepared Oral Suspension	37.5 mL	75 mL	100 mL	125 mL	150 mL
Number of Oseltamivir Phosphate 75 mg Capsules (Total Strength)*	3 (225 mg)	6 (450 mg)	8 (600 mg)	10 (750 mg)	12 (900 mg)
A m ount 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

Step #3: Follow the instructions below for preparing the 75 mg oseltamivir phosphate capsules to produce the oral suspension (6 mg per mL):

a. Place the specified amount of water into a polyethyleneterephthalate (PET) or glass bottle (see Table 4). Constitution in other bottle types is not recommended because there is no stability data with other bottle types.

b. Carefully separate the capsule body and cap and pour the contents of the required number of oseltamivir phosphate 75 mg capsules into the PET or glass bottle.

c. Gently swirl the suspension to ensure adequate wetting of the oseltamivir phosphate powder for at least 2 minutes.

d. Slowly add the specified amount of vehicle to the bottle.

e. 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. The active drug, oseltamivir phosphate, readily dissolves in the specified vehicles. The suspension is caused by inert ingredients of oseltamivir phosphate capsules which are insoluble in these vehicles.

f. Put an ancillary label on the bottle indicating “Shake Well Before Use.”

g. 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.

h. Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, drug name and any other required information to be in compliance with all State and Federal Pharmacy Regulations. Place an appropriate expiration date on the label according to storage conditions below.

i. Include the recommended dosage on the pharmacy label as per Tables 1 and 2 [see Dosage and Administration (2.2, 2.3, and 2.4)].

j. Store the prepared oral suspension in glass or PET bottles either:

● In a refrigerator [2° to 8°C (36° to 46°F)]: Stable for 5 weeks when stored in a refrigerator.

● At room temperature [25°C (77°F)]: Stable for 5 days when stored at room temperature.