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Tamiflu (Oseltamivir Phosphate) - Indications and Dosage

 
 



INDICATIONS AND USAGE

Treatment of Influenza

TAMIFLU is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days.

Prophylaxis of Influenza

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

The following points should be considered before initiating treatment or prophylaxis with TAMIFLU:

  • TAMIFLU is not a substitute for early 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 mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use TAMIFLU.

Description of Clinical Studies: Studies in Naturally Occurring Influenza

Treatment of Influenza

Adult Patients

Two phase III placebo-controlled and double-blind clinical trials were conducted: one in the USA and one outside the USA. Patients were eligible for these trials if they had fever >100F, accompanied by at least one respiratory symptom (cough, nasal symptoms or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue or headache) and influenza virus was known to be circulating in the community. In addition, all patients enrolled in the trials were allowed to take fever-reducing medications.

Of 1355 patients enrolled in these two trials, 849 (63%) patients were influenza-infected (age range 18 to 65 years; median age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected patients, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of unknown type.

TAMIFLU was started within 40 hours of onset of symptoms. Subjects participating in the trials were required to self-assess the influenza-associated symptoms as "none", "mild", "moderate" or "severe". Time to improvement was calculated from the time of treatment initiation to the time when all symptoms (nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were assessed as "none" or "mild". In both studies, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1.3 day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to subjects receiving placebo. Subgroup analyses of these studies by gender showed no differences in the treatment effect of TAMIFLU in men and women.

In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of 150 mg TAMIFLU twice daily for 5 days.

Geriatric Patients

Three double-blind placebo-controlled treatment trials were conducted in patients ≥65 years of age in three consecutive seasons. The enrollment criteria were similar to that of adult trials with the exception of fever being defined as >97.5F. Of 741 patients enrolled, 476 (65%) patients were influenza-infected. Of the 476 influenza-infected patients, 95% were infected with influenza type A and 5% with influenza type B.

In the pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1 day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to those receiving placebo (p=NS). However, the magnitude of treatment effect varied between studies.

Pediatric Patients

One double-blind placebo-controlled treatment trial was conducted in pediatric patients aged 1 to 12 years (median age 5 years), who had fever (>100F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community. Of 698 patients enrolled in this trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian). Of the 452 influenza-infected patients, 67% were infected with influenza A and 33% with influenza B.

The primary endpoint in this study was the time to freedom from illness, a composite endpoint which required 4 individual conditions to be met. These were: alleviation of cough, alleviation of coryza, resolution of fever, and parental opinion of a return to normal health and activity. TAMIFLU treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by 1.5 days compared to placebo. Subgroup analyses of this study by gender showed no differences in the treatment effect of TAMIFLU in males and females.

Prophylaxis of Influenza

Adult Patients

The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and a postexposure prophylaxis study in households. The primary efficacy parameter for all these studies was the incidence of laboratory-confirmed clinical influenza. Laboratory-confirmed clinical influenza was defined as oral temperature ≥99.0F/37.2C plus at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a fourfold increase in virus antibody titers from baseline.

In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 13 to 65 years), TAMIFLU 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory-confirmed clinical influenza from 4.8% (25/519) for the placebo group to 1.2% (6/520) for the TAMIFLU group.

In a seasonal prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU 75 mg once daily taken for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4.4% (12/272) for the placebo group to 0.4% (1/276) for the TAMIFLU group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders.

In a study of postexposure prophylaxis in household contacts (aged ≥13 years) of an index case, TAMIFLU 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days reduced the incidence of laboratory-confirmed clinical influenza from 12% (24/200) in the placebo group to 1% (2/205) for the TAMIFLU group. Index cases did not receive TAMIFLU in the study.

Pediatric Patients

The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in a randomized, open-label, postexposure prophylaxis study in households that included children aged 1 to 12 years, both as index cases and as family contacts. All index cases in this study received treatment. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the household. Laboratory-confirmed clinical influenza was defined as oral temperature ≥100F/37.8C plus cough and/or coryza recorded within 48 hours, plus either a positive virus isolation or a fourfold or greater increase in virus antibody titers from baseline or at illness visits. Among household contacts 1 to 12 years of age not already shedding virus at baseline, TAMIFLU for Oral Suspension 30 mg to 60 mg taken once daily for 10 days reduced the incidence of laboratory-confirmed clinical influenza from 17% (18/106) in the group not receiving prophylaxis to 3% (3/95) in the group receiving prophylaxis.

DOSAGE AND ADMINISTRATION

TAMIFLU may be taken with or without food (see CLINICAL PHARMACOLOGY: Pharmacokinetics). However, when taken with food, tolerability may be enhanced in some patients.

Standard Dosage — Treatment of Influenza

Adults and Adolescents

The recommended oral dose of TAMIFLU for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily for 5 days. Treatment should begin within 2 days of onset of symptoms of influenza.

Pediatric Patients

TAMIFLU is not indicated for treatment of influenza in pediatric patients younger than 1 year.

The recommended oral dose of TAMIFLU for pediatric patients 1 year and older is shown in Table 5. TAMIFLU for Oral Suspension may also be used by patients who cannot swallow a capsule. For pediatric patients who cannot swallow capsules, TAMIFLU for Oral Suspension is the preferred formulation. If the for Oral Suspension product is not available, TAMIFLU Capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup.

Table 5 Oral Dose of TAMIFLU for Treatment of Influenza in Pediatric Patients by Weight
Body Weight (kg) Body Weight (lbs) Recommended Dose for 5 Days Number of Bottles of TAMIFLU for Oral Suspension Needed to Obtain the Recommended Doses for a 5 Day Regimen Number of TAMIFLU Capsules Needed to Obtain the Recommended Doses for a 5 Day Regimen
≤15 kg ≤33 lbs 30 mg twice daily 1 10 TAMIFLU Capsules (30 mg)
>15 kg to 23 kg >33 lbs to 51 lbs 45 mg twice daily 2 10 TAMIFLU Capsules (45 mg)
>23 kg to 40 kg >51 lbs to 88 lbs 60 mg twice daily 2 20 TAMIFLU Capsules (30 mg)
>40 kg >88 lbs 75 mg twice daily 3 10 TAMIFLU Capsules (75 mg)

An oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with the oral suspension; the 75 mg dose can be measured using a combination of 30 mg and 45 mg. It is recommended that patients use this dispenser. In the event that the dispenser provided is lost or damaged, another dosing syringe or other device may be used to deliver the following volumes: 2.5 mL (1/2 tsp) for children ≤15 kg, 3.8 mL (3/4 tsp) for >15 to 23 kg, 5.0 mL (1 tsp) for >23 to 40 kg, and 6.2 mL (1 1/4 tsp) for >40 kg.

Standard Dosage — Prophylaxis of Influenza

Adults and Adolescents

The recommended oral dose of TAMIFLU for prophylaxis of influenza in adults and adolescents 13 years and older following close contact with an infected individual is 75 mg once daily for at least 10 days. Therapy should begin within 2 days of exposure. The recommended dose for prophylaxis during a community outbreak of influenza is 75 mg once daily. Safety and efficacy have been demonstrated for up to 6 weeks. The duration of protection lasts for as long as dosing is continued.

Pediatric Patients

The safety and efficacy of TAMIFLU for prophylaxis of influenza in pediatric patients younger than 1 year of age have not been established.

The recommended oral dose of TAMIFLU for pediatric patients 1 year and older following close contact with an infected individual is shown in Table 6. TAMIFLU for Oral Suspension may also be used by patients who cannot swallow a capsule. For pediatric patients who cannot swallow capsules, TAMIFLU for Oral Suspension is the preferred formulation. If the for Oral Suspension product is not available, TAMIFLU Capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup.

Table 6 Oral Dose of TAMIFLU for Prophylaxis of Influenza in Pediatric Patients by Weight
Body Weight (kg) Body Weight (lbs) Recommended Dose for 10 Days Number of Bottles of TAMIFLU for Oral Suspension Needed to Obtain the Recommended Doses for a 10 Day Regimen Number of TAMIFLU Capsules Needed to Obtain the Recommended Doses for a 10 Day Regimen
≤15 kg ≤33 lbs 30 mg once daily 1 10 TAMIFLU Capsules (30 mg)
>15 kg to 23 kg >33 lbs to 51 lbs 45 mg once daily 2 10 TAMIFLU Capsules (45 mg)
>23 kg to 40 kg >51 lbs to 88 lbs 60 mg once daily 2 20 TAMIFLU Capsules (30 mg)
>40 kg >88 lbs 75 mg once daily 3 10 TAMIFLU Capsules (75 mg)

An oral dosing dispenser with 30 mg, 45 mg, and 60 mg graduations is provided with the oral suspension; the 75 mg dose can be measured using a combination of 30 mg and 45 mg. It is recommended that patients use this dispenser. In the event that the dispenser provided is lost or damaged, another dosing syringe or other device may be used to deliver the following volumes: 2.5 mL (1/2 tsp) for children ≤15 kg, 3.8 mL (3/4 tsp) for >15 to 23 kg, 5.0 mL (1 tsp) for >23 to 40 kg, and 6.2 mL (1 1/4 tsp) for >40 kg.

Prophylaxis in pediatric patients following close contact with an infected individual is recommended for 10 days. Prophylaxis in patients 1 to 12 years of age has not been evaluated for longer than 10 days duration. Therapy should begin within 2 days of exposure.

Special Dosage Instructions

Hepatic Impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (Child-Pugh score ≤9) (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations).

Renal Impairment

For plasma concentrations of oseltamivir carboxylate predicted to occur following various dosing schedules in patients with renal impairment, see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations.

Treatment of Influenza

Dose adjustment is recommended for patients with creatinine clearance between 10 and 30 mL/min receiving TAMIFLU for the treatment of influenza. In these patients it is recommended that the dose be reduced to 75 mg of TAMIFLU once daily for 5 days. No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.

Prophylaxis of Influenza

For the prophylaxis of influenza, dose adjustment is recommended for patients with creatinine clearance between 10 and 30 mL/min receiving TAMIFLU. In these patients it is recommended that the dose be reduced to 75 mg of TAMIFLU every other day or 30 mg TAMIFLU every day. No recommended dosing regimens are available for patients undergoing routine hemodialysis and continuous peritoneal dialysis treatment with end-stage renal disease.

Geriatric Patients

No dose adjustment is required for geriatric patients (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations and PRECAUTIONS).

Preparation of TAMIFLU for Oral Suspension

It is recommended that TAMIFLU for Oral Suspension be constituted by the pharmacist prior to dispensing to the patient:

  1. Tap the closed bottle several times to loosen the powder.
  2. Measure 23 mL of water in a graduated cylinder.
  3. Add the total amount of water for constitution to the bottle and shake the closed bottle well for 15 seconds.
  4. Remove the child-resistant cap and push bottle adapter into the neck of the bottle.
  5. Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.

NOTE: SHAKE THE TAMIFLU FOR ORAL SUSPENSION WELL BEFORE EACH USE.

The constituted TAMIFLU for Oral Suspension (12 mg/mL) should be used within 10 days of preparation; the pharmacist should write the date of expiration of the constituted suspension on a pharmacy label. The patient package insert and oral dispenser should be dispensed to the patient.

Emergency Compounding of an Oral Suspension from TAMIFLU Capsules
(Final Concentration 15 mg/mL)

The following directions are provided for use only during emergency situations. These directions are not intended to be used if the FDA-approved, commercially manufactured TAMIFLU for Oral Suspension is readily available from wholesalers or the manufacturer.

Compounding an oral suspension with this procedure will provide one patient with enough medication for a 5-day course of treatment or a 10-day course of prophylaxis.

Commercially manufactured TAMIFLU for Oral Suspension (12 mg/mL) is the preferred product for pediatric and adult patients who have difficulty swallowing capsules or where lower doses are needed. In the event that TAMIFLU for Oral Suspension is not available, the pharmacist may compound a suspension (15 mg/mL) from TAMIFLU (oseltamivir phosphate) Capsules 75 mg using either of two vehicles: Cherry Syrup (Humco®) or Ora-Sweet® SF (sugar-free) (Paddock Laboratories). Other vehicles have not been studied. This compounded suspension should not be used for convenience or when the FDA-approved TAMIFLU for Oral Suspension is commercially available.

First, calculate the Total Volume of an oral suspension needed to be compounded and dispensed for each patient. The Total Volume required is determined by the weight of each patient. Refer to Table 7.

Table 7 Volume of an Oral Suspension (15 mg/mL) Needed to be Compounded Based Upon the Patient's Weight
Body Weight (kg) Body Weight (lbs) Total Volume to Compound per patient (mL)
≤15 kg ≤33 lbs 30 mL
16 to 23 kg 34 to 51 lbs 40 mL
24 to 40 kg 52 to 88 lbs 50 mL
≥41 kg ≥89 lbs 60 mL

Second, determine the number of capsules and the amount of vehicle (Cherry Syrup or Ora-Sweet SF) that are needed to prepare the Total Volume (calculated from Table 7: 30 mL, 40 mL, 50 mL, or 60 mL) of compounded oral suspension (15 mg/mL). Refer to Table 8.

Table 8 Number of TAMIFLU 75 mg Capsules and Amount of Vehicle (Cherry Syrup OR Ora-Sweet SF) Needed to Prepare the Total Volume of a Compounded Oral Suspension (15 mg/mL)
Total Volume of Compounded Oral Suspension needed to be Prepared 30 mL 40 mL 50 mL 60 mL
Required number of TAMIFLU 75 mg Capsules 6 capsules (450 mg oseltamivir) 8 capsules (600 mg oseltamivir) 10 capsules (750 mg oseltamivir) 12 capsules (900 mg oseltamivir)
Required volume of vehicle
Cherry Syrup (Humco) OR Ora-Sweet SF (Paddock Laboratories) 29 mL 38.5 mL 48 mL 57 mL

Third, follow the procedure below for compounding the oral suspension (15 mg/mL) from TAMIFLU Capsules 75 mg

  1. Carefully separate the capsule body and cap and transfer the contents of the required number of TAMIFLU 75 mg Capsules into a clean mortar.
  2. Triturate the granules to a fine powder.
  3. Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.
  4. Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.
  5. Add another one-third (1/3) of the vehicle to the mortar, rinse the pestle and mortar by a triturating motion and transfer the vehicle into the bottle.
  6. Repeat the rinsing (Step 5) with the remainder of the vehicle.
  7. Close the bottle using a child-resistant cap.
  8. Shake well to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension. (Note: The active drug, oseltamivir phosphate, readily dissolves in the specified vehicles. The suspension is caused by some of the inert ingredients of TAMIFLU Capsules which are insoluble in these vehicles.)
  9. Put an ancillary label on the bottle indicating "Shake Gently Before Use". [This compounded suspension should be gently shaken prior to administration to minimize the tendency for air entrapment, particularly with the Ora-Sweet SF preparation.]
  10. Instruct the parent or guardian that any remaining material 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.
  11. Place an appropriate expiration date label according to storage condition (see below).

STORAGE OF THE PHARMACY-COMPOUNDED SUSPENSION:

Refrigeration: Stable for 5 weeks (35 days) when stored in a refrigerator at 2 to 8C (36 to 46F).

Room Temperature: Stable for five days (5 days) when stored at room temperature, 25C (77F).

Note: The storage conditions are based on stability studies of compounded oral suspensions, using the above mentioned vehicles, which were placed in amber glass and amber polyethyleneterephthalate (PET) bottles. Stability studies have not been conducted with other vehicles or bottle types.

Place a pharmacy label on the bottle that includes the patient's name, dosing instructions, and drug name and any other required information to be in compliance with all State and Federal Pharmacy Regulations. Refer to Table 9 for the proper dosing instructions.

Note: This compounding procedure results in a 15 mg/mL suspension, which is different from the commercially available TAMIFLU for Oral Suspension, which has a concentration of 12 mg/mL.

Table 9 Dosing Chart for Pharmacy-Compounded Suspension from TAMIFLU Capsules 75 mg
Body Weight (kg) Body Weight
(lbs)
Dose
(mg)
Volume per Dose
15 mg/mL
Treatment Dose (for 5 days) Prophylaxis Dose (for 10 days)
Note: 1 teaspoon = 5 mL
≤15 kg ≤33 lbs 30 mg 2 mL 2 mL two times a day 2 mL once daily
16 to 23 kg 34 to 51 lbs 45 mg 3 mL 3 mL two times a day 3 mL once daily
24 to 40 kg 52 to 88 lbs 60 mg 4 mL 4 mL two times a day 4 mL once daily
≥41 kg ≥89 lbs 75 mg 5 mL 5 mL two times a day 5 mL once daily

Consider dispensing the suspension with a graduated oral syringe for measuring small amounts of suspension. If possible, mark or highlight the graduation corresponding to the appropriate dose (2 mL, 3 mL, 4 mL, or 5 mL) on the oral syringe for each patient. The dosing device dispensed with the commercially available TAMIFLU for Oral Suspension should NOT be used with the compounded suspension since they have different concentrations.

HOW SUPPLIED

TAMIFLU Capsules

30-mg capsules (30 mg free base equivalent of the phosphate salt): light yellow hard gelatin capsules. "ROCHE" is printed in blue ink on the light yellow body and "30 mg" is printed in blue ink on the light yellow cap. Available in blister packages of 10 (NDC 0004-0802-85).

45-mg capsules (45 mg free base equivalent of the phosphate salt): grey hard gelatin capsules. "ROCHE" is printed in blue ink on the grey body and "45 mg" is printed in blue ink on the grey cap. Available in blister packages of 10 (NDC 0004-0801-85).

75-mg capsules (75 mg free base equivalent of the phosphate salt): grey/light yellow hard gelatin capsules. "ROCHE" is printed in blue ink on the grey body and "75 mg" is printed in blue ink on the light yellow cap. Available in blister packages of 10 (NDC 0004-0800-85).

Storage

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

TAMIFLU for Oral Suspension

Supplied as a white powder blend for constitution to a white tutti-frutti–flavored suspension. Available in glass bottles containing approximately 33 mL of suspension after constitution. Each bottle delivers 25 mL of suspension equivalent to 300 mg oseltamivir base. Each bottle is supplied with a bottle adapter and 1 oral dispenser (NDC 0004-0810-95).

Storage

Store dry powder at 25C (77F); excursions permitted to 15 to 30C (59 to 86F). [See USP Controlled Room Temperature]

Store constituted suspension under refrigeration at 2 to 8C (36 to 46F). Do not freeze.

Humco® is a registered trademark of Humco Holding Group, Inc.

Ora-Sweet® SF is a registered trademark of Paddock Laboratories

Distributed by:

Roche Laboratories Inc.
340 Kingsland Street
Nutley, New Jersey 07110—1199

Licensor:
Gilead Sciences, Inc.
Foster City, California 94404

27899527

PI Rev. August 2008

Copyright 1999-2008 by Roche Laboratories Inc. All rights reserved.

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