TAMIFLU^®
(oseltamivir phosphate)
CAPSULES
AND FOR ORAL SUSPENSION

TAMIFLU (oseltamivir phosphate) is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 12 mg/mL oseltamivir base. In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone K 30, croscarmellose sodium, and sodium stearyl fumarate. The 30 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and red iron oxide. The 45 mg capsule shell contains gelatin, titanium dioxide, and black iron oxide. The 75 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and red iron oxide. Each capsule is printed with blue ink, which includes FD&C Blue No. 2 as the colorant. In addition to the active ingredient, the powder for oral suspension contains sorbitol, monosodium citrate, xanthan gum, titanium dioxide, tutti-frutti flavoring, sodium benzoate, and saccharin sodium.

Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5-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:

Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.

The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of oseltamivir carboxylate required for inhibition of influenza virus were highly variable depending on the assay method used and the virus tested. The 50% and 90% inhibitory concentrations (IC₅₀ and IC₉₀) were in the range of 0.0008 µM to >35 µM and 0.004 µM to >100 µM, respectively (1 µM=0.284 µg/mL). The relationship between the in vitro antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been established.

Influenza A virus isolates with reduced susceptibility to oseltamivir carboxylate have been recovered in vitro by passage of virus in the presence of increasing concentrations of oseltamivir carboxylate. Genetic analysis of these isolates showed that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance mutations selected in vitro in neuraminidase are I222T and H274Y in influenza A N1 and I222T and R292K in influenza A N2. Mutations E119V, R292K and R305Q have been selected in avian influenza A neuraminidase N9. Mutations A28T and R124M have been selected in the hemagglutinin of influenza A H3N2 and mutation H154Q in the hemagglutinin of a reassortant human/avian virus H1N9.

In clinical studies in the treatment of naturally acquired infection with influenza virus, 1.3% (4/301) of posttreatment isolates in adult patients and adolescents, and 8.6% (9/105) in pediatric patients aged 1 to 12 years showed emergence of influenza variants with decreased neuraminidase susceptibility in vitro to oseltamivir carboxylate. Mutations in influenza A resulting in decreased susceptibility were H274Y in neuraminidase N1 and E119V and R292K in neuraminidase N2. Insufficient information is available to fully characterize the risk of emergence of TAMIFLU resistance in clinical use.

In clinical studies of postexposure and seasonal prophylaxis, determination of resistance was limited by the low overall incidence rate of influenza infection and prophylactic effect of TAMIFLU.

Cross-resistance between zanamivir-resistant influenza mutants and oseltamivir-resistant influenza mutants has been observed in vitro. Due to limitations in the assays available to detect drug-induced shifts in virus susceptibility, an estimate of the incidence of oseltamivir resistance and possible cross-resistance to zanamivir in clinical isolates cannot be made. However, two of the three oseltamivir-induced mutations (E119V, H274Y and R292K) in the viral neuraminidase from clinical isolates occur at the same amino acid residues as two of the three mutations (E119G/A/D, R152K and R292K) observed in zanamivir-resistant virus.

No influenza vaccine interaction study has been conducted. In studies of naturally acquired and experimental influenza, treatment with TAMIFLU did not impair normal humoral antibody response to infection.

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.

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

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.

TAMIFLU is contraindicated in patients with known hypersensitivity to any of the components of the product.

There is no evidence for efficacy of TAMIFLU in any illness caused by agents other than influenza viruses Types A and B.

Use of TAMIFLU should not affect the evaluation of individuals for annual influenza vaccination in accordance with guidelines of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

Efficacy of TAMIFLU in patients who begin treatment after 40 hours of symptoms has not been established.

Efficacy of TAMIFLU in the treatment of subjects with chronic cardiac disease and/or respiratory disease has not been established. No difference in the incidence of complications was observed between the treatment and placebo groups in this population. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.

Safety and efficacy of repeated treatment or prophylaxis courses have not been studied.

Efficacy of TAMIFLU for treatment or prophylaxis has not been established in immunocompromised patients.

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.

The safety and pharmacokinetics in patients with hepatic impairment have not been evaluated.

Dose adjustment is recommended for patients with a serum creatinine clearance <30 mL/min (see DOSAGE AND ADMINISTRATION).

Rare cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in post-marketing experience with TAMIFLU. TAMIFLU should be stopped and appropriate treatment instituted if an allergic-like reaction occurs or is suspected.

There have been postmarketing reports (mostly from Japan) of self-injury and delirium with the use of TAMIFLU in patients with influenza. The reports were primarily among pediatric patients. The relative contribution of the drug to these events is not known. Patients with influenza should be closely monitored for signs of abnormal behavior throughout the treatment period.

Patients should be instructed to begin treatment with TAMIFLU as soon as possible from the first appearance of flu symptoms. Similarly, prevention should begin as soon as possible after exposure, at the recommendation of a physician.

Patients should be instructed to take any missed doses as soon as they remember, except if it is near the next scheduled dose (within 2 hours), and then continue to take TAMIFLU at the usual times.

TAMIFLU is not a substitute for a flu vaccination. Patients should continue receiving an annual flu vaccination according to guidelines on immunization practices.

The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of TAMIFLU, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. Trivalent inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU.

Information derived from pharmacology and pharmacokinetic studies of oseltamivir suggests that clinically significant drug interactions are unlikely.

Oseltamivir is extensively converted to oseltamivir carboxylate by esterases, located predominantly in the liver. Drug interactions involving competition for esterases have not been extensively reported in literature. Low protein binding of oseltamivir and oseltamivir carboxylate suggests that the probability of drug displacement interactions is low.

In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases.

Cimetidine, a non-specific inhibitor of cytochrome P450 isoforms and competitor for renal tubular secretion of basic or cationic drugs, has no effect on plasma levels of oseltamivir or oseltamivir carboxylate.

Clinically important drug interactions involving competition for renal tubular secretion are unlikely due to the known safety margin for most of these drugs, the elimination characteristics of oseltamivir carboxylate (glomerular filtration and anionic tubular secretion) and the excretion capacity of these pathways. Coadministration of probenecid results in an approximate twofold 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.

Coadministration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic secretion pathway is weak.

In six subjects, multiple doses of oseltamivir did not affect the single-dose pharmacokinetics of acetaminophen.

Long-term carcinogenicity tests with oseltamivir are underway but have not been completed. However, a 26-week dermal carcinogenicity study of oseltamivir carboxylate in FVB/Tg.AC transgenic mice was negative. The animals were dosed at 40, 140, 400 or 780 mg/kg/day in two divided doses. The highest dose represents the maximum feasible dose based on the solubility of the compound in the control vehicle. A positive control, tetradecanoyl phorbol-13-acetate administered at 2.5 µg per dose three times per week gave a positive response.

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 and for 2 weeks after mating. There were no effects on fertility, mating performance or early embryonic development at any dose level. The highest dose was approximately 100 times the human systemic exposure (AUC_0-24h) of oseltamivir carboxylate.

In lactating rats, oseltamivir and oseltamivir carboxylate are excreted in the milk. It is not known whether oseltamivir or oseltamivir carboxylate is excreted in human milk. TAMIFLU should, therefore, be used only if the potential benefit for the lactating mother justifies the potential risk to the breast-fed infant.

The safety of TAMIFLU has been established in clinical studies which enrolled 741 subjects (374 received placebo and 362 received TAMIFLU). Some seasonal variability was noted in the clinical efficacy outcomes (see INDICATIONS AND USAGE: Description of Clinical Studies: Studies in Naturally Occurring Influenza: Treatment of Influenza: Geriatric Patients).

Safety and efficacy have been demonstrated in elderly residents of nursing homes who took TAMIFLU for up to 42 days for the prevention of influenza. Many of these individuals had cardiac and/or respiratory disease, and most had received vaccine that season (see INDICATIONS AND USAGE: Description of Clinical Studies: Studies in Naturally Occurring Influenza: Prophylaxis of Influenza: Adult Patients).

The safety and efficacy of TAMIFLU in pediatric patients younger than 1 year of age have not been studied. TAMIFLU is not indicated for either treatment or prophylaxis of influenza in pediatric patients younger than 1 year of age because of uncertainties regarding the rate of development of the human blood-brain barrier and the unknown clinical significance of non-clinical animal toxicology data for human infants (see ANIMAL TOXICOLOGY).

In a 2-week study in unweaned rats, administration of a single dose of 1000 mg/kg oseltamivir phosphate to 7-day-old rats resulted in deaths associated with unusually high exposure to the prodrug. However, at 2000 mg/kg, there were no deaths or other significant effects in 14-day-old unweaned rats. Further follow-up investigations of the unexpected deaths of 7-day-old rats at 1000 mg/kg revealed that the concentrations of the prodrug in the brains were approximately 1500-fold those of the brains of adult rats administered the same oral dose of 1000 mg/kg, and those of the active metabolite were approximately 3-fold higher. Plasma levels of the prodrug were 10-fold higher in 7-day-old rats as compared with adult rats. These observations suggest that the levels of oseltamivir in the brains of rats decrease with increasing age and most likely reflect the maturation stage of the blood-brain barrier. No adverse effects occurred at 500 mg/kg/day administered to 7- to 21-day-old rats. At this dosage, the exposure to prodrug was approximately 800-fold the exposure expected in a 1-year-old child.

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

Adverse events that occurred with an incidence of ≥1% in 1440 patients taking placebo or TAMIFLU 75 mg twice daily in adult phase III treatment studies are shown in Table 3. This summary includes 945 healthy young adults and 495 "at risk" patients (elderly patients and patients with chronic cardiac or respiratory disease). Those events reported numerically more frequently in patients taking TAMIFLU compared with placebo were nausea, vomiting, bronchitis, insomnia, and vertigo.

A total of 4187 subjects (adolescents, healthy adults and elderly) participated in phase III prophylaxis studies, of whom 1790 received the recommended dose of 75 mg once daily for up to 6 weeks. Adverse events were qualitatively very similar to those seen in the treatment studies, despite a longer duration of dosing (see Table 3). Events reported more frequently in subjects receiving TAMIFLU compared to subjects receiving placebo in prophylaxis studies, and more commonly than in treatment studies, were aches and pains, rhinorrhea, dyspepsia and upper respiratory tract infections. However, the difference in incidence between TAMIFLU and placebo for these events was less than 1%. There were no clinically relevant differences in the safety profile of the 942 elderly subjects who received TAMIFLU or placebo, compared with the younger population.

Adverse events included are: all events reported in the treatment studies with frequency ≥1% in the oseltamivir 75 mg bid group.

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

A total of 1032 pediatric patients aged 1 to 12 years (including 698 otherwise healthy pediatric patients aged 1 to 12 years and 334 asthmatic pediatric patients aged 6 to 12 years) participated in phase III studies of TAMIFLU given for the treatment of influenza. A total of 515 pediatric patients received treatment with TAMIFLU for Oral Suspension.

Adverse events occurring in ≥1% of pediatric patients receiving TAMIFLU treatment are uled in Table 4. The most frequently reported adverse event was vomiting. Other events reported more frequently by pediatric patients treated with TAMIFLU included abdominal pain, epistaxis, ear disorder, and conjunctivitis. These events generally occurred once and resolved despite continued dosing. They did not cause discontinuation of drug in the vast majority of cases.

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

Pediatric patients aged 1 to 12 years participated in a postexposure prophylaxis study in households, both as index cases (134) and as contacts (222). Gastrointestinal events were the most frequent, particularly vomiting. The adverse events noted were consistent with those previously observed in pediatric treatment studies (see Table 4).

Adverse events included in Table 4 are: all events reported in the treatment studies with frequency ≥1% in the oseltamivir 75 mg bid group.

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

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

Dermatologic: Dermatitis, rash, eczema, urticaria, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis (see PRECAUTIONS)

Digestive: Hepatitis, liver function tests abnormal

Cardiac: Arrhythmia

Neurologic: Seizure, confusion

Metabolic: Aggravation of diabetes

At present, there has been no experience with overdose. Single doses of up to 1000 mg of TAMIFLU have been associated with nausea and/or vomiting.

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

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

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

• Tap the closed bottle several times to loosen the powder.
• Measure 23 mL of water in a graduated cylinder.
• Add the total amount of water for constitution to the bottle and shake the closed bottle well for 15 seconds.
• Remove the child-resistant cap and push bottle adapter into the neck of the bottle.
• 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.

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.

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.

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

• Carefully separate the capsule body and cap and transfer the spans of the required number of TAMIFLU 75 mg Capsules into a clean mortar.
• Triturate the granules to a fine powder.
• Add one-third (1/3) of the specified amount of vehicle and triturate the powder until a uniform suspension is achieved.
• Transfer the suspension to an amber glass or amber polyethyleneterephthalate (PET) bottle. A funnel may be used to eliminate any spillage.
• 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.
• Repeat the rinsing (Step 5) with the remainder of the vehicle.
• Close the bottle using a child-resistant cap.
• 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.)
• 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.]
• 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.
• Place an appropriate expiration date label according to storage condition (see below).

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 buler 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 buler 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 buler packages of 10 (NDC 0004-0800-85).

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).