VIROZEL

Oseltamivir phosphate, USP, an influenza neuraminidase inhibitor (NAI), is available as: A powder for oral suspension, which when constituted with water as directed contains 6 mg per mL oseltamivir base.

In addition to the active ingredient, the powder for oral suspension contains mannitol, saccharin sodium, sodium benzoate, sodium dihydrogen citrate, sorbitol, sour cherry flavor, titanium dioxide, and xanthan gum.

Oseltamivir phosphate, USP 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

C 16 H 28 N 2 O 4 (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 phosphate for oral suspension is an influenza neuraminidase inhibitor (NAI) indicated for: Treatment of acute, uncomplicated influenza A and B in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours.

Prophylaxis of influenza A and

B in patients 1 year and older.

Not a substitute for annual influenza vaccination.

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

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

Oseltamivir phosphate for oral suspension is not recommended for patients with end-stage renal disease not undergoing dialysis.

Lactation Cardiopathies Immune deficiency Pregnancy

Severe renal impairment Interchangeability Chronic respiratory pathology Patients with swallowing difficulties Hospitalized patient Premature Subject under 18.

Oseltamivir is an antiviral drug with activity against influenza virus. 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.

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) 65 348 AUC 0-12h (ng∙h/mL) 112 2719 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) .

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.

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 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.

Absorbed oseltamivir is primarily (>90%) eliminated by conversion to the active metabolite, oseltamivir carboxylate.

Plasma concentrations of oseltamivir declined with a half-life of 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 to 10 hours in most subjects after oral administration.

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.

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.

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.

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 AUC 48 (ng∙h/mL) AUC normalized to 48 hours. 11224 18476 12008 16818 23200 Recommended Prophylaxis 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 AUC 48 (ng∙hr/mL) 5294 8336 6262 9317 11200 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 min in patients with normal renal function receiving the approved regimen of 75 mg once daily (40 ng/mL).

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

A pooled population pharmacokinetic analysis indicates that the oseltamivir phosphate for oral suspension 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.

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 to 16 years (n=18) and in a small number of pediatric subjects aged 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.

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.

Exposure to oseltamivir carboxylate at steady-state was to 35% higher in geriatric subjects (age range 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.

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. 12.4 Microbiology Mechanism of Action Oseltamivir phosphate is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate.

Oseltamivir carboxylate is an inhibitor of influenza virus neuraminidase affecting release of viral particles.

The median

IC 50 values of oseltamivir against influenza A/H1N1, influenza A/H3N2, and influenza B clinical isolates were 2.5 nM (range 0.93 to 4.16 nM, N=74), 0.96 nM (range 0.13 to 7.95 nM, N=774), and 60 nM (20 to 285 nM, N=256), respectively, in a neuraminidase assay with a fluorescently labeled MUNANA substrate.

The antiviral activity of oseltamivir carboxylate against laboratory strains and clinical isolates of influenza virus was determined in cell culture.

The concentrations of oseltamivir carboxylate required for inhibition of influenza virus in cell culture were highly variable depending on the assay method used and the virus tested.

The 50% and 90% effective concentrations (EC and EC 90 ) were in the range of 0.0008 micromolar to greater than 35 micromolar and 0.004 micromolar to greater than 100 micromolar, respectively (1 micromolar=0.284 microgram per mL).

The relationship between the antiviral activity in cell culture, inhibitory activity in the neuraminidase assay, and the inhibition of influenza virus replication in humans has not been established.

Resistance Cell culture studies

Influenza A virus isolates with reduced susceptibility to oseltamivir carboxylate have been recovered by serial passage of virus in cell culture in the presence of increasing concentrations of oseltamivir carboxylate.

Reduced susceptibility of influenza virus to inhibition by oseltamivir carboxylate may be conferred by amino acid substitutions in the viral neuraminidase and/or hemagglutinin proteins.

Clinical studies

Reduced susceptibility isolates have been obtained during treatment with oseltamivir and from sampling during community surveillance studies.

Changes in the viral neuraminidase that have been associated with reduced susceptibility to oseltamivir carboxylate are summarized in Table 8.

The clinical impact of this reduced susceptibility is unknown.

Hemagglutinin (HA) substitutions selected in cell culture and associated with reduced susceptibility to oseltamivir include (influenza virus subtype‐specific numbering) A11T, K173E, and R453M in H3N2; and H99Q in influenza B virus (Yamagata lineage).

In some cases, HA substitutions were selected in conjunction with known NA resistance substitutions and may contribute to reduced susceptibility to oseltamivir; however, the impact of HA substitutions on antiviral activity of oseltamivir in humans is unknown and likely to be strain‐dependent.

Table 8 Neuraminidase Amin.

Mechanism of action

L-oseltamivir is a systemic antiviral, neuraminidase inhibitor.

Oseltamivir phosphate is the prodrug of the active metabolite (oseltamivir carboxylate).

The active metabolite is a selective inhibitor of influenza neuraminidase enzymes, which are surface virion glycoproteins.

The enzyme activity of viral neuraminidase is important to allow both virus to penetrate uninfected cells and to release newly formed viral particles from infected cells and to spread the virus into the body.

In vitro, oseltamivir carboxylate inhibits the neuraminidases of influenza A and B viruses.

Oseltamivir phosphate inhibits influenza virus infection and viral replication in vitro.

In vivo, in animal models of influenza infection, oseltamivir administered per bone inhibits the replication of influenza A and B viruses and their pathogenicity.

• Liver enzymes (increase) (Uncommon)
• Urticaria (Uncommon)
• Eczema (Uncommon)
• Rash (Uncommon)
• Dermatitis (Uncommon)
• Atopic dermatitis (Uncommon)
• Polymorphic Erythema (Rare)
• Stevens-Johnson Syndrome (Rare)
• Toxic epidermal necrolysis (Rare)
• Lyell's syndrome (Rare)
• Erythema buttocks Allergic dermatitis
• Pain (Common)
• Fever (Common)
• Pain in limbs (Common)
• Fatigue (Common)
• Thrombocytopenia (Rare)
• Hepatic impairment (Rare) fulminant hepatitis (Rare)
• Ictery (Rare)
• Hepatitis (Rare)
• Liver disorder Hypersensitivity (Uncommon)
• Oedema of Quincke (Rare)
• Angioedema (Rare)
• Anaphylactic reaction (Rare)
• Anaphylactoid reaction (Rare)
• Herpes (Common)
• Herpes (awakening) (Common)
• Eye pain (Common)
• Lacrimal hypersecretion (Common)
• Conjunctivitis (Common)
• Eye redness (Common)
• Vision disorder (Rare)
• Tympanic membrane disorder (Uncommon)
• Vertigo (Common)
• Sinusitis (Common)
• Medium otitis (Common)
• Feeling dizzy (Common)
• Rhinophyryngitis (Common)
• Otalgia (Common)
• Rhinorrhea (Common)
• Nasal congestion (Very common)
• Pharyngitis (Common)
• Insomnia (Common)
• Visual Hallucination (Rare)
• Mental confusion (Rare)
• Anxiety (Rare)
• Delicious (Rare)
• Behavioural disorder (Rare)
• Nightmare (Rare)
• Self-harm (Very rare)
• Self-aggressiveness (Rare)
• Hallucination (Rare)
• Agitation (Rare)
• Behavioural disorder (Rare)
• Arrhythmia (Uncommon)
• Abdominal pain (Common)
• Dyspepsia (Common)
• Upper abdominal pain (Common)
• Nausea (Very common)
• Hemorrhagic colitis (Rare)
• Gastrointestinal haemorrhage (Rare)
• Vomiting Diarrhoea
• Alteration of consciousness (Uncommon)
• Convulsions (Uncommon)
• Headache Upper respiratory tract infection (Common)
• Bronchitis (Common)
• Cough.

Reports of overdoses with oseltamivir phosphate have been received from clinical trials and during postmarketing experience.

In the majority of cases reporting overdose, no adverse reactions were reported.

Adverse reactions reported following overdose were similar in nature to those observed with therapeutic doses of oseltamivir phosphate for oral suspension.

Oseltamivir phosphate for oral suspension 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.

Patients with known serious hypersensitivity to oseltamivir or any of the components of oseltamivir phosphate for oral suspension.

Treatment of influenza

Adults and adolescents (13 years and older): 75 mg twice daily for 5 days Pediatric patients to 12 years of age: Based on weight twice daily for 5 days Pediatric patients 2 weeks to less than 1 year of age: 3mg/kg twice daily for 5 days Renally impaired adult patients (creatinine clearance >30 to 60 mL/min): Reduce to 30 mg twice daily for 5 days Renally impaired adult patients (creatinine clearance >10 to 30 mL/min): Reduce to 30 mg once daily for 5 days ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after every hemodialysis cycle.

Treatment duration not to exceed 5 days ESRD patients on CAPD: Reduce to a single 30 mg dose immediately Prophylaxis of influenza Adults and adolescents (13 years and older): 75 mg once daily for at least 10 days Community outbreak: 75 mg once daily for up to 6 weeks Pediatric patients to 12 years of age: Based on weight once daily for 10 days Community outbreak: Based on weight once daily for up to 6 weeks Renally impaired adult patients (creatinine clearance >30 to 60 mL/min): Reduce to 30 mg once daily Renally impaired adult patients (creatinine clearance >10 to 30 mL/min): Reduce to 30 mg once every other day ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after alternate hemodialysis cycles for the recommended duration of prophylaxis ESRD patients on CAPD: Reduce to 30 mg immediately and then 30 mg once weekly for the recommended duration of prophylaxis 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 or for prophylaxis of influenza in patients 1 year and older 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.

The 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. 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 (12.5 mL of oral suspension twice daily) for 5 days.

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 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.

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 (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.

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

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.

Table 1 Oseltamivir Phosphate for Oral Suspension Dosage Recommendations in Pediatric Patients for Treatment and Prophylaxis of Influenza Weight Treat m e nt Dosage for 5 days Prophylaxis Dosage for 10 days Volu m e of Oral Suspens i on (6 mg/mL) for each Dose † Numbe r of Bottles of Oral Suspension to Dispense P atients 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 P atients 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 15.1 kg to 23 kg 45 mg twice daily 45 mg once daily 7.5 mL 2 botles 23.1 kg to 40 kg 60 mg twice daily 60 mg once daily 10 mL 2 bottles 40.1 kg or more 75 mg twice daily 75 mg once daily 12.5 mL 3 bottles 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) 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. § For patients less than 1 year of age, provide an appropriate dosing device that can accurately measure and administer small volumes. 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.

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 Oral suspension 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).

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 Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients. (≤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 for oral suspension is not recommended Oseltamivir phosphate for oral suspension is are not recommended 2.5 Preparation and Storage of Constituted Oseltamivir Phosphate for Oral Suspension Prior to dispensing to the patient, constitute oseltamivir phosphate for oral suspension (supplied as powder): a) Tap the closed bottle containing the supplied oseltamivir phosphate for oral suspension white to light yellow powder several times to loosen the powder. b) Tear off the foil seal after loosening the powder. c) Measure 55 mL of water in a graduated cylinder. d) Add the total amount of water for constitution to the bottle. e) Close bottle with child‐resistant cap tightly and shake the closed bottle well for 15 seconds. f) Label the bottle with instructions to “Shake Well Before Use”. g) The constituted oral suspension contains 360 mg of oseltamivir base per 60 mL of volume (6 mg per mL) and is white to light yellow, sour cherry-flavored).

Use the constituted oral suspension within 17 days of preparation when stored under refrigeration, 2º to 8ºC (36º to 46ºF), or within 10 days if stored at controlled room temperature, 20º to 25ºC (68º to 77ºF).

Keep the bottle in the outer carton in order to protect from light.

Write the expiration date of the constituted oral suspension on the bottle label. h) 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.

Suspension (Supplied as Powder) Supplied as a white to light yellow powder blend in a HDPE bottle.

After constitution, the powder blend produces a white to light yellow sour cherry-flavored oral suspension.

After constitution with 55 mL of water, each bottle delivers a usable volume of 60 mL of oral suspension equivalent to 360 mg oseltamivir base (6 mg/mL) (NDC 0527-5137-62).

Store dry powder at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) .

Preserved in well closed container.

Store constituted oral suspension under refrigeration for up to 17 days at 2º to 8ºC (36º to 46ºF).

Do not freeze.

Alternatively, store constituted oral suspension for up to 10 days at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) .

Keep the bottle in the outer carton in order to protect from light.

Store dry powder at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) .

Preserved in well closed container.

Store constituted oral suspension under refrigeration for up to 17 days at 2º to 8ºC (36º to 46ºF).

Do not freeze.

Alternatively, store constituted oral suspension for up to 10 days at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) .

Keep the bottle in the outer carton in order to protect from light.

There are no adequate and well-controlled studies with oseltamivir phosphate for oral suspension in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

Available published epidemiological data suggest that oseltamivir phosphate for oral suspension, 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.

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

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 to 4% and to 20%, respectively.

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.

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.

Oseltamivir was administered orally during organogenesis to pregnant rats (at 50, 250, or 1500 mg/kg/day on gestation days to 17) and rabbits (at 50, 150, or 500 mg/kg/day on gestation days 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 (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.

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 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.

Based on limited published data, oseltamivir and oseltamivir carboxylate have been shown to be present in human milk at low levels considered unlikely to lead to toxicity in the breastfed infant.

Postmarketing experience has not reported any information to suggest serious adverse effects of oseltamivir exposure via breast milk in infants.

It is not known if oseltamivir affects human milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oseltamivir phosphate and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

The safety and efficacy of oseltamivir phosphate for the treatment of influenza in pediatric patients 2 weeks old to 17 years of age has been established and is based on: 13 to 17 years of age: Safety and efficacy in adolescent patients to 17 years of age was supported by adequate and well-controlled trials in adults and adolescents and younger pediatric patients and safety data in adolescents treated with oseltamivir phosphate in a study of treatment and prophylaxis. 1 year to 12 years of age: Safety and efficacy in pediatric patients 1 year to 12 years of age was supported by results of one double-blind, placebo-controlled trial in 452 pediatric patients with influenza in whom oseltamivir phosphate 2 mg per kg twice daily or placebo was administered within 48 hours of symptom onset.

Additional safety information was provided in a double-blind, placebo-controlled trial in pediatric patients to 12 years of age with known asthma.

Efficacy could not be established in pediatric patients with asthma. 2 weeks to less than 1 year of age: Safety and efficacy in pediatric patients 2 weeks to less than 1 year of age is supported by adequate and well-controlled trials in adults and older pediatric patients and two open-label trials of oseltamivir phosphate (2 to 3.5 mg per kg twice daily for 5 days) in 136 pediatric subjects 2 weeks to less than 1 year of age.

In these two trials, the oseltamivir plasma concentrations in these subjects were similar to or higher than the oseltamivir plasma concentrations observed in older pediatric subjects and adults.

The safety and efficacy of oseltamivir phosphate for treatment of influenza in pediatric patients less than 2 weeks of age have not been established.

The safety and efficacy of oseltamivir phosphate for the prophylaxis of influenza in pediatric patients 1 year to 17 years old has been established and is based on: 13 to 17 years of age: Prophylaxis in adolescent patients to 17 years of age is supported by one randomized, placebo-controlled post-exposure household prophylaxis trial of oseltamivir phosphate 75 mg taken orally once daily for 7 days in household contacts including 207 adolescents. 1 year to 12 years of age: Oseltamivir phosphate for prophylaxis in pediatric patients 1 year to 12 years of age is supported by one randomized, open-label, post-exposure household prophylaxis trial including pediatric subjects 1 year to 12 years of age who received to 60 mg of oseltamivir phosphate for oral suspension (supplied as powder) taken orally once daily for 10 days.

Additional safety information was provided in a 6-week seasonal prophylaxis (community outbreak) safety study in 49 patients 1 year to 12 years of age.

The safety and efficacy of oseltamivir phosphate for prophylaxis of influenza have not been established for pediatric patients less than 1 year of age.

Of the 4,765 adults in clinical trials of oseltamivir phosphate for the treatment of influenza, 948 (20%) were 65 years and older, while 329 (7%) were 75 years and older.

In three double-blind, placebo-controlled trials in the treatment of influenza in patients at least 65 years old, that enrolled 741 subjects (374 received placebo and 362 received oseltamivir phosphate), no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Of the 4,603 adults in clinical trials of oseltamivir phosphate for the prophylaxis of influenza, 1,046 (23%) were 65 years and older, while 719 (16%) were 75 years and older.

In a randomized, placebo-controlled trial in elderly residents of nursing homes who took oseltamivir phosphate for up to 42 days for the prophylaxis of influenza (oseltamivir phosphate n=276, placebo n=272), no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.