Oseltamivir Oral Suspension

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.

Prophylaxis of Influenza

Oseltamivir Phosphate for Oral Suspension is indicated for the prophylaxis of influenza in patients 1 year and older.

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)].

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 must be constituted with water by the pharmacist to produce the oral suspension [see Dosage and Administration (2.5)].

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 [see Dosage and Administration (2.4)].

For patients who cannot swallow capsules, oseltamivir phosphate for oral suspension is the preferred formulation.

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 dose 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.

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

Table 1 displays the recommended 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.

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 (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 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)].

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)].

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):

1. Tap the closed bottle containing the oseltamivir phosphate 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, 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).

Oseltamivir Phosphate for Oral Suspension: 6 mg per mL (final concentration when constituted)

• White to light yellow powder blend for constitution

Serious Skin/Hypersensitivity Reactions

Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with oseltamivir phosphate. Stop oseltamivir phosphate for oral suspension and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of oseltamivir phosphate for oral suspension is contraindicated in patients with known serious hypersensitivity to oseltamivir phosphate [see Contraindications (4) and Adverse Reactions (6.2)].

Neuropsychiatric Events

There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving oseltamivir phosphate [see Adverse Reactions (6.2)]. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on oseltamivir phosphate usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir phosphate to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as hallucinations, delirium, and abnormal behavior in some cases resulting in fatal outcomes.  These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. Closely monitor oseltamivir phosphate treated-patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing oseltamivir phosphate for oral suspension for each patient.

Risk of Bacterial Infections

There is no evidence for efficacy of oseltamivir phosphate for oral suspension in any illness caused by pathogens other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Oseltamivir phosphate for oral suspension has not been shown to prevent such complications. Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

Fructose Intolerance in Patients with Hereditary Fructose Intolerance

Fructose can be harmful to patients with hereditary fructose intolerance. One dose of 75 mg oseltamivir phosphate for oral suspension delivers 2 grams of sorbitol. This is above the daily maximum limit of sorbitol for patients with hereditary fructose intolerance, and may cause dyspepsia and diarrhea.

The following serious adverse reactions are discussed below and elsewhere in the labeling:

• Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1)]
• Neuropsychiatric events [see Warnings and Precautions (5.2)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions from Treatment and Prophylaxis Trials in Adult and Adolescent Subjects (13 years of age and older)

The overall safety profile of oseltamivir phosphate is based on data from 2,646 adult and adolescent subjects that received the recommended dosage of 75 mg orally twice daily for 5 days for treatment of influenza and 1,943 adult and adolescent subjects that received the recommended dosage of 75 mg orally once daily for up to 6 weeks for prophylaxis of influenza in clinical trials.

The most common adverse reactions in the pooled treatment and pooled prophylaxis trials in adults and adolescents are displayed in Table 5. The majority of these adverse reactions were reported on a single occasion, occurred on either the first or second treatment day and resolved spontaneously within 1-2 days. This summary includes otherwise healthy adults/adolescents and subjects "at risk" (subjects at higher risk of developing complications associated with influenza, e.g., elderly patients and patients with chronic cardiac or respiratory disease). In general, the safety profile in the subjects "at risk" was qualitatively similar to that in otherwise healthy adults/adolscents.

Adverse Reactions from Treatment and Prophylaxis Trials in Pediatric Subjects (1 year to 12 years of age)

A total of 1,481 pediatric subjects (including otherwise healthy pediatric subjects aged 1 year to 12 years and asthmatic pediatric subjects aged 6 to 12 years) participated in clinical trials of oseltamivir phosphate given for the treatment of influenza. A total of 859 pediatric subjects received treatment with oseltamivir phosphate for oral suspension either at a 2 mg per kg twice daily for 5 days or weight-band dosing. Vomiting was the only adverse reaction reported at a frequency of ≥1% in subjects receiving oseltamivir phosphate (16%) compared to placebo (8%).

Amongst the 148 pediatric subjects aged 1 year to 12 years who received oseltamivir phosphate at doses of 30 to 60 mg once daily for 10 days in a post-exposure prophylaxis study in household contacts (n = 99), and in a separate 6-week seasonal influenza prophylaxis safety study (n = 49), vomiting was the most frequent adverse reaction (8% on oseltamivir phosphate versus 2% in the no prophylaxis group).

Adverse Reactions from Treatment Trials in Pediatric Subjects (2 weeks to less than 1 year of age)

Assessment of adverse reactions in pediatric subjects 2 weeks to less than 1 year of age was based on two open-label studies that included safety data on 135 influenza-infected subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post conceptional age) exposed to oseltamivir phosphate at doses ranging from 2 to 3.5 mg per kg of the formulation for oral suspension twice daily orally for 5 days. The safety profile of oseltamivir phosphate was similar across the age range studied, with vomiting (9%), diarrhea (7%) and diaper rash (7%) being the most frequently reported adverse reactions, and was generally comparable to that observed in older pediatric and adult subjects.

Adverse Reactions from the Prophylaxis Trial in Immunocompromised Subjects

In a 12-week seasonal prophylaxis study in 475 immunocompromised subjects, including 18 pediatric subjects 1 year to 12 years of age, the safety profile in the 238 subjects receiving oseltamivir phosphate 75 mg once daily was consistent with that previously observed in other oseltamivir phosphate  prophylaxis clinical trials [see Clinical Studies (14.2)].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oseltamivir phosphate. 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 oseltamivir phosphate exposure.

General disorders and administration site conditions: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia

Skin and subcutaneous tissue disorders: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme [see Warnings and Precautions (5.1)]

Gastrointestinal Disorders: Gastrointestinal bleeding, hemorrhagic colitis

Cardiac: Arrhythmia

Hepatobiliary Disorders: Hepatitis, liver function tests abnormal

Nervous System Disorders: Seizure

Metabolism and Nutrition Disorders: Aggravation of diabetes

Psychiatric Disorders: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions [see Warnings and Precautions (5.2)]

Treatment of Influenza

Adults

Two randomized, placebo-controlled, double-blind clinical trials of oseltamivir phosphate were conducted in adults between 18 and 65 years old, one in the U.S. and one outside the U.S., for the treatment of acute uncomplicated influenza. Eligible subjects had fever of at least 100°F, 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.  Subjects were randomized to receive oral oseltamivir phosphate or placebo for 5 days. All enrolled subjects were allowed to take fever-reducing medications.

Of 1,355 subjects enrolled in these two trials, 849 (63%) subjects were influenza-infected (median age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected subjects, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of unknown type.

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

In the treatment of influenza, no increased efficacy was demonstrated in subjects who received higher doses of oseltamivir phosphate.

Adolescents and Adults with Chronic Cardiac or Respiratory Disease

A double-blind, placebo-controlled, multicenter trial was unable to demonstrate efficacy of oseltamivir phosphate (75 mg twice daily for 5 days) in the treatment of influenza in adult and adolescent subjects (13 years or older) with chronic cardiac (excluding chronic idiopathic hypertension) or respiratory diseases, as measured by time to alleviation of all symptoms. However, in patients treated with oseltamivir phosphate there was a more rapid cessation of febrile illness. No difference in the incidence of influenza complications was observed between the treatment and placebo groups in this population.

Geriatric Subjects

Three double-blind placebo-controlled treatment trials were conducted in subjects who were at least 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 higher than 97.5°F. Of 741 subjects enrolled, 476 (65%) subjects were influenza-infected; of these, 95% were infected with influenza type A and 5% with influenza type B.

In the pooled analysis, there was a 1-day reduction in the median time to improvement in influenza-infected subjects who received oseltamivir phosphate 75 mg twice daily for 5 days compared to those who received placebo (p=NS) [see Use in Specific Populations (8.5)]. Some seasonal variability was noted in the clinical efficacy outcomes.

Pediatric Subjects (1 year to 12 years of age)

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

Efficacy in this trial was determined by the time to alleviation or resolution of influenza signs and symptoms, measured by a composite endpoint that required the following four individual conditions be met: i) alleviation of cough, ii) alleviation of corzya, iii) resolution of fever, and iv) parental opinion of a return to normal health and activity. Oseltamivir phosphate treatment of 2 mg per kg twice daily, started within 48 hours of onset of symptoms, reduced the total composite time to freedom from illness by 1.5 days compared to placebo. Subgroup analyses by gender showed no differences in the treatment effect of oseltamivir phosphate in male and female pediatric subjects.

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

Two open-label trials evaluated the safety and pharmacokinetics of oseltamivir and oseltamivir carboxylate in influenza-infected pediatric subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post conceptional age). Subjects received oseltamivir phosphate at doses ranging from 2 to 3.5 mg per kg twice daily for 5 days depending on subject age. These clinical trials were not designed to evaluate clinical efficacy or virologic response.

Of the 136 subjects under the age of 1 year enrolled and dosed in the trials, the majority of the subjects were male (55%), white (79%), non-Hispanic (74%), full term (76%) and infected with influenza A (80%). Pharmacokinetic data indicated that a dose of 3 mg per kg twice daily in pediatric subjects 2 weeks to less than 1 year of age provided oseltamivir phosphate concentrations similar to or higher than those observed in older pediatric subjects and adults receiving the approved dose and provided the basis for approval [see Adverse Reactions (6.1) and Use in Specific Populations (8.4)].

Prophylaxis of Influenza

Adult and Adolescent Subjects (13 years of age and older)

The efficacy of oseltamivir phosphate in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis (community out break) clinical trials and one post-exposure prophylaxis trial in household contacts. The efficacy endpoint for all of these trials was the incidence of laboratory-confirmed clinical influenza defined as meeting all of the following criteria (all signs and symptoms must have been recorded within 24 hours):

• oral temperature greater than or equal to 99.0°F (37.2°C),
• at least one respiratory symptom (cough, sore throat, nasal congestion),
• at least one constitutional symptom (aches and pains, fatigue, headache, chills/sweats), and
• either a positive virus isolation or a four-fold increase in virus antibody titers from baseline.

In a pooled analysis of two seasonal prophylaxis trials in healthy unvaccinated adults (aged 18 to 65 years), oseltamivir phosphate 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory-confirmed clinical influenza from 5% (25/519) for the placebo group to 1% (6/520) for the oseltamivir phosphate group.

In the seasonal (community outbreak) prophylaxis trial in elderly residents of skilled nursing homes, about 80%, 43%, and 14% of the subjects were vaccinated, had cardiac disorders, and had chronic airway obstructive disorders, respectively. In this trial, subjects were randomized to oseltamivir phosphate 75 mg once daily or placebo taken orally for 42 days. The incidence of laboratory-confirmed clinical influenza was 4% (12/272) in the placebo-treated subjects compared to less than 1% (1/276) in the oseltamivir phosphate-treated subjects.

In the post-exposure prophylaxis trial in household contacts (aged 13 years or older) of an index influenza case, oseltamivir phosphate 75 mg once daily or placebo taken orally was administered within 48 hours of onset of symptoms in the index case and continued for 7 days (index cases did not receive oseltamivir phosphate treatment). The incidence of laboratory-confirmed clinical influenza was 12% (24/200) in the placebo-treated subjects compared to 1% (2/205) in the oseltamivir phosphate-treated subjects.

Pediatric Subjects (1 year to 12 years of age)

The efficacy of oseltamivir phosphate in preventing naturally occurring in influenza illness was demonstrated in a randomized, open-label post-exposure prophylaxis trial in household contacts that included pediatric subjects aged 1 year to 12 years, both as index cases and as family contacts. All index cases in this trial received oseltamivir phosphate for oral suspension 30 to 60 mg taken orally once daily for 10 days. The efficacy parameter was the incidence of laboratory-confirmed clinical influenza in the household. Laboratory-confirmed clinical influenza was defined as meting all of the following criteria:

• oral temperature at least 100°F (37.8°C),
• cough and/or corzya recorded within 48 hours, and
• either a positive virus isolation or a four-fold or greater increase in virus antibody titers from baseline or at illness visits.

Among household contacts 1 year to 12 years of age not already shedding virus at baseline, the incidence of laboratory-confirmed clinical influenza was lower in the group who received oseltamivir phosphate prophylaxis [3% (3/95)] compared to the group who did not receive oseltamivir phosphate prophylaxis [17% (18/106)].

Immunocompromised Subjects

A double-blind, placebo-controlled trial was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects (including 18 pediatric subjects 1 year to 12 years of age) who had received solid organ (n=388; liver, kidney, liver and kidney) or hematopoietic stem cell transplants (n=87).  Median time since transplant for solid organ transplant recipients was 1,105 days for the placebo group and 1,379 days for the oseltamivir phosphate group. Median time since transplant for the hematopoietic stem cell transplant recipients was 424 days for the placebo group and 367 days for the oseltamivir phosphate group. Approximately 40% of subjects received influenza vaccine prior to entering the study. The primary efficacy endpoint was the incidence of confirmed clinical influenza, defined as oral temperature higher than 99.0°F (37.2°C) plus cough and/or corzya, all recorded within 24 hours, plus either a positive virus culture or a four-fold increase in virus antibody titers from baseline. Subjects received treatment with oseltamivir phosphate 75 mg or placebo once daily by mouth for 12 weeks. The incidence of confirmed clinical influenza was 3% (7/238) in the placebo group compared with 2% (5/237) in the oseltamivir phosphate group; this difference was not statistically significant. A secondary analysis was performed using the same clinical symptoms and RT-PCR for laboratory confirmation of influenza infection. Among subjects who were not already shedding virus at baseline, the incidence of RT-PCR-confirmed clinical influenza infection was 3% (7/231) in the placebo group and <1% (1/232) in the oseltamivir phosphate group.