Oseltamivir

Dosage Forms & Strengths

capsule

• 30mg
• 45mg
• 75mg

powder for oral suspension

• 6mg/mL

Influenza A and B Prophylaxis

75 mg PO qDay for at least 10 days

Dosing considerations

• Initiate within 48 hours of exposure
• For community outbreak, may administer for up to 6 weeks

Influenza A and B Treatment

75 mg PO q12hr x5 days

Dosing considerations

• Initiate within 48 hours of influenza symptom onset

H1N1 Influenza A (Swine Flu) Prophylaxis (Off-label)

75 mg PO qDay

Dosing considerations

• Postexposure prophylaxis: Initiate within 7 days of exposure and continue for at least 10 days
• Preexposure prophylaxis (community outbreak): Initiate during potential exposure period and continue for 10 days after last known exposure

H1N1 Influenza A (Swine Flu) Treatment (Off-label)

75 mg PO q12hr x5 days

Dosing considerations

• Initiate within 48 hours of influenza symptom onset

Dosing Modifications

Renal impairment

• Treatment
  • CrCl >60 mL/min: No dosage adjustment necessary
  • CrCl >30 to 60 mL/min: 30 mg PO BID
  • CrCl >10 to 30 mL/min: 30 mg PO qDay
  • End-stage renal disease (not undergoing dialysis): Not recommended (not studied)
• Prophylaxis
  • CrCl >60 mL/min: No dose adjustment necessary
  • CrCl >30 to 60 mL/min: 30 mg PO qDay
  • CrCl >10 to 30 mL/min: 30 mg PO every other day
  • End-stage renal disease (not undergoing dialysis): Not recommended (not studied)

Dosage Forms & Strengths

capsule

• 30mg
• 45mg
• 75mg

powder for oral suspension

• 6mg/mL

Influenza A and B Prophylaxis

<1 year: Safety and efficacy not established for prophylaxis

≥1 year

• <15 kg: 30 mg PO qDay x10 days
• 15-23 kg: 45 mg PO qDay x10 days
• 23-40 kg: 60 mg PO qDay x10 days
• >40 kg: 75 mg PO qDay x10 days

Dosing considerations

• Start within 2 days of exposure

Influenza A and B Treatment

<2 weeks: Safety and efficacy not established for treatment

Aged 2 weeks to <1 year

• 3 mg/kg PO BID x5 days

≥1 year

• <15 kg: 30 mg PO q12hr x5 days
• 15-23 kg: 45 mg PO q12hr x5 days
• 23-40 kg: 60 mg PO q12hr x5 days
• >40 kg: 75 mg PO q12hr x5 days

Dosing considerations

• Start within 24-48 hours of symptom onset

H1N1 Influenza A (Swine Flu) Prophylaxis (Off-label)

<1 year

• <3 months: Data limited; not recommended unless situation judged critical
• 3-5 months: 20 mg PO qDay x10 days
• 6-11 months: 25 mg PO qDay x10 days

≥1 year

• <15 kg: 30 mg PO qDay x10 days
• 15-23 kg: 45 mg PO qDay x10 days
• 23-40 kg: 60 mg PO qDay x10 days
• >40 kg: Administer as in adults

H1N1 Influenza A (Swine Flu) Treatment (Off-label)

Acute illness and age <1 year

• <3 months: 12 mg PO q12hr x5 days
• 3-5 months: 20 mg PO q12hr x5 days
• 6-11 months: 25 mg PO q12hr x5 days

Acute illness and age ≥1 year

• <15 kg: 30 mg PO q12hr x5 days
• 15-23 kg: 45 mg PO q12hr x5 days
• 23-40 kg: 60 mg PO q12hr x5 days
• >40 kg: Administer as in adults

1-10%

Abdominal pain

Conjunctivitis

Ear disorder

Epistaxis

Insomnia

Nausea

Vomiting

Vertigo

<1%

Aggravation of diabetes

Anemia

Arrhythmia

Confusion

Delirium

Hemorrhagic colitis

Hepatitis

Humerus fracture

Peritonsillar abscess

Pneumonia

Pseudomembranous colitis

Pyrexia

Rash

Seizure

Transaminases increased

Toxic epidermal necrolysis

Unstable angina

Swelling of face or tongue

Postmarketing Reports

Hypothermia

Diaper rash (2 weeks to <1 year of age)

Dermatitis

Urticaria

Eczema

Stevens-Johnson Syndrome

Erythema multiforme

Gastrointestinal bleeding

Abnormal liver function tests

Oseltamivir may be used to treat and prevent infections from avian (bird) influenza (a virus that usually infects birds but can also cause serious illness in humans). Oseltamivir also may be used to treat and prevent infections from influenza A (H1N1).

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

If you forget to take a dose, take it as soon as you remember it. If it is no longer than 2 hours before your next scheduled dose, skip the missed dose and continue your regular dosing schedule. If you miss several doses, call your doctor for directions. Do not take a double dose to make up for a missed one.

The Centers for Disease Control (CDC) recommends use of oseltamivir for treating flu in pregnant women.

The CDC recommends that women with flu who have recently given birth may be treated with oseltamivir. Oseltamivir is approved for use in children one year old and older, and available evidence suggests that the risk of adverse events is low when oseltamivir is used in children less than 1 year old.

Oseltamivir is part of the drug class:

• Neuraminidase inhibitors

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of oseltamivir there are no specific foods that you must exclude from your diet when receiving this medication.

It is important that you begin your treatment with oseltamivir AS SOON AS POSSIBLE from the first appearance of your flu symptoms or soon after you are exposed to the flu. If you feel worse or develop new symptoms during treatment with oseltamivir, or if your flu symptoms do not start to get better, you should contact your healthcare professional. 

• You can take oseltamivir with food or without food. There is less chance of stomach upset if you take it with a light snack, milk, or a meal.
• If you are taking oseltamivir for oral suspension, your pharmacist will give you a dosing dispenser to measure the proper amount of oral suspension for your dose. Follow your healthcare professional's instructions on how to measure the proper dose for you. Review the instructions below on how to use the dispenser and ask your pharmacist if you have any questions. If you lose or damage the dispenser and cannot use it, contact your healthcare professional or pharmacist for advice on the proper dose.
• If oseltamivir for oral suspension is not available, your healthcare provider may instruct you to open oseltamivir capsules and mix the contents with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar (dissolved in water). Please follow the dosing instructions below.
• If you forget to take your medicine, take the missed dose as soon as you remember, except if it is 2 hours or less before your next dose. Then continue to take oseltamivir at the usual times. Do not take 2 doses at a time to make up for a missed dose. If you miss several doses, tell your healthcare professional and follow the advice given to you.

DOSING INSTRUCTIONS FOR PATIENTS:

To Prepare a Dose of oseltamivir for oral suspension

• Shake closed bottle well for about 5 seconds before each use.
• Remove child-resistant cap.
• Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser. Insert tip firmly into opening of the bottle adapter.
• Turn the entire unit (bottle and oral dispenser) upside down.
• Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser. The 12.5 mL (75 mg) dose is obtained by filling the dispenser twice, once to the 10 mL graduation, and a second fill to the 2.5 mL graduation.
• Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.
• Dispense directly into mouth. Do not mix with any liquid prior to dispensing.
• Close bottle with child-resistant cap after each use.
• Disassemble oral dispenser, rinse under running tap water and air dry prior to next use.

If your healthcare provider directs you to mix the contents of oseltamivir capsules with sweetened liquids, follow instructions carefully to ensure proper dosing.

• Holding one capsule over a small bowl, carefully pull the capsule open and pour the complete contents of the capsule into the bowl.
• Add to the capsule contents a small amount of a sweetened liquid such as chocolate syrup (regular or sugar-free), corn syrup, caramel topping, or light brown sugar (dissolved in water) that the child will consume completely.
• Stir the mixture and give the entire dose to the child.

Take the missed dose as soon as you remember. Skip the missed dose if your next dose is less than 2 hours away. Do not take extra medicine to make up the missed dose.

Do not use a nasal flu vaccine (FluMist) within 48 hours after taking oseltamivir. Oseltamivir may interfere with the drug action of FluMist, making the vaccine less effective. Follow your doctor's instructions.

In the U.S.

• Tamiflu

Available Dosage Forms:

• Powder for Suspension
• Capsule

Therapeutic Class: Antiviral

Pharmacologic Class: Oseltamivir

Oseltamivir belongs to the family of medicines called antivirals, which are used to treat infections caused by viruses. Oseltamivir is used in the treatment of the infection caused by the flu virus (influenza A and influenza B). Oseltamivir may also be used to prevent and treat swine influenza A.

Oseltamivir may reduce flu symptoms (weakness, headache, fever, cough, runny or stuffy nose, and sore throat) by 1 day. Oseltamivir is also used to prevent influenza infection if you have come into close contact with someone who has the flu.

If you receive the flu vaccine every year, continue to do so. Oseltamivir is not a substitute for your yearly flu shot.

oseltamivir is available only with your doctor's prescription.

<content styleCode="bold">5.1       Serious Skin/Hypersensitivity Reactions</content>5.1       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 and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of Oseltamivir phosphate is contraindicated in patients with known serious hypersensitivity to Oseltamivir phosphate [see Contraindications (4)andAdverse Reactions (6.2)].

<content styleCode="bold">5.2       Neuropsychiatric Events</content>5.2       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 each patient.

<content styleCode="bold"> 5.3 Risk of Bacterial Infections</content> 5.3 Risk of Bacterial Infections

There is no evidence for efficacy of Oseltamivir phosphate 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 has not been shown to prevent such complications. Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

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)]

<content styleCode="bold">6.1       Clinical Trials Experience</content>6.1       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 to 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/adolescents.

Table 5 Adverse Reactions Occurring in ≥1% of Adults and Adolescents (13 years of age and older) in Treatment and Prophylaxis Trials*

* Adverse reactions that occurred in ≥1% of  Oseltamivir phosphate-treated adults and adolescents and ≥1% greater in  Oseltamivir phosphate-treated subjects compared to placebo-treated subjects in either the treatment or prophylaxis trials.

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 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)].

<content styleCode="bold">6.2       Postmarketing Experience</content>6.2       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 Disorders: Arrhythmia

Hepatobiliary Disorders: Hepatitis, abnormal liver function tests

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)]

<content styleCode="bold">12.1 Mechanism of Action</content>12.1 Mechanism of Action

Oseltamivir is an antiviral drug with activity against influenza virus [see Microbiology (12.4)].

<content styleCode="bold">12.3 Pharmacokinetics</content> 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 (see Table 6).

Table 6 Mean (% CV) Pharmacokinetic Parameters of Oseltamivir and Oseltamivir Carboxylate Following Multiple Dosing of 75 mg Capsules Twice Daily (n=20)

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) [see Dosage and Administration (2)]. Co-administration 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.

Distribution

The volume of distribution (Vss) of Oseltamivir carboxylate, following intravenous administration in 24 subjects (Oseltamivir phosphate is not available as an IV formulation), ranged between 23 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.

Elimination

Absorbed Oseltamivir is primarily (>90%) eliminated by conversion to the active metabolite, Oseltamivir carboxylate. Plasma concentrations of Oseltamivir declined with a half-life of 1 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 6 to 10 hours in most subjects after oral administration.

Metabolism

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.

Excretion

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.

Specific Populations

Renal Impairment

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 [see Indications and Usage (1.3) andUse in Specific Populations (8.6)].

Table 7 Simulated Median Treatment Exposure Metrics of Oseltamivir Carboxylate in Patients with Normal Renal Function, with Renal Impairment and ESRD Patients on Hemodialysis

*AUC normalized to 48 hours.

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 Cmin (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 Cmin in patients with normal renal function receiving the approved regimen of 75 mg once daily (40 ng/mL).

Hepatic Impairment

In clinical studies, Oseltamivir carboxylate exposure was not altered in subjects with mild or moderate hepatic impairment [see Use in Specific Populations (8.7)].

Pregnant Women

A pooled population pharmacokinetic analysis indicates that the Oseltamivir phosphate 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 [see Use in Specific Populations (8.1)].

Pediatric 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 5 to 16 years (n=18) and in a small number of pediatric subjects aged 3 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 [see Use in Specific Populations (8.4)].

Pediatric 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 [see Use in Specific Populations (8.4)].

Geriatric Patients

Exposure to Oseltamivir carboxylate at steady-state was 25 to 35% higher in geriatric subjects (age range 65 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 [see Use in Specific Populations (8.5)].

Drug Interaction Studies

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.

Co-administration 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 co-administering with probenecid. No clinically relevant pharmacokinetic interactions have been observed when co-administering Oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), rimantadine, amantadine, or warfarin.

<content styleCode="bold">12.4     Microbiology</content>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 IC50 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.

Antiviral Activity

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 (EC50 and EC90) 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, K173G, 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 Amino Acid Substitutions Associated with Reduced Susceptibility to

Oseltamivir

* All numbering is N2, except where indicated

Selection of influenza A viruses resistant to Oseltamivir can occur at higher frequencies in children. The incidence of Oseltamivir treatment-associated resistance in pediatric treatment studies has been detected at rates of 27 to 37% and 3 to 18% (3/11 to 7/19 and 1/34 to 9/50 post-treatment isolates, respectively) for influenza A/H1N1 virus and influenza A/H3N2 virus, respectively. The frequency of resistance selection to Oseltamivir and the prevalence of such resistant virus vary seasonally and geographically.

Circulating seasonal influenza strains expressing neuraminidase resistance-associated substitutions have been observed in individuals who have not received Oseltamivir treatment. The Oseltamivir resistance-associated substitution H275Y was found in more than 99% of US-circulating 2008 H1N1 influenza virus isolates. The 2009 H1N1 influenza virus (“swine flu”) was almost uniformly susceptible to Oseltamivir; however, the frequency of circulating resistant variants can change from season to season. Prescribers should consider available information from the CDC on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use Oseltamivir phosphate.

Cross-resistance

Cross-resistance between Oseltamivir and zanamivir has been observed in neuraminidase biochemical assays. The H275Y (N1 numbering) or N294S (N2 numbering) Oseltamivir resistance-associated substitutions observed in the N1 neuraminidase subtype, and the E119V or N294S Oseltamivir resistance-associated substitutions observed in the N2 subtype (N2 numbering), are associated with reduced susceptibility to Oseltamivir but not zanamivir. The Q136K and K150T zanamivir resistance-associated substitutions observed in N1 neuraminidase, or the S250G zanamivir resistance-associated substitutions observed in influenza B virus neuraminidase, confer reduced susceptibility to zanamivir but not Oseltamivir. The R292K Oseltamivir resistance-associated substitution observed in N2, and the I222T, D198E/N, R371K, or G402S Oseltamivir resistance-associated substitutions observed in influenza B virus neuraminidase, confer reduced susceptibility to both Oseltamivir and zanamivir. These examples do not represent an exhaustive list of cross-resistance-associated substitutions and prescribers should consider available information from the CDC on influenza drug susceptibility patterns and treatment effects when deciding whether to use Oseltamivir phosphate.

No single amino acid substitution has been identified that could confer cross-resistance between the neuraminidase inhibitor class (Oseltamivir, zanamivir) and the M2 ion channel inhibitor class (amantadine, rimantadine). However, a virus may carry a neuraminidase inhibitor-associated substitution in neuraminidase and an M2 ion channel inhibitor associated substitution in M2 and may therefore be resistant to both classes of inhibitors. The clinical relevance of phenotypic cross-resistance evaluations has not been established.

Immune Response

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

<content styleCode="bold">13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility</content>13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in mice and rats given daily oral doses of the prodrug Oseltamivir phosphate up to 400 mg/kg and 500 mg/kg, respectively, the prodrug and the active form Oseltamivir carboxylate induced no statistically significant increases in tumors over controls. The mean maximum daily exposures to the prodrug in mice and rats were approximately 130- and 320-fold, respectively, greater than those in humans at the recommended clinical dose based on AUC comparisons. The respective safety margins of the exposures to the active Oseltamivir carboxylate were 15- and 50-fold.

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 mating, 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 in this study was approximately 100 times the human systemic exposure (AUC0-24h) of Oseltamivir carboxylate that occurs after administration of the maximum recommended human dose.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Serious Skin/Hypersensitivity Reactions

Advise patients and/or caregivers of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions. Instruct patients and/or caregiver to stop Oseltamivir phosphate and seek immediate medical attention if an allergic-like reaction occurs or is suspected [see Warnings and Precautions (5.1)].

Neuropsychiatric Events

Advise patients and/or caregivers of the risk of neuropsychiatric events in  Oseltamivir phosphate-treated patients with influenza and instruct patients to contact their physician if they experience signs of abnormal behavior while receiving Oseltamivir phosphate [see Warnings and Precautions (5.2)].

Important Dosing Information

Instruct patients to begin treatment with Oseltamivir phosphate as soon as possible from the first appearance of flu symptoms, within 48 hours of onset of symptoms. Similarly, instruct patients to start taking Oseltamivir phosphate for prevention as soon as possible after exposure [see Dosage and Administration (2)]. Instruct patients 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 Oseltamivir phosphate at the usual times.

Influenza Vaccines

Instruct patients that Oseltamivir phosphate is not a substitute for receiving an annual flu vaccination. Patients should continue receiving an annual flu vaccination according to guidelines on immunization practices. Because of the potential for Oseltamivir phosphate to inhibit replication of live attenuated influenza vaccine (LAIV) and possibly reduce efficacy of LAIV, avoid administration of LAIV within 2 weeks or 48 hours after Oseltamivir phosphate administration, unless medically necessary [see Drug Interactions (7.1)].

Manufactured for:
AvKARE, Inc.
Pulaski, TN  38478

Manufactured by:                 

Amneal Pharmaceuticals LLC
Brookhaven, NY 11719

• Oseltamivir Phosphate

• Tamiflu

Refer to adult dosing.

Community-acquired pneumonia (influenza suspected or confirmed) (off-label use) (IDSA [Bradley 2011]): Oral:

Prophylaxis:

Infants 3 to 8 months: 3 mg/kg/day once daily

Infants ≥9 months to Children ≤23 months: 3.5 mg/kg/day once daily

Treatment:

Neonates and Infants ≤8 months: 6 mg/kg/day in divided doses twice daily

Infants ≥9 months to Children ≤23 months: 7 mg/kg/day in divided doses twice daily

Influenza prophylaxis: Oral: Initiate prophylaxis within 48 hours of contact with an infected individual

Manufacturer's labeling:

Children: 1 to 12 years:

≤15 kg: 30 mg once daily

>15 kg to ≤23 kg: 45 mg once daily

>23 kg to ≤40 kg: 60 mg once daily

>40 kg: 75 mg once daily

Adolescents ≥13 years: Refer to adult dosing.

Alternate recommendations:

American Academy of Pediatrics: Infants 0 to 11 months (off-label dosing; AAP 2013): Note: Do not exceed maximum dose of weight-based dosing; see manufacturer’s recommendation. Prophylaxis is not recommended for infants <3 months of age unless clinically critical.

0 to 8 months: 3 mg/kg/dose once daily

9 to 11 months: 3.5 mg/kg/dose once daily

Centers for Disease Control: Infants <12 months (off-label dosing) (CDC [Influenza Antiviral Medications] 2014): 3 mg/kg/dose once daily. Note: Do not exceed maximum dose of weight-based dosing; see manufacturer’s recommendation. Prophylaxis is not recommended for infants <3 months of age unless clinically critical. The current CDC weight-based dosing recommendation is not intended for premature neonates.

Infectious Disease Society of America/Pediatric Infectious Disease Society: Infants and Children 3 to 23 months (off-label dosing; Bradley 2011): Note: Do not exceed maximum dose of weight-based dosing; see manufacturer’s recommendation.

3 to 8 months: 3 mg/kg/dose once daily

9 to 23 months: 3.5 mg/kg/dose once daily

Prophylaxis duration:

Individual/household exposure:

Manufacturer's labeling: 10 days

Alternate recommendations: 7 days (CDC [Influenza Antiviral Medications] 2014); 10 days (AAP 2013)

Community/institutional outbreak: Note: The prescribing information states that during community outbreaks, duration of protection lasts for length of dosing period; safety and efficacy have been demonstrated for use up to 6 weeks in immunocompetent patients and safety has been demonstrated for use up to 12 weeks in patients who are immunocompromised.

Manufacturer's labeling: May be used for up to 6 weeks

Alternate recommendations: Continue for ≥2 weeks and until ~7 days after identification of illness onset in the last patient (CDC [Influenza Antiviral Medications] 2014) or until influenza activity in community subsides or immunity obtained from immunization (Bradley 2011).

Influenza treatment: Oral: Initiate treatment within 48 hours of onset of symptoms; usual duration of treatment is 5 days. However, optimal duration is uncertain for severe or complicated influenza. Consider longer duration (eg, >5 days) of therapy in severely ill patients who remain severely ill after 5 days of therapy. Note: Data suggest that increased doses in critically ill patients is not necessary since blood concentrations of oseltamivir were comparable or higher compared to ambulatory patients given similar dosing regimens (Ariano 2010; CDC [Influenza Antiviral Medications] 2014). Initiate as early as possible in any hospitalized patient with suspected/confirmed influenza regardless of the time of presentation from symptom onset (even if >48 hours) (CDC [Influenza Antiviral Medications] 2014); may be administered via naso- or orogastric tube in mechanically-ventilated patients (Taylor 2008).

US manufacturer's labeling: Note: The following dosing is also supported by some clinicians (Bradley 2011):

Infants ≥2 weeks: 3 mg/kg/dose twice daily

Children: 1 to 12 years:

≤15 kg: 30 mg twice daily

>15 kg to ≤23 kg: 45 mg twice daily

>23 kg to ≤40 kg: 60 mg twice daily

>40 kg: 75 mg twice daily

Adolescents ≥13 years: Refer to adult dosing.

Alternate recommendations:

American Academy of Pediatrics: Infants <12 months (off-label dosing; AAP 2013): Note: Age defined as postmenstrual age (first day of mother’s last period to birth plus the time elapsed after birth). Weight-based dosing recommendations for premature infants are lower than for term infants. Do not exceed maximum dose of weight-based dosing; see manufacturer’s recommendation.

Infants, premature:

<38 weeks: 1 mg/kg/dose twice daily

38 to 40 weeks: 1.5 mg/kg/dose twice daily

>40 weeks: 3 mg/kg/dose twice daily

Infants, term:

0 to 8 months: 3 mg/kg/dose twice daily

9 to 11 months: 3.5 mg/kg/dose twice daily

Centers for Disease Control: Infants <2 weeks (off-label dosing) (CDC [Influenza Antiviral Medications] 2014): 3 mg/kg/dose twice daily. Note: Do not exceed maximum dose of weight-based dosing; see manufacturer’s recommendation. The current CDC weight-based dosing recommendation is not intended for premature neonates.

Infectious Disease Society of America/Pediatric Infectious Disease Society: Infants and Children <24 months (off-label dosing; Bradley 2011): Note: Do not exceed maximum dose of weight-based dosing; see manufacturer’s recommendation.

Infants, premature: 1 mg/kg/dose twice daily

0 to 8 months: 3 mg/kg/dose twice daily

9 to 23 months: 3.5 mg/kg/dose twice daily

Capsules: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Oral suspension: Store powder for suspension at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Once reconstituted, store oral suspension under refrigeration at 2°C to 8°C (36°F to 46°F) or at room temperature; do not freeze. Use within 10 days of preparation if stored at room temperature or within 17 days of preparation if stored under refrigeration.

>10%:

Central nervous system: Headache (adolescents and adults: 2% to 17%)

Gastrointestinal: Vomiting (2% to 16%)

1% to 10%:

Central nervous system: Pain (adolescents and adults: 4%)

Gastrointestinal: Nausea (adolescents and adults: 8% to 10%)

<1% (Limited to important or life-threatening): Abnormal behavior, abnormal hepatic function tests, accidental injury, anaphylaxis, cardiac arrhythmia, confusion, delirium, delusions, erythema multiforme, gastrointestinal hemorrhage, hallucination, hemorrhagic colitis, hepatitis, hypersensitivity reaction, impaired consciousness, seizure, Stevens-Johnson syndrome, toxic epidermal necrolysis

Get emergency medical help if you have any of these signs of an allergic reaction to oseltamivir:

• chest pain or tightness, difficult breathing;

• fever, sore throat, swelling in your face or tongue, burning in your eyes; or

• hives, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Some people using oseltamivir have had rare side effects of sudden confusion, shaking, problems with speech, hallucinations (hearing or seeing things that are not there), or seizure (convulsions). These symptoms have occurred most often in children, but it is not known whether oseltamivir was the exact cause. Anyone using this medicine should be watched closely for signs of confusion or unusual behavior, especially a child.

Common oseltamivir side effects may include:

• nausea, vomiting, diarrhea, or stomach pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Usual Adult Dose for Influenza:

75 mg orally twice a day for 5 days

Approved indication: Treatment of acute, uncomplicated influenza infection in patients symptomatic no more than 48 hours

Usual Adult Dose for Influenza Prophylaxis:

Following close contact with an infected individual: 75 mg orally once a day for at least 10 days
During a community outbreak of influenza: 75 mg orally once a day

Comments:
-Therapy should begin within 48 hours of exposure.
-Safety and efficacy have been established for up to 6 weeks in immunocompetent patients; duration of protection lasts as long as dosing is continued.
-Safety has been established for up to 12 weeks in immunocompromised patients.

Usual Pediatric Dose for Influenza:

2 weeks to less than 1 year: 3 mg/kg orally twice a day

1 through 12 years:
15 kg or less: 30 mg orally twice a day
15.1 through 23 kg: 45 mg orally twice a day
23.1 through 40 kg: 60 mg orally twice a day
40.1 kg or greater: 75 mg orally twice a day

13 years or older: 75 mg orally twice a day

Duration of therapy: 5 days

Approved indication: Treatment of acute, uncomplicated influenza infection in patients (2 weeks or older) symptomatic no more than 48 hours

(Not approved by FDA)

American Academy of Pediatrics (AAP) recommendations:
Full-term infants less than 2 weeks: 3 mg/kg orally twice a day

Usual Pediatric Dose for Influenza Prophylaxis:

1 through 12 years:
15 kg or less: 30 mg orally once a day
15.1 through 23 kg: 45 mg orally once a day
23.1 through 40 kg: 60 mg orally once a day
40.1 kg or greater: 75 mg orally once a day

13 years or older: 75 mg orally once a day

Duration of therapy:
-After close contact with an infected individual: 10 days
-During a community outbreak of influenza: May be continued for up to 6 weeks

Comments:
-Therapy should begin within 48 hours of exposure.
-The FDA has not approved dosing for patients less than 1 year of age.

(Not approved by FDA)

AAP recommendations for full-term infants:
Less than 3 months: Not recommended unless situation judged critical.
3 months to less than 1 year: 3 mg/kg orally once a day

Applies to oseltamivir: oral capsule, oral powder for reconstitution

General

The most common side effects were nausea and vomiting.

The most common side effects reported with this drug during studies for the treatment of influenza were nausea, vomiting, headache, bronchitis, insomnia, and vertigo. Nausea and vomiting were generally mild to moderate in severity and usually occurred on the first 2 days of therapy. Less than 1% of patients discontinued this drug early due to nausea and vomiting.

Side effects in prophylaxis studies were similar to those in treatment studies, most commonly nausea, vomiting, headache, and pain. Side effects that occurred more frequently than in treatment studies were aches and pains, rhinorrhea, dyspepsia, and upper respiratory tract infections.[Ref]

Nervous system

Very common (10% or more): Headache (up to 18%)
Common (1% to 10%): Dizziness, vertigo
Frequency not reported: Drowsiness
Postmarketing reports: Seizure/convulsion[Ref]

Side effects with similar or higher incidence among placebo patients included dizziness and vertigo.[Ref]

Gastrointestinal

Very common (10% or more): Nausea
Common (1% to 10%): Nausea (without vomiting), vomiting, diarrhea, abdominal pain, upper abdominal pain, dyspepsia
Frequency not reported: Pseudomembranous colitis
Postmarketing reports: Gastrointestinal bleeding, hemorrhagic colitis[Ref]

Side effects with similar or higher incidence among placebo patients included diarrhea, abdominal pain, upper abdominal pain, and dyspepsia.[Ref]

Respiratory

Common (1% to 10%): Nasal congestion, cough, sore throat, bronchitis, nasopharyngitis, upper respiratory tract infections, influenza, rhinorrhea, sinusitis
Frequency not reported: Pneumonia, peritonsillar abscess, congestion, rhinitis, dry sore throat, epistaxis, asthma, aggravated asthma[Ref]

Side effects with similar or higher incidence among placebo patients included cough, nasal congestion, sore throat, rhinorrhea, bronchitis, sinusitis, nasopharyngitis, upper respiratory tract infections, and influenza.[Ref]

Psychiatric

Common (1% to 10%): Insomnia
Frequency not reported: Mania
Postmarketing reports: Abnormal behavior, delirium, altered level of consciousness, confusion, delusions, hallucinations, agitation, anxiety, nightmares, self-injury[Ref]

Influenza can be associated with various neurologic and behavioral symptoms (including hallucinations, delirium, abnormal behavior), with fatal outcomes in some cases; such events may occur with encephalitis or encephalopathy but can occur without obvious severe disease. There are postmarketing reports (mostly in Japan) of delirium and abnormal behavior leading to injury, with fatal outcomes in some cases, in influenza patients using this drug. Although frequency is unknown, based on usage, these events appear uncommon. These events were primarily reported in pediatric patients, often with abrupt onset and rapid resolution. The contribution of this drug to such events has not been established.

Side effects with similar or higher incidence among placebo patients included insomnia.[Ref]

Other

Side effects with similar or higher incidence among placebo patients included fatigue, pyrexia, influenza-like illness, and pain in limb.[Ref]

Common (1% to 10%): Fatigue, pain, pyrexia, influenza-like illness, pain in limb, otitis media, earache
Uncommon (0.1% to 1%): Tympanic membrane disorder
Frequency not reported: Humerus fracture, malaise, sepsis, facial edema, ear disorder, accidental injury
Postmarketing reports: Hypothermia[Ref]

Dermatologic

Side effects with similar or higher incidence among placebo patients included herpes simplex.[Ref]

Common (1% to 10%): Herpes simplex
Uncommon (0.1% to 1%): Dermatitis (including allergic and atopic dermatitis)
Rare (less than 0.1%): Angioneurotic edema
Postmarketing reports: Rash, urticaria, eczema, serious skin reactions, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme[Ref]

Musculoskeletal

Common (1% to 10%): Back pain, arthralgia, myalgia[Ref]

Side effects with similar or higher incidence among placebo patients included back pain, arthralgia, and myalgia.[Ref]

Genitourinary

Side effects with similar or higher incidence among placebo patients included dysmenorrhea.

Common (1% to 10%): Dysmenorrhea

Ocular

Common (1% to 10%): Conjunctivitis (including red eyes, eye discharge, eye pain)
Rare (less than 0.1%): Visual disturbances[Ref]

Hepatic

Uncommon (0.1% to 1%): Elevated liver enzymes
Rare (less than 0.1%): Hepatic failure, fulminant hepatitis (including fatalities)
Frequency not reported: Hepatic function disorder, jaundice
Postmarketing reports: Hepatitis, abnormal liver function tests[Ref]

Hypersensitivity

Postmarketing reports: Hypersensitivity reactions (e.g., allergic skin reactions), allergy, anaphylactic/anaphylactoid reactions, swelling of the face or tongue[Ref]

Cardiovascular

Frequency not reported: Unstable angina, sudden cardiopulmonary arrest
Postmarketing reports: Cardiac arrhythmia[Ref]

Metabolic

Frequency not reported: Hyperglycemia
Postmarketing reports: Aggravation of diabetes[Ref]

Hematologic

Frequency not reported: Anemia, pancytopenia, lymphadenopathy
Postmarketing reports: Thrombocytopenia[Ref]

Some side effects of oseltamivir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Adults:
Influenza Treatment:
-Mild renal dysfunction (CrCl greater than 60 to 90 mL/min): 75 mg orally twice a day
-Moderate renal dysfunction (CrCl greater than 30 to 60 mL/min: 30 mg orally twice a day
-Severe renal dysfunction (CrCl greater than 10 to 30 mL/min): 30 mg orally once a day
-ESRD not on dialysis (CrCl 10 mL/min or less): Not recommended.

Duration of therapy: 5 days

Influenza Prophylaxis:
-Mild renal dysfunction (CrCl greater than 60 to 90 mL/min): 75 mg orally once a day
-Moderate renal dysfunction (CrCl greater than 30 to 60 mL/min: 30 mg orally once a day
-Severe renal dysfunction (CrCl greater than 10 to 30 mL/min): 30 mg orally every other day
-ESRD not on dialysis (CrCl 10 mL/min or less): Not recommended.

Duration of prophylaxis: Same as recommended with normal renal function