Oseltamavir Phosphate

1 INDICATIONS & USAGE Oseltamivir phosphate capsules USP, 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. ( 1.1 ) • Prophylaxis of influenza A and B in patients 1 year and older. ( 1.2 ) Limitations of Use: • Not a substitute for annual influenza vaccination. ( 1.3 ) • Consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use. ( 1.3 ) • Not recommended for patients with end-stage renal disease not undergoing dialysis. ( 1.3 ) 1.1 Treatment of Influenza Oseltamivir phosphate capsule 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 capsule is indicated for the prophylaxis of influenza A and B in patients 1 year and older. 1.3 Limitations of Use • Oseltamivir phosphate capsule 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 capsules [ see Microbiology ( 12.4 ) ]. • Oseltamivir phosphate capsule 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 ) ].

2 DOSAGE & ADMINISTRATION Treatment of influenza ( 2.2 ) • Adults and adolescents (13 years and older): 75 mg twice daily for 5 days • Pediatric patients 1 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 >30-60 mL/min): Reduce to 30 mg twice daily for 5 days ( 2.4 ) • Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once daily for 5 days ( 2.4 ) • ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days ( 2.4 ) • ESRD patients on CAPD: Reduce to a single 30 mg dose immediately ( 2.4 ) Prophylaxis of influenza ( 2.3 ) • 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 1 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 >30-60 mL/min): Reduce to 30 mg once daily ( 2.4 ) • Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once every other day ( 2.4 ) • ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after alternate hemodialysis cycles for the recommended duration of prophylaxis ( 2.4 ) • ESRD patients on CAPD: Reduce to 30 mg immediately and then 30 mg once weekly for the recommended duration of prophylaxis ( 2.4 ) 2.1 Dosage and Administration Overview Administer oseltamivir phosphate 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 capsules • Oseltamivir phosphate for oral suspension (supplied as a powder). This is the preferred formulation (6 mg per mL) for patients who cannot swallow capsules. The capsules and oral suspension may be taken with or without food; however, tolerability may be enhanced if oseltamivir phosphate capsules is taken with food. Adjust the oseltamivir phosphate 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. When oseltamivir phosphate for oral suspension is not available from wholesaler or the manufacturer, oseltamivir phosphate capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar (dissolved in water). During emergency situations and when neither the oral suspension or the age-appropriate strengths of oseltamivir phosphate capsules to mix with sweetened liquids are available, then a pharmacist may prepare an emergency supply of oral suspension from oseltamivir phosphate capsules 75 mg [ see Dosage and Administration ( 2.6 )]. 2.2 Recommended Dosage for Treatment of Influenza Initiate treatment with oseltamivir phosphate capsules within 48 hours of influenza symptom onset. Adults and Adolescents (13 years of age and older) The recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily (one 75 mg capsule twice daily) for 5 days. Pediatric Patients (2 weeks of age through 12 years of age) Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in pediatric patients 2 weeks of age through 12 years of age and provides information about prescribing the capsule or the formulation for oral suspension. 2.3 Recommended Dosage for Prophylaxis of Influenza Initiate post-exposure prophylaxis with oseltamivir phosphate capsules within 48 hours following close contact with an infected individual. Initiate seasonal prophylaxis with oseltamivir phosphate capsules during a community outbreak. Adults and Adolescents (13 years of age and older) The recommended dosage of oseltamivir phosphate capsules for prophylaxis of influenza in adults and adolescents 13 years and older is 75 mg orally once daily (one 75 mg capsule 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 capsules 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 capsules dosing is continued. Pediatric Patients (1 year to 12 years of age) Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for prophylaxis of influenza in pediatric patients 1 year to 12 years of age based on body weight and provides information about prescribing the capsule or 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 ) ]. Table 1 Oseltamivir Phosphate Dosage Recommendations in Pediatric Patients for Treatment and Prophylaxis of Influenza Weight (kg) Treatment Dosage for 5 days Prophylaxis Dosage for 10 days* Volume of Oral Suspension (6 mg/mL) for each Dose † Number of Bottles of Oral Suspension to Dispense Number of Capsules to Dispense (Strength)‡ Patients 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 Not applicable Patients 1 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 10 Capsules (30 mg) 15.1 kg to 23 kg 45 mg twice daily 45 mg once daily 7.5 mL 2 bottles 10 Capsules (45 mg) 23.1 kg to 40 kg 60 mg twice daily 60 mg once daily 10 mL 2 bottles 20 Capsules (30 mg) 40.1 kg or more 75 mg twice daily 75 mg once daily 12.5 mL 3 bottles 10 Capsules (75 mg) * 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 or capsules) 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. ‡ Oseltamivir phosphate for oral suspension is the preferred formulation for patients who cannot swallow capsules. § 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 [ see Use in Specific Population ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]. 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 * Recommended Prophylaxis Regimen*† Mild (>60-90 mL/minute) 75 mg twice daily for 5 days 75 mg once daily Moderate (>30-60 mL/minute) 30 mg twice daily for 5 days 30 mg once daily Severe (>10-30 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‡ (≤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 capsules are not recommended Oseltamivir phosphate capsules are not recommended * Capsules or 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). ‡ Data derived from studies in continuous ambulatory peritoneal dialysis (CAPD) patients. 2.6 Emergency Preparation of Oral Suspension from 75 mg Oseltamivir Phosphate Capsules The following directions are provided for use only during emergency situations and when FDA-approved, commercially manufactured oseltamivir phosphate for oral suspension is not available from wholesalers or the manufacturer. The following emergency preparation instructions will provide one patient with enough oseltamivir phosphate for a 5-day course of treatment of influenza or a 10-day course of prophylaxis of influenza: Step #1: Determine the dosage of oseltamivir phosphate for the patient [ see Dosage and Administration ( 2.2 , 2.3 , and 2.4 ) ] then determine the total volume of oral suspension needed to be prepared (see Table 3). Table 3 Emergency Preparation: Volume of Prepared Oral Suspension (6 mg per mL) Based Upon Oseltamivir Phosphate Dose Oseltamivir Phosphate Dose* Total Volume to Prepare per Patient 15 mg or less 37.5 mL 30 mg 75 mL 45 mg 100 mL 60 mg 125 mL 75 mg 150 mL * If the oseltamivir phosphate dose is between the doses listed, use the greater listed dose to determine the total volume of prepared oral suspension. Step #2: Preparation must be performed with only one of the following vehicles (other vehicles have not been studied): Cherry Syrup (Humco®), Ora-Sweet® SF (sugar-free) (Paddock Laboratories), or simple syrup. Determine the number of capsules and the amount of water and vehicle needed to prepare the total volume (see Table 3) of prepared oral suspension (6 mg per mL) for a complete treatment or prophylaxis course (see Table 4). Table 4 Emergency Preparation: Number of Oseltamivir Phosphate Capsules 75 mg and Amount of Water and Vehicle Needed to Prepare the Total Volume of a Prepared Oral Suspension (6 mg per mL ) Total Volume of Prepared Oral Suspension 37.5 mL 75 mL 100 mL 125 mL 150 mL Number of Oseltamivir Phosphate Capsules 75 mg (Total Strength)* 3 (225 mg) 6 (450 mg) 8 (600 mg) 10 (750 mg) 12 (900 mg) Amount of Water 2.5 mL 5 mL 7 mL 8 mL 10 mL Volume of Vehicle Cherry Syrup (Humco ® ) OR Ora-Sweet ® SF (Paddock Laboratories) OR simple syrup 34.5 mL 69 mL 91 mL 115 mL 137 mL *Includes overage to ensure all doses can be delivered Step #3: Follow the instructions below for preparing the 75 mg oseltamivir phosphate capsules to produce the oral suspension (6 mg per mL): a. Place the specified amount of water into a polyethyleneterephthalate (PET) or glass bottle (see Table 4). Constitution in other bottle types is not recommended because there is no stability data with other bottle types. b. Carefully separate the capsule body and cap and pour the contents of the required number of oseltamivir phosphate capsules 75 mg into the PET or glass bottle. c. Gently swirl the suspension to ensure adequate wetting of the oseltamivir phosphate capsules powder for at least 2 minutes. d. Slowly add the specified amount of vehicle to the bottle. e. Close the bottle using a child-resistant cap and shake well for 30 seconds to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension. The active drug, oseltamivir phosphate, readily dissolves in the specified vehicles. The suspension is caused by inert ingredients of oseltamivir phosphate capsules which are insoluble in these vehicles. f. Put an ancillary label on the bottle indicating “Shake Well Before Use.” g. Instruct the parent or caregiver that any unused suspension remaining in the bottle following completion of therapy must be discarded by either affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions. h. Place a pharmacy label on the bottle that includes the patient’s name, dosing instructions, drug name and any other required information to be in compliance with all State and Federal Pharmacy Regulations. Place an appropriate expiration date on the label according to storage conditions below. i. Include the recommended dosage on the pharmacy label as per Tables 1 and 2 [ see Dosage and Administration ( 2.2 , 2.3 , and 2.4 ) ]. j. Store the prepared oral suspension in glass or PET bottles either: • In a refrigerator [2° to 8°C (36° to 46°F)]: Stable for 5 weeks when stored in a refrigerator. • At room temperature [25°C (77°F)]: Stable for 5 days when stored at room temperature.

6 ADVERSE REACTIONS 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 ) ] Most common adverse reactions (>1% and more common than with placebo): • Treatment studies – Nausea, vomiting, headache. ( 6.1 ) • Prophylaxis studies – Nausea, vomiting, headache, pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 1-2 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* System Organ Class Adverse Reaction Treatment Trials Prophylaxis Trials Oseltamivir phosphate 75 mg twice daily (n = 2646) Placebo (n = 1977) Oseltamivir phosphate 75 mg once daily (n = 1943) Placebo (n = 1586) Gastrointestinal Disorders Nausea 10% 6% 8% 4% Vomiting 8% 3% 2% 1% Nervous System Disorders Headache General Disorders Pain 2% <1% 1% <1% 17% 4% 16% 3% * 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 ) ]. 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 )]

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) Parameter Oseltamivir Oseltamivir Carboxylate C max (ng/mL) 65 (26) 348 (18) AUC 0-12h (ng·h/mL) 112 (25) 2719 (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 ) ]. 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. 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 ), and Use 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 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)* 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 *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. 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.