Oseltamivir Phosphate (Page 5 of 9)

8.5 Geriatric Use

Treatment of Influenza

Of the 4,765 adults in clinical trials of oseltamivir phosphate for the treatment of influenza, 948 (20%) were 65 years and older, while 329 (7%) were 75 years and older. In three double-blind, placebo-controlled trials in the treatment of influenza in patients at least 65 years old, that enrolled 741 subjects (374 received placebo and 362 received oseltamivir phosphate), no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects [see Clinical Studies (14.1)] .

Prophylaxis of Influenza

Of the 4,603 adults in clinical trials of oseltamivir phosphate for the prophylaxis of influenza, 1,046 (23%) were 65 years and older, while 719 (16%) were 75 years and older. In a randomized, placebo-controlled trial in elderly residents of nursing homes who took oseltamivir phosphate for up to 42 days for the prophylaxis of influenza (oseltamivir phosphate n=276, placebo n=272), no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects [see Clinical Studies (14.2)] .

8.6 Renal Impairment

Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal function which may increase the risk of oseltamivir phosphate-associated adverse reactions. Therefore, dosage adjustment is recommended for patients with a serum creatinine clearance between 10 and 60 mL/minute and for patients with end-stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal dialysis treatment [see Dosage and Administration (2.4)] . Oseltamivir phosphate is not recommended for patients with ESRD not undergoing dialysis [see Indications and Usage (1.3) and Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. The safety and pharmacokinetics in patients with severe hepatic impairment have not been evaluated [see Clinical Pharmacology (12.3)] .

8.8 Use in Patients with Chronic Conditions

Efficacy of oseltamivir phosphate in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease was evaluated in one randomized, placebo-controlled clinical trial. Efficacy in this population, as measured by time to alleviation of all symptoms, was not established, but no new safety signals were identified [see Clinical Studies (14.1)] .

No clinical trial data are available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization.

8.9 Immunocompromised Patients

Efficacy of oseltamivir phosphate for the treatment or prophylaxis of influenza has not been established in immunocompromised patients [see Clinical Studies (14.2)] . Safety of oseltamivir phosphate for prophylaxis of influenza has been demonstrated for up to 12 weeks in immunocompromised patients [see Adverse Reactions (6.1)] .

10 OVERDOSAGE

Reports of overdoses with oseltamivir phosphate have been received from clinical trials and during postmarketing experience. In the majority of cases reporting overdose, no adverse reactions were reported. Adverse reactions reported following overdose were similar in nature to those observed with therapeutic doses of oseltamivir phosphate [see Adverse Reactions (6)] .

11 DESCRIPTION

Oseltamivir phosphate, USP, an influenza neuraminidase inhibitor (NAI), is available as:

  • A powder for oral suspension, which when constituted with water as directed contains 6 mg per mL oseltamivir base.

In addition to the active ingredient, the powder for oral suspension contains monosodium citrate, saccharin sodium, sodium benzoate, sorbitol, titanium dioxide, tutti-frutti flavoring, and xanthan gum.

Oseltamivir phosphate, USP is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C 16 H 28 N 2 O 4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt. The structural formula is as follows:

Structural FormulaStructural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

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)

2,719 (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 (6,218 ng·h/mL under fasted conditions and 6,069 ng·h/mL under fed conditions) of oseltamivir carboxylate.

Distribution

The volume of distribution (V ss ) of oseltamivir carboxylate, following intravenous administration in 24 subjects (oseltamivir phosphate is not available as an IV formulation), ranged between 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 to 140 mL/min (n=57)

Mild Creatinine Clearance 60 to 90 mL/min (n=45)

Moderate Creatinine Clearance 30 to 60 mL/min (n=13)

Severe Creatinine Clearance 10 to 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

1,170

AUC 48 (ng•h/mL)*

11,224

18,476

12,008

16,818

23,200

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)*

5,294

8,336

6,262

9,317

11,200

* 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 C min (160 ng/mL) in patients with normal renal function following 75 mg twice daily. Administration of 30 mg once weekly to CAPD patients resulted in plasma concentrations of oseltamivir carboxylate at the 168-hour blood sample of 63 ng/mL, which were comparable to the C min in patients with normal renal function receiving the approved regimen of 75 mg once daily (40 ng/mL).

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.

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