Fosaprepitant (Page 4 of 8)

7.2 Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant

Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3)]. Coadministration of Fosaprepitant for Injection with drugs that are inhibitors or inducers of CYP3A4 may result in increased or decreased plasma concentrations of aprepitant, respectively, as shown in Table 8.

Table 8 Effects of Other Drugs on Pharmacokinetics of Fosaprepitant/Aprepitant

Moderate to Strong CYP3A4 Inhibitors

Clinical Impact

Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with Fosaprepitant for Injection [see Adverse Reactions (6.1), Clinical Pharmacology (12.3)].

Intervention

Avoid concomitant use of Fosaprepitant for Injection

Examples

Moderate inhibitor: diltiazem

Strong inhibitors:

ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir

Strong CYP3A4 Inducers

Clinical Impact

Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of Fosaprepitant for Injection [see Clinical Pharmacology (12.3)].

Intervention

Avoid concomitant use of Fosaprepitant for Injection

Examples

rifampin, carbamazepine, phenytoin

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on use of fosaprepitant in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic exposures (AUC) approximately equivalent to the exposure at the recommended human dose (RHD) of 150 mg [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1,000 mg/kg twice daily (rats) and up to the maximum tolerated dose of 25 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1,000 mg/kg twice daily and in pregnant rabbits at 25 mg/kg/day were approximately equivalent to the exposure at the RHD of 150 mg. Aprepitant crosses the placenta in rats and rabbits.

8.2 Lactation

Risk Summary

There are no data on the presence of aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Fosaprepitant for Injection and any potential adverse effects on the breastfed infant from Fosaprepitant for Injection or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Upon administration of Fosaprepitant for Injection, the efficacy of hormonal contraceptives may be reduced. Advise females of reproductive potential using hormonal contraceptives to use an effective alternative or back-up non-hormonal contraceptive (such as condoms or spermicides) during treatment with Fosaprepitant for Injection and for 1 month following the last dose [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

8.4 Pediatric Use

This Fosaprepitant for Injection product is not approved for use in pediatric patients.

This Fosaprepitant for Injection product contains 18.8 mg of edetate disodium (EDTA) per vial [see Description (11)]. Edetate disodium is a chelator of metal ions, including calcium. Other fosaprepitant for injection products may contain less edetate disodium.

8.5 Geriatric Use

Of the 1649 adult cancer patients treated with intravenous fosaprepitant in HEC and MEC clinical studies, 27% were aged 65 and over, while 5% were aged 75 and over. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Patients with Hepatic Impairment

The pharmacokinetics of aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients may be warranted when Fosaprepitant for Injection is administered [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant.

In the event of overdose, Fosaprepitant for Injection should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of Fosaprepitant for Injection, drug-induced emesis may not be effective in cases of Fosaprepitant for Injection overdosage.

Aprepitant is not removed by hemodialysis.

11 DESCRIPTION

Fosaprepitant for Injection is a sterile, lyophilized formulation containing fosaprepitant dimeglumine, a prodrug of aprepitant, a substance P/neurokinin-1 (NK1 ) receptor antagonist, an antiemetic agent, chemically described as 1-Deoxy-1-(methylamino)-D-glucitol[3-[[(2R ,3S)-2-[(1R)-1-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H -1,2,4- triazol-1-yl]phosphonate (2:1) (salt).

Its empirical formula is C23 H22 F7 N4 O6 P ⋅ 2(C7 H17 NO5 ) and its structural formula is:

formula image
(click image for full-size original)

Fosaprepitant dimeglumine is a white to off-white amorphous powder with a molecular weight of 1004.83. It is freely soluble in water.

Each vial of Fosaprepitant for Injection for administration as an intravenous infusion contains 150 mg of fosaprepitant (equivalent to 245.3 mg of fosaprepitant dimeglumine) and the following inactive ingredients: edetate disodium (18.8 mg), meglumine (75 mg), povidone k12 (600 mg), and water for injection. Hydrochloric acid and/or meglumine may have been added for pH adjustment.

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