Fosaprepitant (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of fosaprepitant for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis [see Warnings and Precautions (5.2)].

Immune system disorders: hypersensitivity reactions including anaphylaxis and anaphylactic shock [see Contraindications (4), Warnings and Precautions (5.2)].

Nervous system disorders: ifosfamide-induced neurotoxicity reported after fosaprepitant for injection and ifosfamide coadministration.

7 DRUG INTERACTIONS

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

When administered intravenously, fosaprepitant, a prodrug of aprepitant, is converted to aprepitant within 30 minutes. Therefore, drug interactions following administration of fosaprepitant for injection are likely to occur with drugs that interact with oral aprepitant.

Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, and the weak inhibition of CYP3A4 continues for 2 days after single dose administration. Single dose fosaprepitant does not induce CYP3A4. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 [see Clinical Pharmacology (12.3)].

Some substrates of CYP3A4 are contraindicated with fosaprepitant for injection [see Contraindications (4)]. Dosage adjustment of some CYP3A4 and CYP2C9 substrates may be warranted, as shown in Table 7.

Table 7
Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs
CYP3A4 Substrates
Pimozide
Clinical Impact Increased pimozide exposure.
Intervention Fosaprepitant for injection is contraindicated [see Contraindications (4)].
Benzodiazepines
Clinical Impact Increased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention Monitor for benzodiazepine-related adverse reactions.
Dexamethasone
Clinical Impact Increased dexamethasone exposure [see Clinical Pharmacology (12.3)].
Intervention Reduce the dose of oral dexamethasone by approximately 50% [see Dosage and Administration (2.1)].
Methylprednisolone
Clinical Impact Increased methylprednisolone exposure [see Clinical Pharmacology (12.3)].
Intervention Reduce the dose of oral methylprednisolone by approximately 50% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.Reduce the dose of intravenous methylprednisolone by 25% on Days 1 and 2 for patients receiving HEC and on Day 1 for patients receiving MEC.
Chemotherapeutic agents that are metabolized by CYP3A4
Clinical Impact Increased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].
Intervention Vinblastine, vincristine, or ifosfamide or other chemotherapeutic agents
  • Monitor for chemotherapeutic-related adverse reactions.
Etoposide, vinorelbine, paclitaxel, and docetaxel
  • No dosage adjustment needed.
Hormonal Contraceptives
Clinical Impact Decreased hormonal exposure during administration of and for 28 days after administration of the last dose of fosaprepitant for injection [see Warnings and Precautions (5.5), Use in Specific Populations (8.3), and Clinical Pharmacology (12.3)].
Intervention Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used during treatment with fosaprepitant for injection and for 1 month following administration of fosaprepitant for injection.
Examples birth control pills, skin patches, implants, and certain IUDs
CYP2C9 Substrates
Warfarin
Clinical Impact Decreased warfarin exposure and decreased prothrombin time (INR) [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].
Intervention In patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of fosaprepitant for injection with each chemotherapy cycle.
Other
5-HT 3 Antagonists
Clinical Impact No change in the exposure of the 5-HT3 antagonist [see Clinical Pharmacology (12.3)].
Intervention No dosage adjustment needed.
Examples ondansetron, granisetron, dolasetron

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

Aprepitant is a CYP3A4 substrate [see Clinical Pharmacology (12.3)]. Co-administration 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

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