Fosaprepitant (Page 3 of 8)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of another intravenous formulation of fosaprepitant. 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 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), Clinical Pharmacology (12.3)].

Intervention

Effective alternative or back-up methods of contraception (such as condoms or 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-HT3 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

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