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.
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
|
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.
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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