Fosaprepitant (Page 3 of 8)
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The overall safety of fosaprepitant for injection was evaluated in approximately 1800 adult and pediatric patients.
Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with MEC
In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of fosaprepitant for injection in combination with ondansetron and dexamethasone (fosaprepitant for injection regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (standard therapy). The most common adverse reactions are listed in Table 6.
Table 6 Most Common Adverse Reactions in Patients Receiving MEC*
Fosaprepitant for injection, ondansetron, and dexamethasone† (N=504) | Ondansetron and dexamethasone‡ (N=497) | |
fatigue | 15% | 13% |
diarrhea | 13% | 11% |
neutropenia | 8% | 7% |
asthenia | 4% | 3% |
anemia | 3% | 2% |
peripheral neuropathy | 3% | 2% |
leukopenia | 2% | 1% |
dyspepsia | 2% | 1% |
urinary tract infection | 2% | 1% |
pain in extremity | 2% | 1% |
*Reported in ≥2% of patients treated with the fosaprepitant for injection regimen and at a greater incidence than standard therapy.
† Fosaprepitant for injection regimen
‡Standard therapy
Infusion-site reactions were reported in 2.2% of patients treated with the fosaprepitant for injection regimen compared to 0.6% of patients treated with standard therapy. The infusion-site reactions included: infusion site pain (1.2%, 0.4%), injection-site irritation (0.2%, 0.0%), vessel puncture-site pain (0.2%, 0.0%), and infusion-site thrombophlebitis (0.6%, 0.0%), reported in the fosaprepitant for injection regimen compared to standard therapy, respectively.
Adverse Reactions in Adults for the Prevention of Nausea and Vomiting Associated with HEC
In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1143 patients receiving a single dose of fosaprepitant for injection compared to 1169 patients receiving the 3-day regimen of oral fosaprepitant (aprepitant) [see Clinical Studies (14.1)]. The safety profile was generally similar to that seen in the MEC study with fosaprepitant and prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%). The following additional infusion-site reactions occurred in the HEC study and were not reported in the MEC study described above: infusion-site erythema (0.5%, 0.1%), infusion-site pruritus (0.3%, 0.0%), and infusion-site induration (0.2%, 0.1%), reported in the fosaprepitant group compared to the aprepitant group, respectively.
Adverse Reactions in Pediatric Patients 6 Months to 17 Years of Age for the Prevention of Nausea and Vomiting Associated with HEC or MEC
Single-Dose Fosaprepitant for Injection Regimen
The safety of a single dose of fosaprepitant for injection in pediatric patients (6 months to 17 years) was evaluated in two active-controlled and a single-arm clinical study in patients who received either HEC or MEC. Patients also received ondansetron with or without dexamethasone. The adverse reaction profile was similar to adults. The safety analysis included 69 pediatric patients who received the recommended dose. An additional 70 patients received a single, higher-than-recommended dose. The most common adverse reactions that occurred in >15% of patients who received the recommended dose were anemia, neutropenia, thrombocytopenia, and febrile neutropenia.
3-Day Fosaprepitant Regimen
In pediatric patients (12 to 17 years), the safety of the 3-day IV/oral/oral fosaprepitant (aprepitant) regimen was evaluated in a single-arm clinical study including 12 patients who received a regimen of either HEC or MEC. In pediatric patients 6 months to 12 years of age, the safety of the 3-day IV/oral/oral fosaprepitant (aprepitant) regimen was not directly evaluated. The safety of a single-dose of fosaprepitant for injection (3 mg/kg) administered on day 1 of the 3-day IV/oral/oral regimen was evaluated in one active-controlled and one single-arm study including 48 pediatric patients 6 months to 12 years of age who received a regimen of either HEC or MEC.
In these clinical studies, pediatric patients also received ondansetron with or without dexamethasone. The adverse reaction profile in pediatric patients was similar to the profile in adult patients receiving a single dose of fosaprepitant for injection.
Because fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with fosaprepitant for injection. See the full prescribing information for aprepitant capsules for complete safety information regarding studies performed with oral aprepitant.
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-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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