Fosaprepitant (Page 2 of 8)

5 WARNINGS AND PRECAUTIONS

5.1 Clinically Significant CYP3A4 Drug Interactions

Fosaprepitant, a prodrug of aprepitant, is a weak inhibitor of CYP3A4, and aprepitant is a substrate, inhibitor, and inducer of CYP3A4.

  • Use of Fosaprepitant for Injection with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug.
    • Use of pimozide with Fosaprepitant for Injection is contraindicated due to the risk of significantly increased plasma concentrations of pimozide, potentially resulting in prolongation of the QT interval, a known adverse reaction of pimozide [see Contraindications (4)].
  • Use of Fosaprepitant for Injection with strong or moderate CYP3A4 inhibitors (e.g., ketoconazole, diltiazem) may increase plasma concentrations of aprepitant and result in an increased risk of adverse reactions related to Fosaprepitant for Injection.
  • Use of Fosaprepitant for Injection with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of Fosaprepitant for Injection.

See Table 7 and Table 8 for a listing of potentially significant drug interactions [see Drug Interactions (7.1, 7.2)].

5.2 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis and anaphylactic shock, during or soon after infusion of fosaprepitant have occurred. Symptoms including flushing, erythema, dyspnea, hypotension and syncope have been reported [see Adverse Reactions (6.2)].

Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate Fosaprepitant for Injection in patients who experience these symptoms with previous use [see Contraindications (4)].

5.3 Infusion Site Reactions

Infusion site reactions (ISRs) have been reported with the use of Fosaprepitant for Injection [see Adverse Reactions (6.1)]. The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Most ISRs occurred with the first, second or third exposure to single doses of Fosaprepitant for Injection and in some cases, reactions persisted for two weeks or longer. Treatment of severe ISRs consisted of medical, and in some cases surgical, intervention.

Avoid infusion of Fosaprepitant for Injection into small veins or through a butterfly catheter. If a severe ISR develops during infusion, discontinue the infusion and administer appropriate medical treatment.

5.4 Decrease in INR with Concomitant Warfarin

Coadministration of Fosaprepitant for Injection with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time [see Clinical Pharmacology (12.3)]. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of Fosaprepitant for Injection with each chemotherapy cycle [see Drug Interactions (7.1)].

5.5 Risk of Reduced Efficacy of Hormonal Contraceptives

Upon coadministration with Fosaprepitant for Injection, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of Fosaprepitant for Injection [see Clinical Pharmacology (12.3)]. Advise patients to use effective alternative or back-up methods of contraception during treatment with Fosaprepitant for Injection and for 1 month following administration of Fosaprepitant for Injection [see Drug Interactions (7.1), Use in Specific Populations (8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
  • Infusion Site Reactions [see Warnings and Precautions (5.3)]

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 safety of Fosaprepitant for Injection has been established from adequate and well-controlled studies of another intravenous fosaprepitant product in chemotherapy induced nausea and vomiting [see Clinical Studies (14)]. Adverse reactions reported in these studies are described below.

Adverse Reactions 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 adult patients receiving a single intravenous dose of fosaprepitant in combination with ondansetron and dexamethasone (fosaprepitant 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*

Intravenous fosaprepitant, 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 regimen and at a greater incidence than standard therapy.

Fosaprepitant regimen

Standard therapy

Infusion-site reactions were reported in 2.2% of patients treated with the fosaprepitant 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 regimen compared to standard therapy, respectively.

Adverse Reactions 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 adult patients receiving a single intravenous dose of fosaprepitant compared to 1169 patients receiving the 3-day regimen of oral 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.

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.

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