FOSAPREPITANT DIMEGLUMINE Drug Interactions: What You Need to Know

INTERACTIONS See Full Prescribing Information for a list of clinically significant drug interactions. ( 4 , 5.1 , 5.4 , 5.5 , 7.1 , 7.2 ) Pediatric use information is approved for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s Emend (fosaprepitant) for injection. However, due to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Some substrates of CYP3A4 are contraindicated with Fosaprepitant for Injection <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . 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 prolongation of 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-HT 3 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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

Fosaprepitant for injection is contraindicated in patients:

• who are hypersensitive to any component of the product. Hypersensitivity reactions including anaphylactic reactions, flushing, erythema, and dyspnea have been reported [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.2 )].
• taking pimozide. Inhibition of CYP3A4 by aprepitant, the active moiety, could result in elevated plasma concentrations of this drug, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide [see Warnings and Precautions ( 5.1 )].
• Known hypersensitivity to any component of this drug. ( 4 , 5.2 )
• Concurrent use with pimozide. ( 4 )

AND PRECAUTIONS

• CYP3A4 Interactions: Fosaprepitant is a weak inhibitor of CYP3A4, and aprepitant, the active moiety, is a substrate, inhibitor, and inducer of CYP3A4; see Full Prescribing Information for recommendations regarding contraindications, risk of adverse reactions, and dosage adjustment of fosaprepitant and concomitant drugs. ( 4 , 5.1 , 7.1 , 7.2 )
• Hypersensitivity Reactions (including anaphylaxis and anaphylactic shock): May occur during or soon after infusion. If symptoms occur, discontinue the drug. Do not reinitiate fosaprepitant, if symptoms occur with previous use. ( 4 , 5.2 ) · Infusion Site Reactions (including thrombophlebitis, necrosis, and vasculitis): Majority of reactions reported in patients receiving vesicant chemotherapy. Avoid infusion into small veins. Discontinue infusion and administer treatment if a severe reaction develops. ( 5.3 )
• Warfarin (a CYP2C9 substrate) : Risk of decreased INR of prothrombin time; monitor INR in 2–week period, particularly at 7 to 10 days, following initiation of fosaprepitant. ( 5.4 , 7.1 )
• Hormonal Contraceptives: Efficacy of contraceptives may be reduced during and for 28 days following administration of fosaprepitant. Use effective alternative or back-up methods of contraception. ( 5.5 , 7.1 , 8.3 )

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 with other drugs that are CYP3A4 substrates, may result in increased plasma concentration of the concomitant drug. · Use of pimozide with fosaprepitant 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. · Use of fosaprepitant 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. · Use of fosaprepitant with strong CYP3A4 inducers (e.g., rifampin) may result in a reduction in aprepitant plasma concentrations and decreased efficacy of fosaprepitant.

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>. Monitor patients during and after infusion. If hypersensitivity reactions occur, discontinue the infusion and administer appropriate medical therapy. Do not reinitiate fosaprepitant in patients who experience these symptoms with previous use <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

5.3 Infusion Site Reactions Infusion site reactions (ISRs) have been reported with the use of fosaprepitant for injection <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. 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 with warfarin, a CYP2C9 substrate, may result in a clinically significant decrease in the International Normalized Ratio (INR) of prothrombin time <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>. Monitor the INR in patients on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

5.5 Risk of Reduced Efficacy of Hormonal Contraceptives Upon coadministration with fosaprepitant, the efficacy of hormonal contraceptives may be reduced during administration of and for 28 days following the last dose of fosaprepitant <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Advise patients to use effective alternative or back-up methods of contraception during treatment with fosaprepitant and for 1 month following administration of fosaprepitant <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Use in Specific Populations ( 8.3 )]</span>.

5.3 Infusion Site Reactions Infusion site reactions (ISRs) have been reported with the use of fosaprepitant for injection <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. 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.