fosaprepitant dimeglumine
Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION
Indications and Usage for Emend Injection
EMEND for Injection is a substance P/neurokinin-1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the:
- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin [see Dosage and Administration (2.1)]
- prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) [see Dosage and Administration (2.2)].
Limitations of Use
EMEND for Injection has not been studied for the treatment of established nausea and vomiting.
Chronic continuous administration is not recommended [see Warnings and Precautions (5.5)].
Emend Injection Dosage and Administration
Prevention of Nausea and Vomiting Associated with Highly Emetogenic Chemotherapy (HEC)
EMEND for Injection 150 mg (Single Dose Regimen of EMEND):
EMEND for Injection 150 mg is administered intravenously on Day 1 only as an infusion over 20-30 minutes initiated approximately 30 minutes prior to chemotherapy. No capsules of EMEND are administered on Days 2 and 3. EMEND for Injection should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in Table 1. The recommended dosage of dexamethasone with EMEND for Injection 150 mg differs from the recommended dosage of dexamethasone with EMEND for Injection 115 mg on Days 3 and 4.
| Day 1 | Day 2 | Day 3 | Day 4 | |
| ||||
| EMEND | 150 mg intravenous | none | none | none |
| Dexamethasone* | 12 mg orally | 8 mg orally | 8 mg orally twice daily | 8 mg orally twice daily |
| Ondansetron† | 32 mg intravenous | none | none | none |
EMEND for Injection 115 mg (3-Day Dosing Regimen of EMEND):
EMEND for Injection 115 mg is administered on Day 1 only as an infusion over 15 minutes initiated 30 minutes prior to chemotherapy. Capsules of EMEND 80 mg should be administered on Days 2 and 3. EMEND for Injection 115 mg should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in Table 2. The recommended dosage of dexamethasone with EMEND for Injection 115 mg differs from the recommended dosage of dexamethasone with EMEND for Injection 150 mg on Days 3 and 4.
Capsules of EMEND 125 mg may be substituted for EMEND for Injection 115 mg on Day 1.
| Day 1 | Day 2 | Day 3 | Day 4 | |
| ||||
| EMEND | 115 mg intravenous | 80 mg orally | 80 mg orally | none |
| Dexamethasone* | 12 mg orally | 8 mg orally | 8 mg orally once daily | 8 mg orally once daily |
| Ondansetron† | 32 mg intravenous | none | none | none |
Prevention of Nausea and Vomiting Associated with Moderately Emetogenic Chemotherapy (MEC)
EMEND for Injection 115 mg (3-Day Dosing Regimen of EMEND):
EMEND for Injection 115 mg is administered on Day 1 only as an infusion over 15 minutes initiated 30 minutes prior to chemotherapy. Capsules of EMEND 80 mg should be administered on Days 2 and 3. EMEND for Injection 115 mg should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in Table 3. The recommended dosage of dexamethasone with EMEND for Injection 115 mg differs from the recommended dosage of dexamethasone with EMEND for Injection 150 mg on Days 3 and 4.
Capsules of EMEND 125 mg may be substituted for EMEND for Injection 115 mg on Day 1.
| |||
| Day 1 | Day 2 | Day 3 | |
| EMEND | 115 mg intravenous | 80 mg orally | 80 mg orally |
| Dexamethasone* | 12 mg orally | none | none |
| Ondansetron† | 8 mg orally twice daily | none | none |
Preparation of EMEND for Injection
| 115 mg | 150 mg | |
| Step 1 | Aseptically inject 5 mL 0.9% Sodium Chloride for Injection (normal saline) into the vial. Assure that normal saline is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting saline into the vial. | Aseptically inject 5 mL 0.9% Sodium Chloride for Injection (normal saline) into the vial. Assure that normal saline is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting saline into the vial. |
| Step 2 | Aseptically prepare an infusion bag filled with 110 mL of normal saline. | Aseptically prepare an infusion bag filled with 145 mL of normal saline. |
| Step 3 | Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag containing 110 mL of normal saline to yield a total volume of 115 mL and a final concentration of 1 mg/1 mL. | Aseptically withdraw the entire volume from the vial and transfer it into the infusion bag containing 145 mL of normal saline to yield a total volume of 150 mL and a final concentration of 1 mg/1 mL. |
| Step 4 | Gently invert the bag 2-3 times. | Gently invert the bag 2-3 times. |
| Note: The differences in preparation for each dose are displayed as bolded text. | ||
The reconstituted final drug solution is stable for 24 hours at ambient room temperature (at or below 25°C).
Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.
Caution: EMEND for Injection should not be mixed or reconstituted with solutions for which physical and chemical compatibility have not been established. EMEND for Injection is incompatible with any solutions containing divalent cations (e.g., Ca2+, Mg2+), including Lactated Ringer’s Solution and Hartmann's Solution.
Dosage Forms and Strengths
One 150 mg single dose glass vial: White to off-white lyophilized solid (Sterile lyophilized powder for intravenous use only after reconstitution and dilution).
One 115 mg single dose glass vial: White to off-white lyophilized solid (Sterile lyophilized powder for intravenous use only after reconstitution and dilution).
Contraindications
Hypersensitivity
EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80 or any other components of the product. Known hypersensitivity reactions include: flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions (6.2)].
Concomitant Use with Pimozide or Cisapride
Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions (7.1)].
Warnings and Precautions
CYP3A4 Interactions
Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions (7.1)].
Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.
In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered.
Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions (7.1)].
Hypersensitivity Reactions
Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use.
Coadministration with Warfarin (a CYP2C9 substrate)
Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions (7.1)].
Coadministration with Hormonal Contraceptives
Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions (7.1)].
Chronic Continuous Use
Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use.
Adverse Reactions
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.
Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection.
The overall safety of fosaprepitant was evaluated in approximately 1100 individuals and the overall safety of aprepitant was evaluated in approximately 6500 individuals.
Oral Aprepitant
Highly Emetogenic Chemotherapy (HEC)
In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone.
In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy.
The most common adverse reactions reported in patients treated with the aprepitant regimen with an incidence ≥1% and greater than standard therapy are listed in Table 5.
Aprepitant Regimen (N=544) | Standard Therapy (N=550) | |
| Respiratory System | ||
| hiccups | 4.6 | 2.9 |
| Body as a Whole/Site Unspecified | ||
| asthenia/fatigue | 2.9 | 1.6 |
| Investigations | ||
| ALT increased | 2.8 | 1.5 |
| AST increased | 1.1 | 0.9 |
| Digestive System | ||
| constipation | 2.2 | 2.0 |
| dyspepsia | 1.5 | 0.7 |
| diarrhea | 1.1 | 0.9 |
| Nervous System | ||
| headache | 2.2 | 1.8 |
| Metabolism and Nutrition | ||
| anorexia | 2.0 | 0.5 |
A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than standard therapy are presented in the Less Common Adverse Reactions subsection below.
In an additional active-controlled clinical study in 1169 patients receiving aprepitant and highly emetogenic chemotherapy, the adverse experience profile was generally similar to that seen in the other HEC studies with aprepitant.
Moderately Emetogenic Chemotherapy (MEC)
In 2 well-controlled clinical trials in patients receiving moderately emetogenic cancer chemotherapy, 868 patients were treated with the aprepitant during Cycle 1 of chemotherapy and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In both studies, oral aprepitant was given in combination with ondansetron and dexamethasone (aprepitant regimen).
In the combined analysis of Cycle 1 data for these 2 studies, adverse reactions were reported in approximately 14% of patients treated with the aprepitant regimen compared with approximately 15% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.7% of patients treated with the aprepitant regimen compared with 0.2% of patients treated with standard therapy.
The most common adverse reactions reported in patients treated with the aprepitant regimen with an incidence ≥1% and greater than standard therapy are listed in Table 6.
Aprepitant Regimen (N=868) | Standard Therapy (N=846) | |
| Gastrointestinal disorders | ||
| eructation | 1.0 | 0.1 |
| General disorders and administration site conditions | ||
| fatigue | 1.4 | 0.9 |
A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than standard therapy are presented in the Less Common Adverse Reactions subsection below.
Less Common Adverse Reactions
Adverse reactions reported in either HEC or MEC studies in patients treated with the aprepitant regimen with an incidence <1% and greater than standard therapy are listed in Table 7.
| Infection and infestations | candidiasis, staphylococcal infection |
| Blood and the lymphatic system disorders | anemia, febrile neutropenia |
| Metabolism and nutrition disorders | weight gain, polydipsia |
| Psychiatric disorders | disorientation, euphoria, anxiety |
| Nervous system disorders | dizziness, dream abnormality, cognitive disorder, lethargy, somnolence |
| Eye disorders | conjunctivitis |
| Ear and labyrinth disorders | tinnitus |
| Cardiac disorders | bradycardia, cardiovascular disorder, palpitations |
| Vascular disorders | hot flush, flushing |
| Respiratory, thoracic and mediastinal disorders | pharyngitis, sneezing, cough, postnasal drip, throat irritation |
| Gastrointestinal disorders | nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, faeces hard, neutropenic colitis, flatulence, stomatitis |
| Skin and subcutaneous tissue disorders | rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion |
| Musculoskeletal and connective tissue disorders | muscle cramp, myalgia, muscular weakness |
| Renal and urinary disorders | polyuria, dysuria, pollakiuria |
| General disorders and administration site condition | edema, chest discomfort, malaise, thirst, chills, gait disturbance |
| Investigations | alkaline phosphatase increased, hyperglycemia, microscopic hematuria, hyponatremia, weight decreased, neutrophil count decreased |
In another chemotherapy induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy.
The adverse experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1.
Fosaprepitant
In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy, safety was evaluated for 1143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared to 1169 patients receiving the 3-day regimen of EMEND (aprepitant). The safety profile was generally similar to that seen in 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 reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.
The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above.
| General disorders and administration site conditions | infusion site erythema, infusion site pruritus, infusion site induration, infusion site pain |
| Investigations | blood pressure increased |
| Skin and subcutaneous tissue disorders | erythema |
| Vascular disorders | thrombophlebitis (predominantly, infusion-site thrombophlebitis) |
Other Studies with Postoperative Nausea and Vomiting
In well-controlled clinical studies in patients receiving general balanced anesthesia, 564 patients were administered 40 mg aprepitant orally and 538 patients were administered 4 mg ondansetron intravenously.
Adverse reactions were reported in approximately 4% of patients treated with 40 mg aprepitant compared with approximately 6% of patients treated with 4 mg ondansetron intravenously.
In patients treated with aprepitant, increased ALT (1.1%) was seen at a greater incidence than with ondansetron (1.0%). The following additional adverse reactions were observed in patients treated with aprepitant at an incidence <1% and greater than with ondansetron.
| Psychiatric disorders | insomnia |
| Nervous system disorders | dysarthria, hypoesthesia, sensory disturbance |
| Eye disorders | miosis, visual acuity reduced |
| Cardiac disorders | bradycardia |
| Respiratory, thoracic and mediastinal disorders | dyspnea, wheezing |
| Gastrointestinal disorders | abdominal pain upper, bowel sounds abnormal, dry mouth, nausea, stomach discomfort |
In addition, two serious adverse reactions were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: one case of constipation, and one case of subileus.
Other Studies
Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of fosaprepitant and aprepitant. 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 the drug.
Skin and subcutaneous tissue disorders: pruritus, rash, urticaria.
Immune system disorders: hypersensitivity reactions including anaphylactic reactions.
Drug Interactions
Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant.
Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9.
Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4, and does not induce CYP3A4. Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.
The following information was derived from data with oral aprepitant, two studies conducted with fosaprepitant and oral midazolam, and one study conducted with fosaprepitant and dexamethasone.
Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents
CYP3A4 Substrates:
Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications (4)].
5-HT3 antagonists:
In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).
Corticosteroids:
Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-24hr of dexamethasone, administered as a single 8 mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg intravenous on Day 1.
An oral aprepitant regimen of 125 mg on Day 1, and 80 mg/day on Days 2 through 5, coadministered with 20 mg oral dexamethasone on Day 1 and 8 mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant.
Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25%, and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant.
Chemotherapeutic agents:
Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions (5.1)].
Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions (5.1)].
Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment.
The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or back-up methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant.
Midazolam:
Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”).
| Dose of fosaprepitant/ aprepitant | Dose of Midazolam | Observed Drug Interactions |
| fosaprepitant 150 mg on Day 1 | oral 2 mg on Days 1 and 4 | AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4 |
| fosaprepitant 100 mg on Day 1 | oral 2 mg | oral midazolam AUC ↑ 1.6-fold |
| oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5 | oral 2 mg SD on Days 1 and 5 | oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 |
| oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3 | intravenous 2 mg prior to 3-day regimen of aprepitant and on Days 4, 8 and 15 | intravenous midazolam AUC ↑ 25 % on Day 4, AUC ↓ 19 % on Day 8 and AUC ↓ 4 % on Day 15 |
| oral aprepitant 125 mg | intravenous 2 mg given 1 hour after aprepitant | intravenous midazolam AUC ↑ 1.5-fold |
A difference of less than 2-fold increase of midazolam AUC was not considered clinically important.
The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant.
CYP2C9 Substrates (Warfarin, Tolbutamide):
Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle.
Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15.
Effect of Other Agents on the Pharmacokinetics of Aprepitant
Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.
Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy.
Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously.
Rifampin: When a single 375-mg dose of
No comments:
Post a Comment