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Emend Injection

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Emend Injection

Emend Injection

SIDE EFFECTS

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 (fosaprepitant dimeglumine injection) for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND (fosaprepitant dimeglumine injection) 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.

Table 5 : Adverse Reactions (incidence ≥ 1%) in patients receiving HEC with a greater incidence in the Aprepitant Regimen relative to Standard Therapy

  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.

Table 6: Adverse Reactions (incidence ≥ 1%) in patients receiving MEC with a greater incidence in the Aprepitant Regimen relative to Standard Therapy

  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.

Table 7 : Adverse Reactions (incidence < 1%) in patients observed in either HEC or MEC Studies with a greater incidence in the Aprepitant Regimen relative to Standard Therapy

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 mediastinaldiso rders 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 (fosaprepitant dimeglumine injection) for Injection 150 mg compared to 1169 patients receiving the 3-day regimen of EMEND (fosaprepitant dimeglumine injection) (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.

Table 8 : Adverse Reactions (incidence > 0.1%) in patients receiving Fosaprepitant 150 mg and not reported above for the Oral Aprepitant Regimen

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 orallyand 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.

Table 9 : Adverse Reactions (incidence < 1%) in patients receiving Aprepitant 40 mg with a greater incidence in the Aprepitant group relative to 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.

Read the Emend Injection (fosaprepitant dimeglumine injection) Side Effects Center for a complete guide to possible side effects

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 3day 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].

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].

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].

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 “↔”).

Table 10 : Pharmacokinetic Interaction Data for Aprepitant/Fosaprepitant and Coadministered Midazolam

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 oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.

Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.

Additional Interactions

Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure [mean (SD) of 24.3 (± 10.2) mm Hg with fosaprepitant versus 15.6 (± 4.1) mm Hg without fosaprepitant] and resulted in a small further maximum decrease in systolic blood pressure [mean (SD) of 29.5 (± 7.9) mm Hg with fosaprepitant versus 23.8 (± 4.8) mm Hg without fosaprepitant], which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval, beyond those changes induced by diltiazem alone.

In the same study, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine.

Last reviewed on RxList: 12/15/2010
This monograph has been modified to include the generic and brand name in many instances.

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