EMEND IV Fosaprepitant for injection Ref.[27979] Active ingredients: Fosaprepitant

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. Patients should be monitored during and after infusion. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. The infusion should not be reinitiated in patients who experience hypersensitivity reactions (see CONTRAINDICATIONS).

Infusion site reactions (ISRs) have been reported with the use of EMEND IV (see ADVERSE REACTIONS). The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (e.g., 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 EMEND IV 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 EMEND IV into small veins or through a butterfly catheter. If a severe ISR develops during infusion, discontinue the infusion and administer appropriate medical treatment.

Drug Interactions

CYP3A4 substrates: EMEND IV is a weak inhibitor of CYP3A4. Caution should be used when EMEND IV is coadministered with CYP3A4 substrates, including chemotherapeutic agents (see DRUG INTERACTIONS).

Serious post-marketing reports of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported in patients after oral aprepitant and ifosfamide coadministration. As EMEND IV is rapidly converted to aprepitant after administration, caution and careful monitoring are advised if coadministered with ifosfamide. Refer to IFEX (ifosfamide for injection) product monograph. (see ADVERSE REACTIONS / Post-Market Adverse Drug Reactions and DRUG INTERACTIONS).

Warfarin: Coadministration of EMEND IV with warfarin may cause a clinically significant decrease in the INR. 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 EMEND IV with each chemotherapy cycle (see DRUG INTERACTIONS).

Hormonal contraception: EMEND IV may reduce the efficacy of hormonal contraception. Alternative or backup methods should be used during and for 1 month following the last dose of EMEND IV (see DRUG INTERACTIONS).

Special Populations

Pregnant Women: There are no adequate and well-controlled studies in pregnant women; therefore, EMEND IV is not recommended for use during pregnancy unless clearly necessary (see TOXICOLOGY, Reproduction and Development).

Nursing Women: EMEND IV, when administered intravenously, is rapidly converted to aprepitant. Aprepitant is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk; therefore, breastfeeding is not recommended during treatment with EMEND IV.

Pediatrics (<18 years of age): Safety and effectiveness of EMEND IV in pediatric patients have not been established.

Geriatrics (≥65 years of age): In 2 well-controlled clinical studies, of the total number of patients (N=544) treated with aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

Hepatic Impairment: There are no clinical data or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). EMEND IV should be used with caution in these patients (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

Clinical Trial Adverse Experiences

The overall safety of fosaprepitant was evaluated in approximately 1600 individuals.

Moderately Emetogenic Chemotherapy (MEC)

In an active-controlled clinical trial in patients receiving MEC, safety was evaluated in 504 patients receiving a single dose of EMEND IV in combination with ondansetron and dexamethasone (fosaprepitant regimen) compared to 497 patients receiving ondansetron and dexamethasone alone (control regimen).

Table 1 shows the percent of patients with clinical adverse experiences reported with fosaprepitant at an incidence ≥3%, regardless of causality.

Table 1. All adverse experiences, regardless of causality (incidence ≥3%), occurring in patients receiving moderately emetogenic chemotherapy who were treated with fosaprepitant for chemotherapy induced nausea and vomiting (CINV) in a clinical study:

Since fosaprepitant is converted to aprepitant, those adverse experiences associated with aprepitant might also be expected to occur with EMEND IV. The following additional adverse experiences occurring at ≥3% in patients receiving oral aprepitant with moderately emetogenic chemotherapy and not already reported above include:

Gastrointestinal disorders: dyspepsia, stomatitis.

Nervous system disorders: dizziness.

Psychiatric disorders: insomnia.

Skin and subcutaneous tissue disorders: alopecia.

Additional Clinical Trial Adverse Experiences (>0.5% and greater than standard therapy), Regardless of Causality, Occurring in Patients Receiving Moderately Emetogenic Chemotherapy who were treated with Fosaprepitant

Blood and lymphatic system disorders: anemia, leukopenia.

Gastrointestinal disorders: abdominal discomfort, dry mouth, dyspepsia, dysphagia haemorrhoidal haemorrhage.

General disorders and administration site: chest pain, chills, influenza like illness, infusion site pain, mucosal inflammation, pain.

Infections and Infestations: oral candidiasis, urinary tract infection.

Investigations: blood glucose increased, weight decreased.

Metabolism and nutrition disorders: dehydration, hypokalemia.

Musculoskeletal and connective tissue disorders: pain in extremity.

Nervous system disorders: neuropathy peripheral, peripheral sensory neuropathy, syncope.

Psychiatric disorders: anxiety.

Respiratory, thoracic and mediastinal disorder: dyspnea, epistaxis, haemoptysis, hiccups, rhinorrhea.

Skin and subcutaneous tissue disorders: erythema.

Vascular disorders: thrombophlebitis.

Abnormal Hematologic and Clinical Chemistry Findings

No laboratory adverse experiences were reported at an incidence ≥3% in patients receiving moderately emetogenic chemotherapy.

Other Abnormal Hematological and Clinical Chemistry Findings Observed in Clinical Trials in Patients Receiving Moderately Emetogenic Chemotherapy

The following additional laboratory adverse experiences, regardless of causality, were reported at an incidence >0% in patients treated with the fosaprepitant regimen: alanine aminotransferase increased, aspartate aminotransferase increased, blood albumin decreased, blood creatinine increased, blood glucose increased, blood magnesium decreased, fibrin D dimer increased, gamma-glutamyltransferase increased, international normalized ratio increased, lymphocyte count decreased, neutrophil count decreased, platelet count decreased, urine analysis abnormal, weight decreased, white blood cell count decreased.

Highly Emetogenic Chemotherapy

In an active-controlled clinical study in patients receiving highly emetogenic chemotherapy, safety was evaluated for 1143 patients receiving a single dose of EMEND IV 150 mg compared to 1169 patients receiving the 3-day regimen of EMEND (aprepitant). The safety profile was generally similar to that seen inthe MEC study with fosaprepitant.

Infusion-site reactions occurred at a higher incidence in the fosaprepitant group (3.0%) compared to those in the aprepitant group (0.5%), and there were significantly more cases of infusionassociated thrombophlebitis and infusion-site pain in the fosaprepitant group compared to those in the aprepitant group (thrombophlebitis: 0.8% vs. 0.1%; infusion-site pain: 1.4% vs. 0.1%). Infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

In addition, there were more patients with adverse events of hypertension in the fosaprepitant group (1.5%) than in the aprepitant group (0.6%), as well as more patients with potential hypersensitivity adverse events in the fosaprepitant group (3.7%) than in the aprepitant group (3.1%).

Table 2 shows the percent of patients with clinical adverse experiences reported with fosaprepitant at an incidence ≥3%, regardless of causality.

Table 2. All adverse experiences, regardless of causality (incidence ≥3%), occurring in patients receiving highly emetogenic chemotherapy who were treated with fosaprepitant for CINV in a clinical study:

Clinically significant laboratory analysis during the follow-up time period (Day 6 to 29) indicated a higher incidence of serum alanine aminotransferase >5 X ULN in patients treated with the fosaprepitant regimen (1.8%) compared to patients treated with the aprepitant regimen (0.5%).

Since fosaprepitant is converted to aprepitant, those adverse experiences associated with aprepitant might also be expected to occur with EMEND IV. Adverse experiences occurring at ≥3% in patients receiving oral aprepitant with highly emetogenic chemotherapy, and not already reported above include:

Gastrointestinal disorders: gastritis, stomatitis.

General disorders and administration site conditions: pyrexia.

Metabolism and nutrition disorders: decreased appetite, dehydration.

Ear and labyrinth disorders: tinnitus.

Psychiatric disorders: insomnia.

Other Clinical Trials

Isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies.

Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving oral aprepitant with cancer chemotherapy in another CINV study.

In addition to those adverse experiences listed above, clinical trial adverse experiences occurring at >0.5% and greater than standard therapy, in patients receiving highly and moderately emetogenic chemotherapy who were treated with oral aprepitant for CINV include:

Neutropenia, thrombocytopenia, epigastric discomfort, eructation, flatulence, gastroesophageal reflux disease, odynophagia, salivary hypersecretion, edema peripheral, malaise, pharyngitis, septic shock, diabetes mellitus, musculoskeletal pain, dysgeusia, confusion, depression, cough, oral pharyngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance, hyperhidrosis, acne, rash, deep vein thrombosis, flushing, hot flush, hypertension, hypotension, dysuria, renal insufficiency, myocardial infarction, palpitations, tachycardia, conjunctivitis, weight decreased.

See the product monograph for EMEND for complete safety information regarding studies performed with oral aprepitant.

Post-Market Adverse Drug Reactions

Regardless of causality, the following post-marketing adverse events have been reported rarely or very rarely and occur with multiple confounding factors: loss of consciousness, depressed level of consciousness, convulsion, somnolence, paresthesia, syndrome of inappropriate antidiuretic hormone, hallucination, pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis, and hypersensitivity reactions including anaphylactic reactions/anaphylactic shock.

Serious post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported in patients after oral aprepitant and ifosfamide coadministration including acute psychosis, encephalopathy, toxic encephalopathy, delirium, convulsion, decreased level of consciousness and hallucination (see DRUG INTERACTIONS).

Immediate hypersensitivity reactions have been observed during the infusion of fosaprepitant which may include the following: flushing, erythema, dyspnea (see WARNINGS AND PRECAUTIONS).

Following the infusion of fosaprepitant 150 mg, a higher aprepitant C_max (~2.6-fold) was observed compared to oral aprepitant (125 mg). A theoretical risk for increased adverse experiences due to a higher peak aprepitant exposure cannot be ruled out.

Serious Drug Interactions

• Fosaprepitant is rapidly converted to aprepitant, which is an inhibitor of CYP3A4. Fosaprepitant should be used with caution in patients receiving concomitant medicinal products that are primarily metabolized through CYP3A4 and CYP2C9, including chemotherapy agents. Moderate inhibition of CYP3A4 by aprepitant and weak inhibition of CYP3A4 by fosaprepitant 150 mg could result in elevated plasma concentrations of these concomitant medicinal products. Induction of CYP2C9 by aprepitant could result in decreased plasma concentrations of these concomitant medicinal products (see CONTRAINDICATIONS and Drug-Drug Interactions below).
• Coadministration of oral aprepitant with warfarin results in decreased prothrombin time, reported as International Normalized Ratio (INR). 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 (see Drug-Drug Interactions below).
• The efficacy of hormonal contraceptives during and for 28 days after administration of fosaprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 1 month following administration (see DrugDrug Interactions below).

Overview

Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. The following information was derived from studies conducted with oral aprepitant and studies conducted with fosaprepitant coadministered with dexamethasone, midazolam or diltiazem.

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.

Chronic continuous use of EMEND IV is not recommended because it has not been studied and because the drug interaction profile may change during chronic dosing.

Effect of fosaprepitant/aprepitant on the pharmacokinetics of other agents

Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of orally coadministered medicinal products that are metabolized through CYP3A4 (see CONTRAINDICATIONS). Aprepitant may increase the plasma concentration of orally administered CYP3A4 substrates to a greater extent than if the substrate was administered intravenously.

Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of fosaprepitant or oral aprepitant with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs.

Effect of other agents on the pharmacokinetics of aprepitant

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached cautiously. Moderate CYP3A4 inhibitors (e.g., diltiazem) resulted in a 2-fold increase in plasma concentrations of aprepitant; therefore, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy.

Drug-Drug Interactions

Chemotherapeutic agents: 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, paclitaxel and cyclophosphamide. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies, oral aprepitant did not influence the pharmacokinetics of IV administered vinorelbine or docetaxel. However, EMEND IV may increase the plasma concentration of oral CYP3A4 substrates to a greater extent than if the substrates were administered intravenously. No additional drug-drug interaction studies with chemotherapeutic agents metabolized by CYP3A4 were carried out.

Serious post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported in patients after oral aprepitant and ifosfamide coadministration. Refer to IFEX (ifosfamide for injection) product monograph.

Caution and careful monitoring are advised in patients receiving chemotherapy agents metabolized by CYP3A4, particularly those that were not studied in the clinical trials (see WARNINGS AND PRECAUTIONS).

Established or potential drug-drug interactions:

Legend: CT = Clinical Trial; T = Theoretica

5-HT₃ antagonists: In clinical drug interaction studies, oral aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron administered intravenously, granisetron administered orally, or hydrodolasetron (the active metabolite of dolasetron) following oral administration of dolasetron.

P-glycoprotein transporter substrates: Fosaprepitant is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in a clinical drug interaction study.

Drug-Food Interactions

EMEND IV may be administered with or without food.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.