1. Name Of The Medicinal Product
IVEMEND®
2. Qualitative And Quantitative Composition
Each vial contains fosaprepitant dimeglumine equivalent to 150 mg fosaprepitant. After reconstitution and dilution 1 ml of solution contains 1 mg fosaprepitant (1 mg/ml) (see section 6.6).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder for solution for infusion.
White to off-white amorphous powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy in adults.
Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults.
IVEMEND 150 mg is given as part of a combination therapy (see section 4.2).
4.2 Posology And Method Of Administration
IVEMEND is a lyophilised prodrug of aprepitant for intravenous administration.
Since IVEMEND is also available as a 115 mg vial*, it is important to note that the preparation (volume for dilution), infusion rate and doses of concomitant therapy for IVEMEND 150 mg are different from those for IVEMEND 115 mg. See also section 6.6 for preparation.
* Ivemend 115 mg is no longer available in the UK
Oral aprepitant on Days 2 and 3 is only administered in combination with IVEMEND 115 mg on Day 1. No aprepitant is administered orally in combination with IVEMEND 150 mg.
The recommended dose of dexamethasone with IVEMEND 150 mg differs from the recommended dose of dexamethasone with IVEMEND 115 mg on Days 3 and 4.
Posology
IVEMEND 150 mg is administered as an infusion over 20-30 minutes on Day 1 only, initiated approximately 30 minutes prior to chemotherapy (see section 6.6). IVEMEND should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in the tables below.
The following regimen is recommended for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.
Highly Emetogenic Chemotherapy Regimen
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Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. Dexamethasone should also be administered in the evenings on Days 3 and 4. The dose of dexamethasone accounts for active substance interactions.
Ondansetron should be administered intravenously 30 minutes prior to chemotherapy treatment on Day 1.
Moderately Emetogenic Chemotherapy Regimen
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Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for active substance interactions.
One 8 mg capsule of ondansetron should be administered 30 to 60 minutes prior to chemotherapy treatment and one 8 mg capsule should be administered 8 hours after first dose on Day 1.
Efficacy data on combination with other corticosteroids and 5-HT3 antagonists are limited. For additional information on the co-administration with corticosteroids, see section 4.5.
Refer to the Summary of Product Characteristics of co-administered antiemetic medicinal products.
Special populations
Elderly (
No dose adjustment is necessary for the elderly (see section 5.2).
Gender
No dose adjustment is necessary based on gender (see section 5.2).
Renal impairment
No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2).
Hepatic impairment
No dose adjustment is necessary for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. IVEMEND should be used with caution in these patients (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of IVEMEND in children and adolescents below the age of 18 years of age has not yet been established. No data are available.
Method of administration
IVEMEND 150 mg should be administered intravenously and should not be given by the intramuscular or subcutaneous route. Intravenous administration occurs preferably through a running intravenous infusion over 20-30 minutes (see section 6.6). Do not administer IVEMEND as a bolus injection or undiluted solution.
4.3 Contraindications
Hypersensitivity to fosaprepitant, aprepitant, or to polysorbate 80 or any of the other excipients.
Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).
4.4 Special Warnings And Precautions For Use
Patients with moderate to severe hepatic impairment
There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. IVEMEND should be used with caution in these patients (see section 5.2).
CYP3A4 interactions
IVEMEND should be used with caution in patients receiving concomitant active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine (see section 4.5). Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity.
Co-administration of fosaprepitant with ergot alkaloid derivatives, which are CYP3A4 substrates, may result in elevated plasma concentrations of these active substances. Therefore, caution is advised due to the potential risk of ergot-related toxicity.
Concomitant administration of fosaprepitant with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the combination could result in reductions of the plasma concentrations of aprepitant (see section 4.5). Concomitant administration of fosaprepitant with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended.
Concomitant administration of fosaprepitant with active substances that inhibit CYP3A4 activity (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors) should be approached cautiously as the combination is expected to result in increased plasma concentrations of aprepitant (see section 4.5).
Co-administration with warfarin (a CYP2C9 substrate)
Co-administration of oral aprepitant with warfarin results in decreased prothrombin time, reported as International Normalised Ratio (INR). In patients on chronic warfarin therapy, the INR should be monitored closely for 2 weeks following the use of fosaprepitant for the prevention of chemotherapy induced nausea and vomiting (see section 4.5).
Co-administration with hormonal contraceptives
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of fosaprepitant. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 2 months following the use of fosaprepitant (see section 4.5).
Hypersensitivity reactions
Isolated reports of immediate hypersensitivity reactions including flushing, erythema, and dyspnea have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who experience hypersensitivity reactions.
Administration and infusion site reactions
IVEMEND should not be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see section 4.2). IVEMEND should not be administered intramuscularly or subcutaneously (see section 5.3). Mild injection site thrombosis has been observed at higher doses (see section 4.9). If signs or symptoms of local irritation occur, the injection or infusion should be terminated and restarted in another vein.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
When administered intravenously fosaprepitant is rapidly converted to aprepitant.
Interactions with other medicinal products following administration of intravenous fosaprepitant are likely to occur with active substances that interact with oral aprepitant. The following information was derived from studies conducted with oral aprepitant and studies conducted with intravenous fosaprepitant co-administered with dexamethasone, midazolam, or diltiazem.
Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4. Fosaprepitant or aprepitant does not seem to interact with the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin. It is anticipated that fosaprepitant would cause less or no greater induction of CYP2C9, CYP3A4 and glucuronidation than that caused by the administration of oral aprepitant. Data are lacking regarding effects on CYP2C8 and CYP2C19.
Effect of fosaprepitant on the pharmacokinetics of other active substances
CYP3A4 inhibition
As a weak inhibitor of CYP3A4, the fosaprepitant 150 mg single dose can cause a transient increase in plasma concentrations of co-administered active substances that are metabolised through CYP3A4. The total exposure of CYP3A4 substrates may increase up to 2-fold on Days 1 and 2 after co-administration with a single 150 mg fosaprepitant dose. Fosaprepitant must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by fosaprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions (see section 4.3). Caution is advised during concomitant administration of fosaprepitant and active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine (see section 4.4).
Corticosteroids
Dexamethasone: The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50 % when co-administered with fosaprepitant 150 mg on Day 1 to achieve exposures of dexamethasone similar to those obtained when given without fosaprepitant 150 mg. Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-24hr of dexamethasone, a CYP3A4 substrate, by 100 % on Day 1 86 % on Day 2 and 18 % on Day 3 when dexamethasone was co-administered as a single 8 mg oral dose on Days 1, 2, and 3.
Chemotherapeutic medicinal products
Interaction studies with fosaprepitant 150 mg and chemotherapeutic medicinal products have not been conducted; however, based on studies with oral aprepitant and docetaxel and vinorelbine, IVEMEND 150 mg is not expected to have a clinically relevant interaction with intravenously administered docetaxel and vinorelbine. An interaction with orally administered chemotherapeutic medicinal products metabolised primarily or in part by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving such medicinal products (see section 4.4).
Immunosuppressants
Following a single 150 mg fosaprepitant dose, a transient moderate increase for two days possibly followed by a mild decrease in exposure of immunosuppressants metabolised by CYP3A4 (e.g. cyclosporine, tacrolimus, everolimus and sirolimus) is expected. Given the short duration of increased exposure, dose reduction of the immunosuppressant based on Therapeutic Dose Monitoring is not recommended on the day of and the day after administration of IVEMEND.
Midazolam
Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0- of midazolam by 77 % on Day 1 and had no effect on Day 4 when midazolam was co-administered as a single oral dose of 2 mg on Days 1 and 4. Fosaprepitant 150 mg is a weak CYP3A4 inhibitor as a single dose on Day 1 with no evidence of inhibition or induction of CYP3A4 observed on Day 4.
The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these medicinal products with IVEMEND.
Diltiazem
Interaction studies with fosaprepitant 150 mg and diltiazem have not been conducted; however, the following study with 100 mg of fosaprepitant should be considered when using IVEMEND 150 mg with diltiazem. In patients with mild to moderate hypertension, infusion of 100 mg of fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.4-fold increase in diltiazem AUC and a small but clinically meaningful decrease in blood pressure, but did not result in a clinically meaningful change in heart rate, or PR interval.
Induction
The fosaprepitant 150 mg single dose did not induce CYP3A4 on Days 1 and 4 in the midazolam interaction study. It is anticipated that IVEMEND would cause less or no greater induction of CYP2C9, CYP3A4, and glucuronidation than that caused by the administration of the 3-day oral aprepitant regimen, for which a transient induction with its maximum effect 6-8 days after first aprepitant dose has been observed. The 3-day oral aprepitant regimen resulted in an about 30-35 % reduction in AUC of CYP2C9 substrates and up to a 64 % decrease in ethinyl estradiol trough concentrations. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is advised when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are known to be metabolised by CYP2C9 are administered with IVEMEND.
Warfarin
In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with and for 2 weeks following the use of IVEMEND for the prevention of chemotherapy induced nausea and vomiting (see section 4.4).
Hormonal contraceptives
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of fosaprepitant. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 2 months following the use of fosaprepitant.
5-HT3 antagonists
Interaction studies with fosaprepitant 150 mg and 5-HT3 antagonists have not been conducted; however, in clinical interaction studies, the oral aprepitant regimen did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Therefore, there is no evidence of interaction with the use of IVEMEND 150 mg and 5-HT3 antagonists.
Effect of other medicinal products on the pharmacokinetics of aprepitant resulting from administration of fosaprepitant 150 mg
Concomitant administration of fosaprepitant with active substances that inhibit CYP3A4 activity (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors) should be approached cautiously, as the combination is expected to result in several-fold increased plasma concentrations of aprepitant (see section 4.4). Ketoconazole increased the terminal half-life of oral aprepitant about 3-fold.
Concomitant administration of fosaprepitant with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the combination could result in reductions of the plasma concentrations of aprepitant that may result in decreased efficacy. Concomitant administration of fosaprepitant with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended. Rifampicin decreased the mean terminal half-life of oral aprepitant by 68 %.
Diltiazem
Interaction studies with fosaprepitant 150 mg and diltiazem have not been conducted; however, the following study with 100 mg of fosaprepitant should be considered when using IVEMEND 150 mg with diltiazem. Infusion of 100 mg fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant AUC. This effect was not considered clinically important.
4.6 Pregnancy And Lactation
Pregnancy
For fosaprepitant and aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicities of fosaprepitant and aprepitant have not been fully characterised, since exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential effects on reproduction of alterations in neurokinin regulation are unknown. IVEMEND should not be used during pregnancy unless clearly necessary.
Breast-feeding
Aprepitant is excreted in the milk of lactating rats after intravenous administration of fosaprepitant as well as after oral administration of aprepitant. It is not known whether aprepitant is excreted in human milk. Therefore, breast-feeding is not recommended during treatment with IVEMEND and oral aprepitant.
Fertility
The potential for effects of fosaprepitant and aprepitant on fertility have not been fully characterised because exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects of IVEMEND on the ability to drive and use machines have been performed. However, when driving or operating machines, it should be taken into account that dizziness and fatigue have been reported after using IVEMEND (see section 4.8).
4.8 Undesirable Effects
Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with fosaprepitant. Prior to approval of fosaprepitant 150 mg, the safety profiles of fosaprepitant and aprepitant were evaluated in approximately 1,100 individuals and 6,500 individuals, respectively. In clinical studies, various formulations of fosaprepitant have been administered to a total of 2,183 individuals including 371 healthy subjects and 1,579 patients with CINV.
Oral aprepitant
Adverse reactions were reported in approximately 19 % of patients treated with the aprepitant regimen compared with approximately 14 % of patients treated with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC). Aprepitant 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. In a combined analysis of 2 clinical studies of patients receiving Moderately Emetogenic Chemotherapy (MEC), clinical adverse reactions were reported in approximately 14 % of patients treated with the aprepitant regimen compared with approximately 15 % of patients treated with standard therapy. Aprepitant 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 at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving HEC were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), ,), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.2 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving MEC was fatigue (1.4 % versus 0.9 %).
The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy or in postmarketing use.
Frequencies are defined as: very common (
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*Nausea and vomiting were efficacy parameters in the first 5-days of post-chemotherapy treatment and were reported as adverse reactions only thereafter.
The adverse reactions profiles in the Multiple-Cycle extension of HEC and MEC studies for up to 6 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.
In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant.
Additional adverse reactions were observed in patients treated with aprepitant for postoperative nausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, constipation,* dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, sub-ileus*, visual acuity reduced, wheezing.
* Reported in patients taking a higher dose of aprepitant.
Fosaprepitant
In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of IVEMEND 150 mg compared to 1,169 patients receiving the 3-day regimen of aprepitant. The safety profile was generally similar to that seen in the aprepitant table above.
The following are clinically important adverse reactions reported in patients receiving fosaprepitant in clinical studies or postmarketing that have not been reported with aprepitant as described above.
Frequencies are defined as: very common (
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4.9 Overdose
In the event of overdose, fosaprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by a medicinal product may not be effective.
Aprepitant cannot be removed by haemodialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04A D12.
Fosaprepitant is the prodrug of aprepitant and when administered intravenously is converted rapidly to aprepitant (see section 5.2). The contribution of fosaprepitant to the overall antiemetic effect has not fully been characterised, but a transient contribution during the initial phase cannot be ruled out. Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1) receptors. The pharmacological effect of fosaprepitant is attributed to aprepitant.
3 -Day regimen of aprepitant
In 2 randomised, double-blind studies encompassing a total of 1,094 patients receiving chemotherapy that included cisplatin 2, aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with a standard regimen (placebo plus ondansetron 32 mg intravenously administered on Day 1 plus dexamethasone 20 mg orally on Day 1 and 8 mg orally twice daily on Days 2 to 4).
Efficacy was based on evaluation of the following composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. The results were evaluated for each individual study and for the 2 studies combined.
A summary of the key study results from the combined analysis is shown in Table 1.
Table 1
Percent of patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase — Cycle 1
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* The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which were included in the primary analysis of odds ratios and logistic models.
† One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses; one patient in the Standard Regimen only had data in the delayed phase and was excluded from the overall and acute phase analyses.
The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1.
Figure 1
Percent of patients receiving Highly Emetogenic Chemotherapy who remain emesis free over time – Cycle 1
Statistically significant differences in efficacy were also observed in each of the 2 individual studies.
In the same 2 clinical studies, 851 patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was maintained during all cycles.
In a randomised, double-blind study in a total of 866 patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1,500 mg/m2; or cyclophosphamide 500-1,500 mg/m2 and doxorubicin (2) or epirubicin (2), aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).
Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1.
A summary of the key study results is shown in Table 2.
Table 2
Percent of patients responding by treatment group and phase —Cycle 1 Moderately Emetogenic Chemotherapy
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