Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Hypersensitivity to the active substance or to polysorbate 80 or any of the other excipients listed in section 6.1.
Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).
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).
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, ergot alkaloid derivatives, 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.
In patients on chronic warfarin therapy, the International Normalised Ratio (INR) should be monitored closely for 14 days following the use of fosaprepitant (see section 4.5).
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of fosaprepitant. Alternative non-hormonal 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).
Immediate hypersensitivity reactions including flushing, erythema, dyspnoea, and anaphylaxis/anaphylactic shock have occurred during or soon after 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.
Infusion site reactions (ISRs) have been reported with the use of IVEMEND (see section 4.8). 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. Mild injection site thrombosis has been observed at higher doses without concomitant vesicant chemotherapy.
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). If signs or symptoms of local irritation occur, the injection or infusion should be terminated and restarted in another vein.
When administered intravenously fosaprepitant is rapidly converted to aprepitant.
Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4. Fosaprepitant 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.
Interactions with other medicinal products following administration of intravenous fosaprepitant are likely to occur with active substances that interact with oral aprepitant. The potential for interactions with multi-day fosaprepitant regimens are anticipated to be no greater than those for oral aprepitant regimens. Therefore, the recommendations for use of IVEMEND with other medicinal products in paediatric patients are based upon adult data from fosaprepitant and aprepitant studies. When using combined IVEMEND and EMEND regimens, please refer to the Summary of Product Characteristics (SmPC) section 4.5 for EMEND capsules or EMEND for oral suspension.
The following information was derived from studies conducted with oral aprepitant and studies conducted with intravenous single-dose fosaprepitant co-administered with dexamethasone, midazolam, or diltiazem.
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).
Dexamethasone: The oral dexamethasone dose should be reduced by approximately 50% when co-administered with fosaprepitant (see section 4.2). 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.
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 partly by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving medicinal products metabolized primarily or partly by CYP3A4 (see section 4.4). Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration.
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.
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.
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.
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.
In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with and for 14 days following the use of IVEMEND for the prevention of chemotherapy induced nausea and vomiting (see section 4.4).
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of fosaprepitant. Alternative non-hormonal back-up methods of contraception should be used during treatment with fosaprepitant and for 2 months following the use of fosaprepitant.
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.
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%.
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.
Interaction studies have only been performed in adults.
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of fosaprepitant. Alternative non-hormonal back-up methods of contraception should be used during treatment with fosaprepitant and for 2 months following the last dose of fosaprepitant (see sections 4.4 and 4.5).
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.
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.
The potential for effects of fosaprepitant and aprepitant on fertility has 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).
IVEMEND may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of IVEMEND (see section 4.8).
In clinical studies, various formulations of fosaprepitant have been administered to a total of 2,687 adults including 371 healthy subjects and 2,084 patients, and 199 children and adolescents with chemotherapy induced nausea and vomiting (CINV). Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with fosaprepitant. The safety profile of aprepitant was evaluated in approximately 6,500 adults and 184 children and adolescents.
The most common adverse reactions reported at a greater incidence in adults 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 (2.0% 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 most common adverse reactions reported at a greater incidence in paediatric patients treated with the aprepitant regimen than with the control regimen while receiving emetogenic cancer chemotherapy were hiccups (3.3% versus 0.0%) and flushing (1.1% versus 0.0%).
The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with oral aprepitant than with standard therapy in adults or paediatric patients or in postmarketing use.
The frequency categories given in the table are based on the studies in adults; the observed frequencies in the paediatric studies were similar or lower, unless shown in the table. Some less common ADRs in the adult population were not observed in the paediatric studies.
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).
Table 5. Tabulated list of adverse reactions – aprepitant:
rare: candidiasis, staphylococcal infection
uncommon: febrile neutropenia, anaemia
not known: hypersensitivity reactions including anaphylactic reactions
common: decreased appetite
rare: polydipsia
uncommon: anxiety
rare: disorientation, euphoric mood
common: headache
uncommon: dizziness, somnolence
rare: cognitive disorder, lethargy, dysgeusia
rare: conjunctivitis
rare: tinnitus
uncommon: palpitations
rare: bradycardia, cardiovascular disorder
uncommon: hot flush/flushing
common: hiccups
rare: oropharyngeal pain, sneezing, cough, postnasal drip, throat irritation
common: constipation, dyspepsia
uncommon: eructation, nausea*, vomiting*, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence
rare: duodenal ulcer perforation, stomatitis, abdominal distension, faeces hard, neutropenic colitis
uncommon: rash, acne
rare: photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysis
not known: pruritus, urticaria not known
rare: muscular weakness, muscle spasms
uncommon: dysuria
rare: pollakisuria
common: fatigue
uncommon: asthaenia, malaise
rare: oedema, chest discomfort, gait disturbance
common: ALT increased
uncommon: AST increased, blood alkaline phosphatase increased
rare: red blood cells urine positive, blood sodium decreased, weight decreased, neutrophil count decreased, glucose urine present, urine output increased
The adverse reactions profiles in the Multiple-Cycle extension of HEC and MEC studies in adults 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 adult 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 adult 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 adult 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. Additionally, in a placebo-controlled clinical trial in adult patients receiving MEC, safety was evaluated for 504 patients receiving a single dose of IVEMEND 150 mg compared to 497 patients receiving the control regimen.
In a pooled analysis of 3 active-controlled clinical studies in paediatric patients (aged 6 months to 17 years) receiving either HEC or MEC and a single dose of IVEMEND at or above the recommended 1-day regimen dose, safety was evaluated for 139 patients receiving the 1-day regimen of IVEMEND. In the same analysis, safety was evaluated for 199 patients receiving either HEC or MEC and a single dose of IVEMEND at or above the recommended 3-day regimen of IVEMEND. Safety data following the administration of the 3-day IV/oral/oral regimen were also included.
No data are available following the administration of a 3-day IV fosaprepitant regimen in paediatric patients. The safety profile of the 3-day IV fosaprepitant regimen in paediatric patients is expected to be similar to that of the 1-day fosaprepitant regimen as the low daily trough levels do not significantly increase the exposures on subsequent days.
The safety profile of fosaprepitant in adult and paediatric patients was generally similar to that observed with aprepitant.
The following are adverse reactions reported in adult patients receiving fosaprepitant in clinical studies or postmarketing that have not been reported with aprepitant as described above. The frequency categories in the table are based on studies in adults; the observed frequencies in the paediatric studies were similar or lower. Some adverse reactions that are commonly observed in the adult population were not observed in the paediatric studies. Infusion site reactions (ISRs) have been reported with the use of IVEMEND (see section 4.4).
Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).
Table 6. Tabulated list of adverse reactions – fosaprepitant:
uncommon: flushing, thrombophlebitis (predominantly, infusion-site thrombophlebitis)
uncommon: erythema
uncommon: infusion site erythema, infusion site pain, infusion site pruritus
rare: infusion site induration
not known: immediate hypersensitivity reactions including flushing, erythema, dyspnoea, anaphylactic reactions/anaphylactic shock
uncommon: blood pressure increased
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
IVEMEND is incompatible with any solutions containing divalent cations (e.g. Ca2+, Mg2+), including Hartman’s and lactated Ringer’s solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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