Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Hypersensitivity to the active substance or to any of the 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. EMEND should be used with caution in these patients (see section 5.2).
EMEND should be used with caution in patients receiving concomitant orally administered 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 during treatment with EMEND and for 14 days following each 3-day course of EMEND (see section 4.5).
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see section 4.5).
EMEND capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
Aprepitant (125 mg/80 mg) is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment with EMEND, CYP3A4 is inhibited. After the end of treatment, EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin.
As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) can increase plasma concentrations of co-administered active substances that are metabolised through CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase up to approximately 3-fold during the 3-day treatment with EMEND; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. EMEND must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Caution is advised during concomitant administration of EMEND and orally administered 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 usual oral dexamethasone dose should be reduced by approximately 50% when co-administered with EMEND 125 mg/80 mg regimen. The dose of dexamethasone in chemotherapy induced nausea and vomiting clinical trials was chosen to account for active substance interactions (see section 4.2). EMEND, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone co-administered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5.
Methylprednisolone: The usual intravenously administered methylprednisolone dose should be reduced approximately 25%, and the usual oral methylprednisolone dose should be reduced approximately 50% when co-administered with EMEND 125 mg/80 mg regimen. EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was co-administered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.
During continuous treatment with methylprednisolone, the AUC of methylprednisolone may decrease at later time points within 2 weeks following initiation of the EMEND dose, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone.
In pharmacokinetic studies, EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, did not influence the pharmacokinetics of docetaxel administered intravenously on Day 1 or vinorelbine administered intravenously on Day 1 or Day 8. Because the effect of EMEND on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of EMEND on the pharmacokinetics of intravenously administered CYP3A4 substrates, 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.
During the 3-day CINV regimen, a transient moderate increase 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 the 3-day regimen and the time-dependent limited changes in exposure, dose reduction of the immunosuppressant is not recommended during the 3 days of co-administration with EMEND.
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 EMEND (125 mg/80 mg).
EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of 2 mg midazolam was co-administered on Days 1 and 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 to 5.
In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and 2 mg midazolam was given intravenously prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam 25% on Day 4 and decreased the AUC of midazolam 19% on Day 8 and 4% on Day 15. These effects were not considered clinically important.
In a third study with intravenous and oral administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, together with ondansetron 32 mg Day 1, dexamethasone 12 mg Day 1 and 8 mg Days 2-4. This combination (i.e. EMEND, ondansetron and dexamethasone) decreased the AUC of oral midazolam 16% on Day 6, 9% on Day 8, 7% on Day 15 and 17% on Day 22. These effects were not considered clinically important.
An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous 2 mg midazolam was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not considered clinically important.
As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes within two weeks following initiation and treatment. This effect may become apparent only after the end of a 3-day treatment with EMEND. For CYP2C9 and CYP3A4 substrates, the induction is transient with a maximum effect reached 3-5 days after end of the EMEND 3-day treatment. The effect is maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after end of EMEND treatment. Mild induction of glucuronidation is also seen with 80 mg oral aprepitant given for 7 days. 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 during this time period.
In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with EMEND and for 2 weeks following each 3-day course of EMEND for chemotherapy induced nausea and vomiting (see section 4.4). When a single 125 mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilised on chronic warfarin therapy, there was no effect of EMEND on the plasma AUC of R(+) or S() warfarin determined on Day 3; however, there was a 34% decrease in S() warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in INR 5 days after completion of treatment with EMEND.
EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) 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 EMEND and on Days 4, 8, and 15.
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND.
In a clinical study, single doses of an oral contraceptive containing ethinyl estradiol and norethindrone were administered on Days 1 through 21 with EMEND, given as a regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg intravenously on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. During days 9 through 21 in this study, there was as much as a 64% decrease in ethinyl estradiol trough concentrations and as much as a 60% decrease in norethindrone trough concentrations.
In clinical interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).
Concomitant administration of EMEND 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 several-fold in increased plasma concentrations of aprepitant (see section 4.4).
Concomitant administration of EMEND with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the combination results in reductions of the plasma concentrations of aprepitant that may result in decreased efficacy of EMEND. Concomitant administration of EMEND with herbal preparations containing St. John’s Wort (Hypericum perforatum) is not recommended.
When a single 125 mg dose of 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.
When a single 375 mg dose of aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased 91% and the mean terminal half-life decreased 68%.
Interaction studies have only been performed in adults.
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal back-up methods of contraception should be used during treatment with EMEND and for 2 months following the last dose of EMEND (see sections 4.4 and 4.5).
For aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicity of aprepitant has not been fully characterised, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg dose 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. EMEND should not be used during pregnancy unless clearly necessary.
Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with EMEND.
The potential for effects of 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).
EMEND may have minor influence on the ability to drive, cycle and use machines. Dizziness and fatigue may occur following administration of EMEND (see section 4.8).
The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials.
The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (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 Moderately Emetogenic Chemotherapy (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 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).
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
rare: muscular weakness, muscle spasms
uncommon: dysuria
rare: pollakiuria
† 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 adults 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 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.
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.
Not applicable.
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