Emetend 150 Mg Solution

EMETEND 150 mg, in combination with other anti-emetic medicines, is indicated for the prevention of acute (0 to 24 hours) and delayed (> 24 to 120 hours) nausea and vomiting associated with initial and repeat courses of:

• Highly emetogenic cancer chemotherapy (see section 4.2)
• Moderately emetogenic cancer chemotherapy (see section 4.2)

Posology

EMETEND 150 mg for intravenous administration is a lyophilised prodrug of aprepitant. The recommended dose is 150 mg administered as an infusion over 20-30 minutes on Day 1, initiated approximately 30 minutes prior to chemotherapy (see section 6.6). Fosaprepitant should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in the tables below. The professional information for the co-administered 5-HT3 antagonist must be consulted prior to initiation of treatment with EMETEND 150 mg.

The following regimens recommended for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy.

Table 1: Recommended dosing for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy

Table 2: Recommended dosing for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy

** Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for interactions. Efficacy data in 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 professional information of co-administered 5-HT3 antagonist medicinal products.

Special populations

Elderly (u2265 65 years)

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 to moderate hepatic impairment (Child-Pugh score 5 to 9). There is no clinical data in patients with severe hepatic impairment (Child-Pugh > 9). Fosaprepitant should be used with caution in these patients (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of EMETEND 150 mg in children and adolescents below 18 years of age has not yet been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

EMETEND 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 EMETEND 150 mg as a bolus injection or undiluted solution. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

• Hypersensitivity to aprepitant or any of the other excipients listed in section 6.1.
• Co-administration with pimozide or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these medicines potentially causing serious or life-threatening reactions. (see section 4.5).
• Pregnancy and lactation (see section 4.6)
• Safety and efficacy of EMETEND 150 mg in paediatric patients has not been established.

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. EMETEND 150 mg should be used with caution in these patients (see section 5.2).

CYP3A4 interactions

EMETEND 150 mg 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 ciclosporin, 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.

Concomitant administration of EMETEND 150 mg with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. The effect of oral aprepitant on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of oral aprepitant on the pharmacokinetics of intravenously administered CYP3A4 substrates.

Co-administration with warfarin (a CYP2C9 substrate)

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).

Co-administration with hormonal contraceptives

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 one month following the use of fosaprepitant (see section 4.5).

Hypersensitivity reactions

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.

Administration and infusion site reactions

Fosaprepitant should not be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see section 4.2). Fosaprepitant should not be administered intramuscularly or subcutaneously. Infusion site reactions (ISRs) have been reported with the use of EMETEND 150 mg (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. 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 following information was derived from studies conducted with oral aprepitant and studies conducted with intravenous fosaprepitant co-administered with dexamethasone, midazolam, or diltiazem.

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 ciclosporin, 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.

Methylprednisolone: Oral aprepitant, 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.

Paroxetine

Co-administration 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.

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, EMETEND 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, cyclophosphamide, 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 coadministration.

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. ciclosporin, 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 fosaprepitant.

Midazolam

Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-u221e 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 fosaprepitant.

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 EMETEND 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 fosaprepitant 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 fosaprepitant.

Warfarin

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 fosaprepitant 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 non-hormonal back-up methods of contraception should be used during treatment with fosaprepitant and for one month 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 fosaprepitant 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, phenobarbitone) 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. Johnu2019s Wort (Hypericum perforatum) is not recommended. Rifampicin decreased the mean terminal half-life of oral aprepitant by 68 %.

Paediatric population

Interaction studies have only been performed in adults.

Contraception in males and females

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 one month following the last dose of fosaprepitant (see sections 4.4 and 4.5).

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. EMETEND 150 mg should not be used during pregnancy.

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 EMETEND 150 mg.

Fertility

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.

EMETEND 150 mg may have an influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of EMETEND 150 mg (see section 4.8).

Summary of the safety profile

Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with fosaprepitant.

Oral aprepitant

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 %).

Table 3: Tabulated list of adverse reactions - aprepitant

* Nausea and vomiting were efficacy parameters in the first 5-days of post-chemotherapy treatment and were reported as adverse reactions only thereafter.

Description of selected adverse reactions

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. 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

The safety profile was generally similar to that seen in the aprepitant table above.

Tabulated list of adverse reactions - fosaprepitant

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:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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.