Prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and paediatric patients aged 6 months and older.

Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusionis given as part of a combination therapy (see section 4.2).

Posology

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 SPC 150mg/Vial for Injection Powder for solution for infusion should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in the tables below.

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

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.

Moderately Emetogenic Chemotherapy Regimen

Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for active substance interactions.

Paediatric population

Paediatric patients aged 6 months and older, and not less than 6 kg

The recommended dose regimen of Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusion, to be administered with a 5-HT3 antagonist, with or without a corticosteroid, for the prevention of nausea and vomiting associated with administration of single or multi-day chemotherapy regimens of Highly Emetogenic Chemotherapy (HEC) or Moderately Emetogenic Chemotherapy (MEC), is shown in Table 1. Single day chemotherapy regimens include those regimens in which HEC or MEC is administered for a single day only. Multi-day chemotherapy regimens include chemotherapy regimens in which HEC or MEC is administered for 2 or more days.

An alternative dose regimen that may be used with single-day chemotherapy regimens is shown in Table 2.

Dosing for Single or Multi-Day Chemotherapy Regimens For paediatric patients receiving single or multi-day regimens of HEC or MEC, administer Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusionas an intravenous infusion through a central venous catheter on Days 1, 2, and 3. Fosaprepitant dimeglumine capsules or Fosaprepitant dimeglumine for oral suspension may be used on Days 2 and 3 instead of Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusion, as shown in Table 1. See the Summary of Product Characteristics (SmPC) for Fosaprepitant dimeglumine capsules or Fosaprepitant dimeglumine for oral suspension for appropriate dosing instructions.

Table 1

Recommended dosing for the prevention of nausea and vomiting associated with single or multi-day regimens of HEC or MEC

* For paediatric patients 12 years and older, administer Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusionintravenously over 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy. For paediatric patients less than 12 years, administer Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusionintravenously over 60 minutes, completing the infusion approximately 30 minutes prior to chemotherapy.

** Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. Alternative Dosing for Single Day Chemotherapy Regimens

For paediatric patients receiving single day HEC or MEC, Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusionmay be administered as an intravenous infusion through a central venous catheter on Day 1.

Table 2 Alternative dosing for the prevention of nausea and vomiting associated with single day regimens of HEC or MEC

* For paediatric patients 12 years and older, administer Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusion intravenously over 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy. For paediatric patients less than 12 years, administer Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusion intravenously over 60 minutes, completing the infusion approximately 30 minutes prior to chemotherapy.

** Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The safety and efficacy of Fosaprepitant SPC 150mg/Vial for Injection Powder for solution for infusion in infants below 6 months of age have not been established. No data are available.

General

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 Summary of Product Characteristics of co-administered 5-HT3 antagonist medicinal products.

Special populations

Older people (≥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 hemodialysis (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. Fosaprepitant for Injection 150 mg/ Vial for Injection should be used with caution in these patients (see sections 4.4 and 5.2).

Method of administration

Fosaprepitant SPC 150mg/Vial for Injection 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.

Intravenous administration in paediatric patients aged 6 months and older is recommended through a central venous catheter and should be administered over 30 minutes in patients aged 12 years and older or over 60 minutes in patients less than 12 years of age (See section 6.6). Do not administer Fosaprepitant SPC 150mg/Vial for Injection a bolus injection or undiluted solution.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

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. Fosaprepitant SPC 150mg/Vial for Injection should be used with caution in these patients (see section 5.2).

CYP3A4 interactions

Fosaprepitant SPC 150mg/Vial for Injection 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.

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 2 months following the use of fosaprepitant (see section 4.5).

Hypersensitivity reactions

Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnoea and anaphylaxis/anaphylactic shock 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

Fosaprepitant SPC 150mg/Vial for Injection 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 SPC 150mg/Vial for Injection should not be administered intramuscularly or subcutaneously (see section 5.3). 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 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 Fosaprepitant SPC 150mg/Vial for Injection with other medicinal products in paediatric patients are based upon adult data from fosaprepitant and aprepitant studies. When using combined Fosaprepitant SPC 150mg/Vial for Injection and Fosaprepitant dimeglumine regimens, please refer to the Summary of Product Characteristics (SmPC) section 4.5 for Fosaprepitant dimeglumine capsules or Fosaprepitant dimeglumine 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.

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 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.

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, Fosaprepitant for Injection 150 mg/ Vial 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 metabolised 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. 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 Fosaprepitant SPC 150mg/Vial for Injection.

Midazolam

Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC 0-∞ 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 SPC 150mg/Vial for Injection

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 Fosaprepitant SPC 150mg/Vial for Injection 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 SPC 150mg/Vial for Injection 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 Dimeglumine SPC 150mg/Vial Powder for solution for infusion.

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 SPC 150mg/Vial for Injection 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 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 Fosaprepitant SPC 150mg/Vial Powder for solution for infusion 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 Fosaprepitant SPC 150mg/Vial for Injection 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.

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 2 months following the last dose of fosaprepitant (see sections 4.4 and 4.5).

Pregnancy

For fosaprepitant and prepatent no clinical data on exposed pregnancies are available. The potential for reproductive toxicities of fosaprepitant and prepatent have been not fully characterized, 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. Fosaprepitant SPC 150mg/Vial for Injection 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 Fosaprepitant SPC 150mg/Vial for Injection

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 (see section 5.3).

Fosaprepitant SPC 150mg/Vial for Injection may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of Fosaprepitant SPC 150mg/Vial for Injection (see section 4.8).

Summary of the safety profile

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.

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 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 %).

Tabulated list of adverse reactions - aprepitant

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 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).

*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 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, tomach 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 Fosaprepitant SPC 150mg/Vial for Injection compared to 1,169 patients receiving the 3-day regimen of aprepitant. Additionally, in a placebo- controlled clinical trial in patients receiving MEC, safety was evaluated for 504 patients receiving a single dose of Fosaprepitant SPC 150mg/Vial for Injection 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 Fosaprepitant SPC 150mg/Vial for Injection at or above the recommended 1-day regimen dose, safety was evaluated for 139 patients receiving the 1-day regimen of Fosaprepitant SPC 150mg/Vial for Injection In the same analysis, safety was evaluated for 199 patients receiving either HEC or MEC and a single dose of Fosaprepitant SPC 150mg/Vial for Injection at or above the recommended 3-day regimen of Fosaprepitant SPC 150mg/Vial for Injection. 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 through levels do not significantly increase the exposures on subsequent days.

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 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.

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).

Reporting of suspected adverse reactions

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.

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

Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12.

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

1-Day Regimen of Fosaprepitant in Adults

Highly Emetogenic Chemotherapy (HEC)

In a randomized, parallel, double-blind, active-controlled study, Fosaprepitant SPC 150mg/Vial for Injection (N=1,147) was compared with a 3-day aprepitant regimen (N=1,175) in adult patients receiving a HEC regimen that included cisplatin (≥70 mg/m2). The fosaprepitant regimen consisted of fosaprepitant 150 mg on Day 1 in combination with ondansetron 32 mg IV on Day 1 and dexamethasone 12 mg on Day 1, 8 mg on Day 2, and 8 mg twice daily on Days 3 and 4. The aprepitant regimen consisted of aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 and 3 in combination with ondansetron 32 mg IV on Day 1 and dexamethasone 12 mg on Day 1 and 8 mg daily on Days 2 through 4. Fosaprepitant placebo, aprepitant placebo, and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding (see section 4.2). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See the product information for the selected 5-HT3 antagonist for appropriate dosing information.

Efficacy was based on evaluation of the following composite measures: complete response in both the overall and delayed phases and no vomiting in the overall phase. Fosaprepitant SPC 150mg/Vial for Injection on was shown to be noninferior to that of the 3day regimen of aprepitant. A summary of the primary and secondary endpoints is shown in Table 1.

*Primary end point is bolded.

**N: Number of patients included in the primary analysis of complete response.

†Difference and confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for Gender.

‡Complete response = no vomiting and no use of rescue therapy.

§Overall = 0 to 120 hours postinitiation of cisplatin chemotherapy.

§§Delayed phase = 25 to 120 hours postinitiation of cisplatin chemotherapy.

Moderately Emetogenic Chemotherapy (MEC)

In a randomized, parallel, double-blind, placebo-controlled study, Fosaprepitant SPC 150mg/Vial for Injection (N=502) in combination with ondansetron and dexamethasone was compared with ondansetron and dexamethasone alone (control regimen) (N=498) in adult patients receiving a moderately emetogenic chemotherapy regimen. The fosaprepitant regimen consisted of fosaprepitant 150 mg on Day 1 in combination with oral ondansetron 8 mg for 2 doses and oral dexamethasone 12 mg. On Days 2 and 3, patients in the fosaprepitant group received placebo for ondansetron every 12 hours. The control regimen onsisted of fosaprepitant placebo 150 mg IV on Day 1 in combination with oral ondansetron 8 mg for 2 doses.

and oral dexamethasone 20 mg. On Days 2 and 3, patients in the control group received 8 mg oral ondansetron every 12 hours. Fosaprepitant placebo and dexamethasone placebo (on Day 1) were used to maintain blinding.

The efficacy of fosaprepitant was evaluated based on the primary and secondary endpoints listed in Table 2 and was shown to be superior to the control regimen with regard to complete response in the delayed and overall phases.

*Primary endpoint is bolded.

**N: Number of adult patients included in the intention to treat population.

† Complete response = no vomiting and no use of rescue therapy.

‡ Delayed phase = 25 to 120 hours post-initiation of chemotherapy.

§Overall = 0 to 120 hours post-initiation of chemotherapy.

§§Acute= 0 to 24 hours post-initiation of chemotherapy.

The estimated time to first emesis is depicted by the Kaplan Meier plot in Figure 1. Figure 1

Percent of patients receiving Moderately Emetogenic Chemotherapy who remain emesis free over time

Paediatric population

In 3 active-controlled, open-label clinical studies, paediatric patients aged 6 months to 17 years received either highly or moderately emetogenic chemotherapy and a single dose of fosaprepitant at or above the recommended 1-day regimen dose (139 patients) or 3-day regimen (199 patients), in combination with ondansetron with or without dexamethasone.

Paediatric Patients Receiving 1-Day Fosaprepitant Regimen

The efficacy of the 1-day fosaprepitant regimen in paediatric patients was extrapolated from that demonstrated in adults receiving the 1-day fosaprepitant regimen as described in the 1-Day Regimen of Fosaprepitant in Adults subsection.

The efficacy of a 1-day fosaprepitant regimen in paediatric patients is expected to be similar to that of the 1-day adult fosaprepitant regimen.

Paediatric Patients Receiving 3-Day Fosaprepitant Regimen

The efficacy of the 3-day fosaprepitant regimen in paediatric patients was based on that demonstrated in paediatric mpatients receiving the 3-day oral aprepitant regimen.

The efficacy of a 3-day fosaprepitant regimen in paediatric patients is expected to be similar to that of the 3-day oral aprepitant regimen. See the summary of product characteristics for Fosaprepitant capsules and Fosaprepitant powder for oral suspension for complete clinical information regarding studies performed with oral aprepitant.

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant. Plasma concentrations of fosaprepitant are below quantifiable levels within 30 minutes of the completion of infusion.

Aprepitant after fosaprepitant administration

Following a single intravenous 150-mg dose of fosaprepitant administered as a 20-minute infusion to healthy volunteers, the mean AUC0-∞ of aprepitant was 35.0 µg•hr/ml and the mean maximal aprepitant concentration was 4.01 µg/ml.

Distribution

Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean volume of distribution at steady state (Vdss) of aprepitant estimated from a single 150 mg intravenous dose of fosaprepitant is approximately 82 l in humans.

Biotransformation

Fosaprepitant was rapidly converted to aprepitant in in vitro incubations with liver preparations from humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9 preparations from other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple tissues. In humans, fosaprepitant administered intravenously was rapidly converted to aprepitant within 30 minutes following the end of infusion.

Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19 % of the radioactivity in plasma over 72 hours following a single intravenous administration 100 mg dose of [14C]- fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19.

All metabolites observed in urine, faeces and plasma following an intravenous 100 mg [14C]- fosaprepitant dose were also observed following an oral dose of [14C]-aprepitant. Upon conversion of 245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of meglumine are liberated.

Elimination

Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [14C]- fosaprepitant to healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces.

The pharmacokinetics of aprepitant is non-linear across the clinical dose range. The terminal half-life of aprepitant following a 150 mg intravenous dose of fosaprepitant was approximately 11 hours. The geometric mean plasma clearance of aprepitant following a 150 mg intravenous dose of fosaprepitant was approximately 73 ml/min.

Pharmacokinetics in special populations

Hepatic impairment: Fosaprepitant is metabolized in various extrahepatic tissues; therefore, hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant. Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is necessary for patients with mild hepatic impairment. Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) on aprepitant pharmacokinetics cannot be drawn from available data. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment: A single 240 mg dose of oral aprepitant was administered to patients with severe renal impairment (CrCl< 30 ml/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis.

In patients with severe renal impairment, the AUC 0-∞of total aprepitant (unbound and protein bound) decreased by 21 % and Cmax decreased by 32 %, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC0-∞ of total aprepitant decreased by 42 % and Cmax decreased by 32 %. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound aprepitant was not significantly affected in patients with renal impairment compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2 % of the dose was recovered in the dialysate.

No dose adjustment is necessary for patients with renal impairment or for patients with ESRD undergoing haemodialysis.

Paediatric population: As part of a 3-day IV/IV/IV regimen, simulated median AUC0-24hr of aprepitant with median peak plasma concentration (Cmax) on Day 1 and the median concentrations at the end of Day 1, Day 2 and Day 3 in paediatric patients (6 months to 17 years old) are shown in Table 5.

Table 5:

Pharmacokinetic parameters of aprepitant for 3-day IV fosaprepitant regimen in paediatric patients

In the 1-day IV fosaprepitant setting, simulated median AUC0-24hr of aprepitant with median peak plasma concentration (Cmax) on Day 1 and the median concentrations at the end of Day 1, Day 2 and Day 3 in paediatric patients (6 months to < 12 years old) and observed mean AUC0-24hr with median peak plasma concentration (Cmax) on Day 1 and mean concentrations at the end of Day 1, Day 2 and Day 3 in paediatric patients (12 to 17 years old) are shown in Table 6

Table 6: Pharmacokinetic parameters of aprepitant for 1-day IV fosaprepitant regimen in paediatric patients

*NR = Not Reported

A population pharmacokinetic analysis of aprepitant in paediatric patients (aged 6 months through 17 years) suggests that gender and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.

Relationship between concentration and effect

Positron emission tomography (PET) imaging studies, using a highly specific NK1-receptor tracer, in healthy young men administered a single intravenous dose of 150 mg fosaprepitant (N=8) demonstrated brain NK1 receptor occupancy of ≥100 % at Tmax, and 24 hours, ≥97 % at 48 hours, and between 41 % and 75 % at 120 hours, following dosing. Occupancy of brain NK1 receptors, in this study, correlate well with aprepitant plasma concentrations.

Pre-clinical data obtained with intravenous administration of fosaprepitant and oral administration of aprepitant reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity (including in vitro tests), and toxicity to reproduction and development.

Carcinogenic potential in rodents was only investigated with orally administered aprepitant. However, it should be noted that the value of the toxicity studies carried out with rodents, rabbits and monkeys, including the reproduction toxicity studies, are limited since systemic exposures to fosaprepitant and aprepitant were only similar or even lower than therapeutic exposure in adult humans. In the performed safety pharmacology and repeated dose toxicity studies with dogs, fosaprepitant Cmax and aprepitant AUC values were up to 3 times and 40 times, respectively, higher than clinical values.

In a toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4 mg/kg/day. In a juvenile toxicity study in rats treated with aprepitant from postnatal day 10 to day 63, earlier vaginal opening in females from 250 mg/kg b.i.d. And delayed preputial separation in males from 10 mg/kg b.i.d was seen. There were no treatment-related effects on mating, fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. There were no margins to clinically relevant exposure of aprepitant. For short term treatment, these findings are considered unlikely to be clinically relevant.

In laboratory animals, fosaprepitant in non-commercial formulations caused vascular toxicity and hemolysis at concentrations below 1 mg/ml and higher, dependent on the formulation. In human washed blood cells also evidence of hemolysis was found with non-commercial formulations at fosaprepitant concentrations of 2.3 mg/ml and higher, although tests in human whole blood were negative. No hemolysis was found with the commercial formulation up to a fosaprepitant concentration of 1 mg/ml in human whole blood and washed human erythrocytes.

In rabbits, fosaprepitant caused initial transient local acute inflammation following paravenous, subcutaneous and intramuscular administration. At the end of the follow-up period (post-dose day 8), up to slight local subacute inflammation was noted following paravenous and intramuscular administration and additional up to moderate focal muscle degeneration/necrosis with muscle regeneration following intramuscular administration.

Disodium edetate, Polysorbate 80, Lactose anhydrous, Sodium hydroxide Pellets, Hydrochloric acid and Water for Injection.

Fosaprepitant SPC 150mg/Vial for Injection 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.

Store in a refrigerator (2°C - 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

10 mL Type-1 clear tubular glass vial with 13 mm neck containing Fosaprepitant Dimeglumine for

Injection 150 mg/ vial in lyophilized cake or powder form is stoppered with 13 mm Bromo butyl

double slotted rubber stopper sealed with 13 mm aluminium flip off seal with Green color plastic disc.

Pack sizes: 1 vial.

Fosaprepitant SPC 150mg/Vial for Injection must be reconstituted and then diluted prior to administration.

Preparation of Fosaprepitant SPC 150mg/Vial for Injection for intravenous administration:

1.  Inject 5 ml sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial. Assure that sodium chloride 9 mg/ml (0.9 %) solution for injection is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial.

2.  Prepare an infusion bag filled with 145 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection (for example, by removing 105 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection from a 250 ml sodium chloride 9 mg/ml (0.9 %) solution for injection infusion bag)..

3.  Withdraw the entire volume from the vial and transfer it into an infusion bag containing 145 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection to yield a total volume of 150 ml. Gently invert the bag 2-3 times.

4.  Determine the volume to be administered from this prepared infusion bag, based on the recommended dose (see section 4.2).

Adults

The entire volume of the prepared infusion bag (150 ml) should be administered. Paediatrics

In patients 12 years and older, the volume to be administered is calculated as follows:

·        Volume to administer (ml) equals the recommended dose (mg)

In patients 6 months to less than 12 years, the volume to be administered is calculated as follows:

·        Volume to administer (ml) = recommended dose (mg/kg) x weight (kg) o Note: Do not exceed maximum doses (see section 4.2).

5.  If necessary, for volumes less than 150 ml, the calculated volume can be transferred to an appropriate size bag or syringe prior to administration by infusion.

The appearance of the reconstituted solution is the same as the appearance of the diluent.

The reconstituted and diluted medicinal product should be inspected visually for particulate matter and discoloration before administration.

Discard any remaining solution and waste material. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

The medicinal product must not be reconstituted or mixed with solutions for which physical and chemical compatibility has not been established (see section 6.2).