Fopitant

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT FOPITANT (FOPITANT)

Composition:

Active substance: fosaprepitant;

1 vial contains fosaprepitant dimeglumine equivalent to 150 mg of fosaprepitant;

Excipients: lactose monohydrate, disodium edetate, polysorbate 80, sodium hydroxide, hydrochloric acid.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: lyophilized solid or powder, white to almost white.

Pharmacotherapeutic group.

Antiemetics and drugs used to treat nausea.

ATC code A04AD12.

Pharmacological Properties

Pharmacodynamics

Fosaprepitant is a prodrug of aprepitant which, after intravenous administration, is rapidly converted to aprepitant (see section "Pharmacokinetics"). The contribution of fosaprepitant to the overall antiemetic effect has not been fully determined, but a transient contribution during the initial phase cannot be excluded. Aprepitant is a highly selective antagonist of human substance P neurokinin-1 (NK1) receptors. The pharmacological activity of fosaprepitant is mediated by aprepitant.

Results from randomized, parallel-group, double-blind, active-controlled studies in adult patients receiving highly or moderately emetogenic chemotherapy demonstrated that a single 150 mg intravenous dose of fosaprepitant (as a lyophilized powder for solution for infusion) was at least as effective as a 3-day oral regimen of aprepitant (in capsules). Administration of 150 mg fosaprepitant corresponds to the 3-day aprepitant dosing regimen.

Three open-label, active-controlled clinical trials were conducted in children and adolescents aged 6 months to 17 years who received highly or moderately emetogenic chemotherapy and fosaprepitant at the recommended or higher dose, administered either on a single-day regimen (139 patients) or a 3-day regimen (199 patients), in combination with ondansetron with or without dexamethasone.

Children and adolescents receiving fosaprepitant on a single-day regimen

The efficacy of fosaprepitant administered on a single-day regimen in children and adolescents was extrapolated from data in adults who received fosaprepitant on a single-day regimen, as demonstrated in a prior adult study using a single-day fosaprepitant regimen.

The efficacy of fosaprepitant administered on a single-day regimen in children and adolescents is expected to be similar to that observed with fosaprepitant in adults.

Children and adolescents receiving fosaprepitant on a 3-day regimen

The efficacy of fosaprepitant administered on a 3-day regimen in children and adolescents was based on efficacy demonstrated in children and adolescents receiving oral aprepitant on a 3-day regimen.

The efficacy of fosaprepitant administered on a 3-day regimen in children and adolescents is expected to be similar to that of aprepitant administered on a 3-day oral regimen.

Pharmacokinetics

Plasma concentrations of fosaprepitant are below quantifiable levels within 30 minutes after completion of infusion.

Aprepitant after administration of fosaprepitant

After a single 20-minute intravenous infusion of 150 mg fosaprepitant in healthy volunteers, the mean AUC_0–∞ of aprepitant was 35.0 µg•h/mL, and the mean maximum concentration (C_max) of aprepitant was 4.01 µg/mL.

Distribution

Aprepitant is approximately 97% bound to plasma proteins. The mean steady-state volume of distribution (V_dss) of aprepitant, estimated after a single 150 mg dose of fosaprepitant, is approximately 82 L in humans.

Biotransformation

Fosaprepitant is rapidly converted to aprepitant upon in vitro incubation with human liver preparations. Furthermore, fosaprepitant undergoes rapid and nearly complete conversion to aprepitant in S9 fractions of other human tissues, including kidney, lung, and colon. Thus, the conversion of fosaprepitant to aprepitant may occur in various tissues. In humans, intravenously administered fosaprepitant is rapidly converted to aprepitant within 30 minutes after the end of infusion. Aprepitant undergoes extensive metabolism. After a single intravenous dose of 100 mg [14C]-labelled fosaprepitant administered to a healthy young adult, aprepitant accounted for approximately 19% of plasma radioactivity over 72 hours, indicating significant presence of metabolites in plasma. Twelve metabolites of aprepitant have been identified in human plasma. Metabolism of aprepitant occurs primarily through oxidation of the morpholine ring and its side chains; the resulting metabolites exhibit weak activity. In vitro studies using human liver microsomes showed that aprepitant is primarily metabolized by CYP3A4, with potential minor contributions from CYP1A2 and CYP2C19.

All metabolites detected in urine, feces, and plasma after intravenous administration of 100 mg [14C]-fosaprepitant were also observed after oral administration of [14C]-aprepitant. The conversion of 245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant) to aprepitant releases 23.9 mg of phosphoric acid and 95.3 mg of meglumine.

Elimination

Aprepitant is not excreted unchanged in urine. Metabolites are eliminated via urine and biliary excretion in feces. After intravenous administration of a single 100 mg dose of [14C]-fosaprepitant to healthy subjects, 57% of radioactivity was excreted in urine and 45% in feces.

The pharmacokinetics of aprepitant over the clinical dose range is nonlinear. The elimination half-life of aprepitant after a 150 mg intravenous dose of fosaprepitant is approximately 11 hours. The mean geometric plasma clearance of aprepitant after a 150 mg intravenous dose of fosaprepitant is approximately 73 mL/min.

Pharmacokinetics in specific populations

Hepatic impairment

Fosaprepitant is metabolized in various extrahepatic tissues; therefore, hepatic impairment does not affect the conversion of fosaprepitant to aprepitant. Mild hepatic impairment (Child-Pugh Class A) does not have a clinically significant effect on the pharmacokinetics of aprepitant. Dose adjustment is not required in patients with mild hepatic impairment. There are no adequate clinical or pharmacokinetic data available regarding the effect of moderate hepatic impairment (Child-Pugh Class B) on aprepitant pharmacokinetics. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (Child-Pugh Class C).

Renal impairment

A single 240 mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) and to patients with end-stage renal disease (ESRD) requiring hemodialysis.

In patients with severe renal impairment, the AUC_0–∞ of total aprepitant (both protein-bound and unbound) was reduced by 21% and C_max by 32%, compared to healthy volunteers. In patients with ESRD on hemodialysis, AUC_0–∞ of total aprepitant was reduced by 42% and C_max by 32%. Due to the minimal plasma protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly altered in patients with renal impairment compared to healthy volunteers. Hemodialysis performed 4 or 48 hours after dose administration had minimal effect on aprepitant pharmacokinetics; less than 0.2% of the administered dose was recovered in the dialysate.

Dosage adjustment of fosaprepitant is not necessary in patients with severe renal impairment or in patients with ESRD on hemodialysis.

Pediatric population

Data from the 3-day intravenous (i.v.) regimen: modeled median AUC_0–24h of aprepitant, median maximum plasma concentration (C_max) on Day 1, and median concentrations at the end of Day 1, Day 2, and Day 3 in children and adolescents (aged 6 months to 17 years) are presented in Table 1.

Table 1: Pharmacokinetic parameters of aprepitant following 3-day intravenous administration of fosaprepitant in children

On Day 1 following intravenous administration of fosaprepitant, modeled median AUC0–24h of aprepitant, median maximum plasma concentration (Cmax) on Day 1, and median concentrations at the end of Day 1, Day 2, and Day 3 in children and adolescents (aged 6 months to <12 years), as well as observed mean median AUC0–24h, median maximum plasma concentration (Cmax) on Day 1, and mean concentrations at the end of Day 1, Day 2, and Day 3 in children and adolescents (aged 6 months to 17 years) are presented in Table 2.

Table 2: Pharmacokinetic parameters of aprepitant after single-dose intravenous administration of fosaprepitant in pediatric patients

*NP – not reported

Population pharmacokinetic analysis of data obtained during administration of aprepitant to children and adolescents (from 6 months to 17 years of age) indicates that sex and race do not have a clinically significant effect on the pharmacokinetic characteristics of aprepitant.

Concentration-effect relationship

Positron emission tomography studies using a highly specific NK1 receptor radioligand, conducted in healthy young men, demonstrated that after administration of a single 150 mg intravenous dose of fosaprepitant, binding to brain NK1 receptors was ≥ 100 % at Tmax and remained ≥ 97 % over 24 hours, ≥ 97 % over 48 hours, and between 41 % and 75 % over 120 hours after dose administration. Binding to brain NK1 receptors, as assessed in this study, correlated well with plasma concentrations of aprepitant.

Clinical characteristics.

Indications.

In combination therapy:

• Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy based on cisplatin in adults and children aged 6 months and older;
• Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults and children aged 6 months and older.

Contraindications.

Hypersensitivity to the active substance or to polysorbate-80, or to any excipient of the medicinal product.

Concomitant use with pimozide, terfenadine, astemizole, or cisapride (see "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

After intravenous administration, fosaprepitant is rapidly converted into aprepitant.

Fosaprepitant 150 mg administered as a single dose is a weak inhibitor of CYP3A4. Fosaprepitant or aprepitant is considered not to interact with transporters such as P-glycoprotein, as demonstrated by the lack of interaction between oral aprepitant and digoxin. Fosaprepitant is expected to cause less or no greater induction of CYP2C9 and CYP3A4 and glucuronidation than oral aprepitant. Data on the effect on CYP2C8 and CYP2C19 isoenzymes are lacking.

After intravenous administration of fosaprepitant, interactions may occur with drugs containing active substances that interact with oral aprepitant. The following information is derived from studies conducted with oral aprepitant and studies with intravenous fosaprepitant administered with dexamethasone, midazolam, or diltiazem.

Effect of fosaprepitant on the pharmacokinetics of other active substances.

Inhibition of CYP3A4 activity

As a moderate inhibitor of CYP3A4, fosaprepitant (150 mg) given as a single dose may increase plasma concentrations of active substances metabolized by CYP3A4 when co-administered. Total exposure to orally administered CYP3A4 substrates may approximately double on days 1 and 2 after co-administration with the drug. Fosaprepitant must not be taken concomitantly with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 activity by fosaprepitant may lead to increased plasma concentrations of these active substances, potentially causing life-threatening adverse reactions. Caution is recommended when administering fosaprepitant concomitantly with oral drugs that are predominantly metabolized by CYP3A4 and have a narrow therapeutic index: cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamine, ergotamine, fentanyl, and quinidine.

Corticosteroids

Dexamethasone. When used concomitantly with the drug, the oral dose of dexamethasone should be reduced by approximately 50% on days 1 and 2 to achieve dexamethasone exposure similar to that achieved without fosaprepitant.

Fosaprepitant 150 mg administered intravenously as a single dose on day 1 increased the area under the concentration-time curve (AUC) of dexamethasone, a CYP3A4 substrate, by 100% on day 1, by 86% on day 2, and by 18% on day 3, when dexamethasone was administered orally at a single dose of 8 mg on days 1, 2, and 3.

Chemotherapeutic agents

Interaction studies between fosaprepitant and chemotherapeutic agents have not been conducted. However, based on studies with oral aprepitant, docetaxel, and vinorelbine, a clinically significant interaction between fosaprepitant 150 mg and these intravenously administered agents is not expected. Interaction between fosaprepitant and orally administered chemotherapeutic agents that are mainly or partially metabolized by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Patients taking such oral agents should be cautious and require additional monitoring (see section "Special precautions for use"). Cases of neurotoxicity have been reported in the post-marketing period, potentially related to ifosfamide's adverse effect following its concomitant use with aprepitant.

Immunosuppressants

After a single 150 mg dose of fosaprepitant, a transient (for 2 days) increase followed by a slight decrease in exposure of immunosuppressants metabolized by CYP3A4 (e.g., cyclosporine, tacrolimus, everolimus, and sirolimus) is expected. Given the short duration of treatment and limited time-dependent changes in exposure, dose reduction of immunosuppressants during concomitant use with Fopitant is not recommended.

Midazolam

Fosaprepitant 150 mg administered as a single dose on day 1 increased the AUC of midazolam by 77% on day 1 and had no effect on this parameter on day 4, when midazolam was administered orally at a dose of 2 mg on days 1 and 4. Fosaprepitant 150 mg is a weak inhibitor of CYP3A4, as a single dose on day 1 did not show inhibition or induction of CYP3A4 on day 4.

Potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized by CYP3A4 (alprazolam, triazolam) should be considered when these drugs are co-administered with Fopitant.

Diltiazem

Interaction studies between fosaprepitant 150 mg and diltiazem have not been conducted. However, results from a study using fosaprepitant 100 mg should be considered when using fosaprepitant 150 mg with diltiazem. In patients with mild to moderate hypertension, infusion of fosaprepitant 100 mg over 15 minutes concomitantly with diltiazem 120 mg three times daily increased the AUC of diltiazem by 1.4 times and resulted in a small but clinically significant reduction in blood pressure, though no clinically significant changes in heart rate or PR interval were observed.

Induction

Based on interaction study results with midazolam, fosaprepitant 150 mg administered as a single dose does not induce CYP3A4 on days 1 and 4.

Fosaprepitant is expected to cause less or no greater induction of CYP2C9 and CYP3A4 and glucuronidation than the 3-day oral regimen of aprepitant, which shows transient induction with a maximum effect on days 6–8 after the first aprepitant dose. The 3-day oral regimen of aprepitant reduces the AUC of CYP2C9 substrates by approximately 30–35% and reduces ethinylestradiol residual concentrations to 64%. Information on the effect on CYP2C8 and CYP2C19 is lacking. Caution is recommended when using fosaprepitant concomitantly during this period with warfarin, acenocoumarol, tolbutamide, phenytoin, or other active substances known to be metabolized by CYP2C9.

Warfarin

In patients receiving long-term warfarin therapy, close monitoring of prothrombin time (INR) is recommended during treatment and for 2 weeks after administration of fosaprepitant used for the prevention of chemotherapy-induced nausea and vomiting.

Hormonal contraceptives

During and for 28 days after administration of fosaprepitant, the effectiveness of hormonal contraceptives may be reduced. Alternative non-hormonal contraceptive methods should be used during treatment with fosaprepitant and for 2 months after the last dose of fosaprepitant.

5-HT3 antagonists

Interaction studies between fosaprepitant and 5-HT3 antagonists have not been conducted. However, in clinical studies, aprepitant did not show a clinically significant effect on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (active metabolite of dolasetron).

Effect of other drugs on the pharmacokinetics of aprepitant following administration of fosaprepitant 150 mg.

Fosaprepitant should be used with caution concomitantly with active substances that inhibit CYP3A4 activity (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors), as such combinations are expected to increase plasma concentrations of aprepitant several-fold (see section "Special precautions for use"). Ketoconazole increases the elimination half-life of oral aprepitant by approximately 3 times.

Concomitant use of fosaprepitant with active substances that strongly induce CYP3A4 activity (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided, as such combinations lead to reduced plasma concentrations of aprepitant, potentially resulting in reduced efficacy. Concomitant use of fosaprepitant with herbal products containing St. John’s wort (Hypericum perforatum) is not recommended. Rifampicin reduces the mean terminal elimination half-life of aprepitant by 68%.

Diltiazem

Interaction studies between fosaprepitant 150 mg and diltiazem have not been conducted; however, the following study with 100 mg fosaprepitant should be considered when using the drug with diltiazem. A 15-minute infusion of 100 mg fosaprepitant with diltiazem 120 mg three times daily resulted in a 1.5-fold increase in the AUC of aprepitant. This effect was not considered clinically significant.

Children:

Interaction studies have been conducted only in adults.

Special precautions for use.

Patients with moderate and severe hepatic impairment

Information on the use of the drug in patients with moderate hepatic impairment is limited, and there is no information available on its use in patients with severe hepatic impairment. Therefore, the drug should be used with caution in such patients (see section "Pharmacokinetics").

Interactions with CYP3A4

Fosaprepitant should be used with caution in patients who are concurrently receiving medicinal products that are primarily metabolized by the CYP3A4 system and have a narrow therapeutic index, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (see section "Interaction with other medicinal products and other forms of interaction"). Additionally, concomitant use with irinotecan requires special caution, as this combination may increase toxicity.

Concomitant use with warfarin (CYP2C9 substrate)

In patients receiving ongoing warfarin therapy, careful monitoring of the international normalized ratio (INR) should be performed for 14 days following completion of a course of fosaprepitant treatment (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with hormonal contraceptives

During and for 28 days after the end of fosaprepitant treatment, the effectiveness of hormonal contraceptives may be reduced. Alternative non-hormonal contraceptive methods should be used during treatment with fosaprepitant and for 2 months after the last dose of fosaprepitant (see section "Interaction with other medicinal products and other forms of interaction").

Hypersensitivity reactions

Rare cases of immediate hypersensitivity reactions, including flushing, erythema, and dyspnea, have occurred during fosaprepitant infusion. Such hypersensitivity reactions usually resolve upon discontinuation of the infusion and with appropriate treatment. Re-initiation of the infusion is not recommended in patients who experience hypersensitivity reactions.

Local reactions to infusion (LRI)

Reports of local reactions to infusion (LRI) have been reported with the use of the drug (see section "Adverse reactions"). Most severe LRIs, including thrombophlebitis and vasculitis, were reported in patients receiving concomitant chemotherapy causing skin ulceration (e.g., anthracycline-based), particularly when associated with extravasation. Necrosis has also been reported in some patients receiving concomitant chemotherapy causing skin ulceration.

Fosaprepitant must not be administered as a bolus injection; it must be diluted and administered by slow intravenous infusion (see section "Dosage and administration"). The drug must not be administered intramuscularly or subcutaneously.

If signs or symptoms of local irritation occur, the injection or infusion should be discontinued and restarted in another vein.

Sodium

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Contraception in men and women.

The effectiveness of hormonal contraceptives may be reduced during and for 28 days after fosaprepitant administration. Alternative non-hormonal contraceptive methods should be used during treatment with fosaprepitant and for 2 months after the last dose of fosaprepitant (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Pregnancy.

There are no clinical data on the use of fosaprepitant or aprepitant during pregnancy. The potential for reproductive toxicity of fosaprepitant and aprepitant has not been fully established, as exposure levels exceeding therapeutic exposure in humans cannot be achieved in animal studies. These studies did not show any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. The potential impact of neurokinin regulation on reproductive function is unknown. Fosaprepitant should not be used during pregnancy except in cases of clear medical need.

Breastfeeding.

Aprepitant passes into the milk of lactating rats after intravenous administration of fosaprepitant, similar to the transfer observed after oral administration of aprepitant. It is unknown whether the drug passes into human breast milk; therefore, breastfeeding is not recommended during treatment with this medicinal product.

Fertility.

The potential effect of fosaprepitant and aprepitant on fertility has not been fully studied, as exposure levels exceeding therapeutic exposure in humans cannot be achieved in animal studies. Animal fertility studies did not demonstrate any direct or indirect adverse effects on mating, fertility, embryonic/fetal development, sperm count, or sperm motility.

Ability to affect reaction speed when driving or operating machinery.

Fosaprepitant may have a minor influence on the ability to drive or operate machinery. Dizziness and fatigue may occur after administration of the drug (see section "Adverse reactions").

Method of administration and dosage.

The medication is administered intravenously and must not be given intramuscularly or subcutaneously. The medication should not be administered as an intravenous bolus injection or as an undiluted solution.

Adults

The recommended dose of fosaprepitant is 150 mg administered as an infusion over 20–30 minutes on only the first day, starting approximately 30 minutes prior to chemotherapy (see below "Preparation of the solution for intravenous administration"). The medication should be used as part of a regimen including a corticosteroid and a 5-HT3 antagonist according to the data provided in Table 3.

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

Table 3: Recommended dosing regimen for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy (HEC) in adult patients:

Dexamethasone should be administered 30 minutes prior to chemotherapy on day 1 and in the morning on days 2 through 4. Dexamethasone should also be administered in the evening on days 3 and 4. The dose of dexamethasone should be determined considering the interactions of active substances.

Table 4: Recommended dosing regimen for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy (MEC) in adult patients:

Dexamethasone should be administered 30 minutes before chemotherapy on Day 1. The dose of dexamethasone was selected considering drug interactions.

Children and adolescents

Patients aged 6 months and older and weighing at least 6 kg

The recommended dosing regimen of Fosaprepitant when used in combination with a 5-HT3 antagonist, with or without corticosteroids, for the prevention of nausea and vomiting associated with single-day or multi-day chemotherapy regimens containing highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) is described in Table 5. Single-day chemotherapy regimens include those in which HEC and MEC are administered only on one day, while multi-day chemotherapy regimens involve administration for two or more days.

Alternative dosing regimens applicable for single-day chemotherapy administration are shown in Table 6.

Dosing for single-day and multi-day chemotherapy regimens

Children and adolescents receiving single-day or multi-day chemotherapy regimens with high or moderate emetogenic potential should receive fosaprepitant 150 mg administered as an intravenous infusion via a central venous catheter on Days 1, 2, and 3. Fosaprepitant in capsule form or as an oral suspension may be administered on Days 2 and 3 instead of intravenous administration, as shown in Table 5. See the prescribing information for these dosage forms, which contains appropriate dosing instructions.

Table 5: Recommended dosing regimen for the prevention of nausea and vomiting associated with single-day or multi-day HEC or MEC regimens in children and adolescents

* For adolescents aged 12 years and older, fosaprepitant should be administered intravenously over more than 30 minutes; the infusion should be completed approximately 30 minutes before the start of chemotherapy. For children under 12 years of age, fosaprepitant should be administered intravenously over more than 60 minutes; the infusion should be completed approximately 30 minutes before the start of chemotherapy.

** Dexamethasone should be administered approximately 30 minutes before the start of chemotherapy on Day 1.

Alternative dosing for single-day chemotherapy regimen

Children and adolescents receiving a single-day BEACOPP or PEPCOPP regimen may be given fosaprepitant as an intravenous infusion via a central venous catheter on Day 1.

Table 6: Alternative dosing regimen for the prevention of nausea and vomiting associated with single-day BEACOPP or PEPCOPP chemotherapy in children and adolescents

* For adolescents aged 12 years and older, fosaprepitant should be administered intravenously over more than 30 minutes, and the infusion should be completed approximately 30 minutes prior to the start of chemotherapy. For children under 12 years of age, fosaprepitant should be administered intravenously over more than 60 minutes, and the infusion should be completed approximately 30 minutes prior to the start of chemotherapy.

** Dexamethasone should be administered approximately 30 minutes prior to the start of chemotherapy on Day 1.

General

Information regarding the efficacy of combinations with other corticosteroids and 5-HT3 antagonists is very limited. For additional information on concomitant use with corticosteroids, see section "Interaction with other medicinal products and other forms of interaction".

For combined use with 5-HT3 antagonists, refer to the prescribing information for those agents.

Prior to administration, Fopitant, lyophilisate for infusion solution, must be reconstituted and diluted.

Preparation of infusion solution (150 mg):

1. Add 5 mL of 9 mg/mL (0.9%) sodium chloride injection solution to the vial. Inject the 9 mg/mL (0.9%) sodium chloride injection solution slowly along the wall of the vial to avoid foaming. Gently swirl the vial without shaking and without injecting the 9 mg/mL (0.9%) sodium chloride injection solution under pressure into the vial.
2. Prepare an infusion bag or vial containing 145 mL of 9 mg/mL (0.9%) sodium chloride injection solution (e.g., remove 105 mL from a 250 mL infusion bag or vial containing 9 mg/mL (0.9%) sodium chloride injection solution).
3. Withdraw the entire contents of the vial and transfer them into the infusion bag containing 145 mL of 9 mg/mL (0.9%) sodium chloride injection solution to obtain a total volume of 150 mL. After reconstitution and dilution, each mL of solution contains 1 mg of fosaprepitant (1 mg/mL). Gently invert the bag or vial 2–3 times.
4. Determine the volume to be administered from this prepared infusion bag according to the recommended dose (see section "Dosage and administration").

Adults

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

Children and adolescents

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

• Volume to be administered (mL) = recommended dose (mg)

For patients aged 6 months to 12 years, the volume to be administered is calculated as follows:

• Volume to be administered (mL) = recommended dose (mg/kg) × body weight (kg)

Note. Do not exceed the maximum doses (see section "Dosage and administration")

In children, the entire volume of the infusion bag may not be required.

1. If necessary, when the required volume is less than 150 mL, the calculated volume of the drug may be transferred before administration into a smaller infusion bag or syringe.

The reconstituted solution should have the same appearance as the diluent.

The reconstituted and diluted preparation should be visually inspected for the presence of particulate matter and discoloration prior to administration.

The medicinal product must not be reconstituted or mixed with solutions whose chemical and physical compatibility has not been established.

There are no special requirements for disposal of the medicinal product.

Special patient groups.

Elderly patients (≥ 65 years). Dose adjustment is not required for elderly patients.

Gender. Dose adjustment based on gender is not required.

Patients with renal impairment. Dose adjustment is not required for patients with renal impairment or for patients with end-stage renal disease undergoing hemodialysis.

Patients with hepatic impairment. Dose adjustment is not required for patients with mild hepatic impairment. Data on use in patients with moderate hepatic impairment are limited, and there is no information available on use in patients with severe hepatic impairment. Fosaprepitant should be used with caution in these patients.

Pediatric patients.

The safety and efficacy of the drug in children under 6 months of age have not been established; data are lacking.

Overdose.

Information on fosaprepitant overdose is lacking. In case of overdose, discontinue administration of the drug and provide general supportive treatment and monitoring. Due to the antiemetic activity of aprepitant, emetic agents will be ineffective. Aprepitant cannot be removed by hemodialysis.

Adverse Reactions

Summary of Safety Profile

Fosaprepitant has been administered in various dosage forms to over 2687 adult patients in clinical studies, including 371 healthy volunteers, 2084 patients, and 199 pediatric and adolescent patients with chemotherapy-induced nausea and vomiting (CINV). Since fosaprepitant is converted to aprepitant, adverse reactions associated with aprepitant may also occur with fosaprepitant.

The safety profile of aprepitant was evaluated in approximately 6500 adult patients and 184 pediatric and adolescent patients.

Oral Aprepitant

In adult patients treated with aprepitant during highly emetogenic chemotherapy (HEC), the most commonly reported treatment-related adverse reactions were hiccups (4.6%), increased alanine aminotransferase (ALT) levels (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2.0%), and decreased appetite (2.0%). During moderately emetogenic chemotherapy, increased fatigue was the most commonly reported adverse reaction (1.4%). In pediatric patients, the most commonly reported adverse reactions during emetogenic chemotherapy were hiccups (3.3%) and hot flashes (1.1%).

Tabulated List of Adverse Reactions – Aprepitant

Based on analysis of pooled data from HEC and MEC studies, the following adverse reactions were observed more frequently with oral aprepitant than with standard therapy in adults or pediatric and adolescent patients, or during post-marketing use.

The frequency categories listed in the table are based on data from studies conducted in adults; the frequency observed in pediatric and adolescent studies was similar or lower, unless otherwise stated. Some less common adverse drug reactions observed in adults were not observed in pediatric and adolescent studies.

Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), not known (frequency cannot be estimated from available data).

* Nausea and vomiting were efficacy parameters during the first 5 days following chemotherapy and were considered adverse reactions only after this period.

Description of individual adverse reactions

The nature of adverse reactions observed during multiple cycles (up to 6 cycles) of chemotherapy was similar to that observed in the first cycle.

In an additional clinical study in patients receiving aprepitant and chemotherapy with high emetogenic potential, the adverse reaction profile was generally similar to that observed in other high emetogenic chemotherapy studies using aprepitant.

Additional adverse reactions observed in patients receiving aprepitant for treatment of postoperative nausea and vomiting (PONV), and occurring more frequently than with ondansetron, included: upper abdominal pain, pathological bowel sounds, constipation*, dysarthria, dyspnea, hypoesthesia, insomnia, miosis, nausea, sensory disturbances, stomach discomfort, partial intestinal obstruction*, decreased visual acuity, and wheezing.

* Reported in patients who received aprepitant at high doses.

Fosaprepitant.

In an active-controlled clinical trial involving patients receiving chemotherapy with high emetogenic potential, safety was evaluated in 1143 patients who received a single-day regimen of fosaprepitant 150 mg, compared to 1169 patients who received a three-day regimen of aprepitant. Additionally, in a placebo-controlled clinical trial conducted in adults receiving PONV, safety was assessed in 504 patients receiving fosaprepitant 150 mg compared to 497 patients receiving the control regimen.

An analysis of pooled data from three active-controlled clinical trials involving children and adolescents (aged 6 months to 17 years) who received HEC or MEC and fosaprepitant, administered as a single dose equal to or exceeding the recommended dose for the single-day regimen, evaluated safety in 139 patients who received fosaprepitant as a single dose. During the same analysis, safety was assessed in 199 patients who received HEC or MEC and fosaprepitant as a single dose equal to or exceeding the recommended dose for the three-day regimen. Data from three-day IV/oral/oral administration were also included.

Data on three-day intravenous administration of fosaprepitant in children and adolescents are not available. The safety profile of the three-day IV regimen in children and adolescents is expected to be similar to that of the single-day regimen of fosaprepitant, as low trough levels are unlikely to increase exposure on subsequent days.

The safety profile of fosaprepitant use in adults, children, and adolescents is generally similar to that observed with aprepitant.

Tabulated list of adverse reactions – fosaprepitant.

Below are listed adverse reactions reported in adult patients receiving fosaprepitant in clinical trials and during the post-marketing period, which were not observed during aprepitant use. Frequency categories listed in the table are based on data from studies in adults; the frequency observed in studies in children and adolescents was similar or lower. Some adverse reactions commonly observed in adults were not observed in studies involving children and adolescents. Local reactions to infusion (LRI) were observed during administration of fosaprepitant (see section "Special precautions for use").

Frequency was defined as follows: 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); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after authorization of the medicinal product is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life.

2 years.

After reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C.

From a microbiological standpoint, the product should be used immediately after dilution. If not used immediately, the user is responsible for the duration and conditions of storage during use, which generally should not exceed 24 hours at 2–8 °C.

Storage conditions.

Store in a refrigerator at 2–8 °C. Keep out of the reach of children.

Incompatibilities.

The medicinal product must not be reconstituted or mixed with solutions whose chemical and physical compatibility has not been established. Fosaprepitant is incompatible with any solutions containing divalent cations (e.g., Ca\2+, Mg\2+), including Hartmann's and Ringer's solutions. The product must not be mixed with other medicinal products except as specified above.

Packaging.

Lyophilisate for solution for infusion in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Aspiro Pharma Limited.

Manufacturer's address and location of operations.

Sy.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.