post-title portfolio-title Fosaprepitant Dimeglumine For Injection IP 150mg Taj Pharma 2020-03-06 08:26:25 no no

Fosaprepitant Dimeglumine For Injection IP 150mg Taj Pharma

Fosaprepitant Dimeglumine For Injection IP 150mg Taj Pharma

Overview

INTRODUCTION

Fosaprepitant Dimeglumine 150mg Injection is a prescription medicine used to prevent nausea and vomiting caused by chemotherapy.

Fosaprepitant Dimeglumine 150mg Injection is given under the supervision of healthcare professional. Moreover, it is better to take it at a fixed time and you should not stop taking this medication suddenly without talking to your doctor. In case you have missed a dose than it is better to take it as soon as you remember it and finish the full course of treatment even if you feel better. Your doctor may advice for regular monitoring of liver function test while taking this medicine.

It has side effects like headache, loss of appetite, increase liver enzymes, fatigue and constipation. Dizziness and sleepiness may also occur as a side effect, so do not drive or do anything that requires mental focus until you know how this medicine affects you.

USES OF FOSAPREPITANT DIMEGLUMINE INJECTION

  • Nausea and vomiting due to chemotherapy

SIDE EFFECTS OF FOSAPREPITANT DIMEGLUMINE INJECTION

Common

  • Fatigue

HOW TO USE FOSAPREPITANT DIMEGLUMINE INJECTION

Your doctor or nurse will give you this medicine. Kindly do not self administer.

HOW FOSAPREPITANT DIMEGLUMINE INJECTION WORKS

Fosaprepitant Dimeglumine 150mg Injection is an antiemetic medication. It works by blocking the action of a chemical messenger (neurokinin) in the brain that may cause nausea and vomiting during anti-cancer treatment (chemotherapy).

SAFETY ADVICE

warningsAlcohol

UNSAFE

It is unsafe to consume alcohol with Fosaprepitant Dimeglumine 150mg Injection.

warningsPregnancy

SAFE IF PRESCRIBED

Fosaprepitant Dimeglumine 150mg Injection is generally considered safe to use during pregnancy. Animal studies have shown low or no adverse effects to the developing baby; however, there are limited human studies.

warningsBreastfeeding

CONSULT YOUR DOCTOR

Fosaprepitant Dimeglumine 150mg Injection is probably unsafe to use during breastfeeding. Limited human data suggests that the drug may pass into the breastmilk and harm the baby.

warningsDriving

UNSAFE

Fosaprepitant Dimeglumine 150mg Injection may decrease alertness, affect your vision or make you feel sleepy and dizzy. Do not drive if these symptoms occur.

warningsKidney

SAFE IF PRESCRIBED

Fosaprepitant Dimeglumine 150mg Injection is safe to use in patients with kidney disease. No dose adjustment of Fosaprepitant Dimeglumine 150mg Injection is recommended.

warningsLiver

CAUTION

Fosaprepitant Dimeglumine 150mg Injection should be used with caution in patients with severe liver disease. Dose adjustment of Fosaprepitant Dimeglumine 150mg Injection may be needed. Please consult your doctor.
No dose adjustment is recommended in patients with moderate to severe liver disease.

WHAT IF YOU FORGET TO TAKE FOSAPREPITANT DIMEGLUMINE INJECTION?

If you miss a dose of Fosaprepitant Dimeglumine 150mg Injection, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular schedule. Do not double the dose.

Fosaprepitant Dimeglumine For Injection IP 150mg Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

Fosaprepitant Dimeglumine For Injection IP 150mg Taj Pharma

2.QUALITATIVE AND QUANTITATIVE COMPOSITION??????????????????????????????

Each vial contains:
Fosaprepitant dimeglumine IP
equivalent to 150 mg fosaprepitant, which corresponds to 130.5 mg of aprepitant.
After reconstitution and dilution 1 ml of solution contains 1 mg fosaprepitant (1 mg/ml) (see section 6.6).

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM????

Powder for solution for infusion.

White to off-white amorphous powder.

4.CLINICAL PARTICULARS

4.1 Therapeutic indications

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

Fosaprepitant is given as part of a combination therapy (see section 4.2).

4.2 Posology and method of administration

Posology

Adults

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 following regimens are 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 chemotherapy regimen in adults

Day 1Day 2Day 3Day 4
FOSAPREPITANT150 mg intravenouslynonenonenone
Dexamethasone12 mg orally8 mg orally8 mg orally twice daily8 mg orally twice daily
5-HT3?antagonistsStandard dose of 5-HT3?antagonists. See the product information for the selected 5-HT3?antagonist for appropriate dosing informationnonenonenone

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.

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

Day 1
Fosaprepitant150 mg intravenously
Dexamethasone12 mg orally
5-HT3?antagonistsStandard dose of 5-HT3?antagonists. See the product information for the selected 5-HT3?antagonist for appropriate dosing information

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, 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 3. 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 4.

Dosing for Single or Multi-Day Chemotherapy Regimens

For paediatric patients receiving single or multi-day regimens of HEC or MEC, administer FOSAPREPITANT as an intravenous infusion through a central venous catheter on Days 1, 2, and 3. EMEND capsules or EMEND for oral suspension may be used on Days 2 and 3 instead of FOSAPREPITANT, as shown in Table 3. See the Summary of Product Characteristics (SmPC) for EMEND capsules or EMEND for oral suspension for appropriate dosing instructions.

Table 3: Recommended dosing for the prevention of nausea and vomiting associated with single or multi-day regimens of HEC or MEC in paediatric patients

PopulationDay 1Day 2Day 3
FOSAPREPITANT*Paediatric patients 12 years and older115 mg intravenously80 mg intravenously

OR

80 mg orally

(EMEND capsules)

80 mg intravenously

OR

80 mg orally

(EMEND capsules)

Paediatric patients 6 months to less than 12 years and not less than 6 kg3 mg/kg intravenously

Maximum dose 115 mg

2 mg/kg intravenously

OR

2 mg/kg orally

(EMEND oral suspension)

Maximum dose 80 mg

2 mg/kg intravenously

OR

2 mg/kg orally

(EMEND oral suspension)

Maximum dose 80 mg

Dexamethasone**All paediatric patientsIf a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on days 1 through 4
5-HT3?antagonistAll paediatric patientsSee selected 5-HT3?antagonist prescribing information for the recommended dosage

* For paediatric patients 12 years and older, administer Fosaprepitant intravenously over 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy. For paediatric patients less than 12 years, administer Fosaprepitant 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.

Alternative Dosing for Single Day Chemotherapy Regimens

For paediatric patients receiving single day HEC or MEC, FOSAPREPITANT may be administered as an intravenous infusion through a central venous catheter on Day 1.

Table 4: Alternative dosing for the prevention of nausea and vomiting associated with single day regimens of HEC or MEC in paediatric patients

PopulationDay 1
FOSAPREPITANT*Paediatric patients 12 years and older150 mg intravenously
Paediatric patients 2 to less than 12 years4 mg/kg intravenously

Maximum dose 150mg

Paediatric patients 6 months to less than 2 years and not less than 6 kg5 mg/kg intravenously

Maximum dose 150mg

Dexamethasone**All paediatric patientsIf a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on days 1 and 2.
5-HT3?antagonistAll paediatric patientsSee selected 5-HT3?antagonist prescribing information for the recommended dosage

* For paediatric patients 12 years and older, administer FOSAPREPITANT intravenously over 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy. For paediatric patients less than 12 years, administer FOSAPREPITANT 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 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

Elderly (?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 hepatic impairment. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. FOSAPREPITANT should be used with caution in these patients (see sections 4.4 and 5.2).

Method of administration

Fosaprepitant should be administered intravenously and should not be given by the intramuscular or subcutaneous route. Intravenous administration in adults 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 as a bolus injection or undiluted solution.

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

4.3 Contraindications

Hypersensitivity to the active substance or to polysorbate 80 or any of the other excipients listed in section 6.1.

Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).

4.4 Special warnings and precautions for use

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 should be used with caution in?these patients (see section 5.2).

CYP3A4 interactions

FOSAPREPITANT 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

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

Infusion site reactions (ISRs) have been reported with the use of FOSAPREPITANT (see section 4.8). The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (e.g., anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Mild injection site thrombosis has been observed at higher doses without concomitant vesicant chemotherapy.

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 (see section 5.3). If signs or symptoms of local irritation occur, the injection or infusion should be terminated and restarted in another vein.

4.5 Interaction with other medicinal products and other forms of interaction

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 with other medicinal products in paediatric patients are based upon adult data from fosaprepitant and aprepitant studies. When using combined FOSAPREPITANT and EMEND regimens, please refer to the Summary of Product Characteristics (SmPC) section 4.5 for EMEND capsules or EMEND for oral suspension.

The following information was derived from studies conducted with oral aprepitant and studies conducted with intravenous single-dose fosaprepitant co-administered with dexamethasone, midazolam, or diltiazem.

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 is not expected to have a clinically relevant interaction with intravenously administered docetaxel and vinorelbine. An interaction with orally administered chemotherapeutic medicinal products metabolised primarily or partly by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving medicinal products metabolized primarily or partly by CYP3A4 (see section 4.4). Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration.

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.

Midazolam

Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-??of midazolam by 77 % on Day 1 and had no effect on Day 4 when midazolam was co-administered as a single oral dose of 2 mg on Days 1 and 4. Fosaprepitant 150 mg is a weak CYP3A4 inhibitor as a single dose on Day 1 with no evidence of inhibition or induction of CYP3A4 observed on Day 4.

The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these medicinal products with 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 Fosaprepitant 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 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 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 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.

4.6 Fertility, pregnancy and lactation

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 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. FOSAPREPITANT 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.

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).

4.7 Effects on ability to drive and use machines

FOSAPREPITANT may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of FOSAPREPITANT (see section 4.8).

4.8 Undesirable effects

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 in adults or paediatric patients or in postmarketing use.

The frequency categories given in the table are based on the studies in adults; the observed frequencies in the paediatric studies were similar or lower, unless shown in the table. Some less common ADRs in the adult population were not observed in the paediatric studies.

Frequencies are defined as: very common (?1/10); common (?1/100 to <1/10); uncommon (?1/1,000 to <1/100); rare (?1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 5: Tabulated list of adverse reactions – aprepitant

System organ classAdverse reactionFrequency
Infection and infestationscandidiasis, staphylococcal infectionrare
Blood and lymphatic system disordersfebrile neutropenia, anaemiauncommon
Immune system disordershypersensitivity reactions including anaphylactic reactionsnot known
Metabolism and nutrition disordersdecreased appetitecommon
polydipsiarare
Psychiatric disordersanxietyuncommon
disorientation, euphoric moodrare
Nervous system disordersheadachecommon
dizziness, somnolenceuncommon
cognitive disorder, lethargy, dysgeusiarare
Eye disordersconjunctivitisrare
Ear and labyrinth disorderstinnitusrare
Cardiac disorderspalpitationsuncommon
bradycardia, cardiovascular disorderrare
Vascular disordershot flush/flushinguncommon
Respiratory, thoracic and mediastinal disordershiccupscommon
oropharyngeal pain, sneezing, cough, postnasal drip, throat irritationrare
Gastrointestinal disordersconstipation, dyspepsiacommon
eructation, nausea*, vomiting*, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulenceuncommon
duodenal ulcer perforation, stomatitis, abdominal distension, faeces hard, neutropenic colitisrare
Skin and subcutaneous tissue disordersrash, acneuncommon
photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysisrare
pruritus, urticarianot known
Musculoskeletal and connective tissue disordersmuscular weakness, muscle spasmsrare
Renal and urinary disordersdysuriauncommon
pollakisuriarare
General disorders and administration site conditionsfatiguecommon
asthaenia, malaiseuncommon
oedema, chest discomfort, gait disturbancerare
InvestigationsALT increasedcommon
AST increased, blood alkaline phosphatase increaseduncommon
red blood cells urine positive, blood sodium decreased, weight decreased, neutrophil count decreased, glucose urine present, urine output increasedrare

*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.

In an additional active-controlled clinical study in 1,169 adult patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant.

Additional adverse reactions were observed in adult patients treated with aprepitant for postoperative nausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, constipation*, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, sub-ileus*, visual acuity reduced, wheezing.

*Reported in patients taking a higher dose of aprepitant.

Fosaprepitant

In an active-controlled clinical study in adult patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of Fosaprepitant compared to 1,169 patients receiving the 3-day regimen of aprepitant. Additionally, in a placebo-controlled clinical trial in adult patients receiving MEC, safety was evaluated for 504 patients receiving a single dose of Fosaprepitant 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 at or above the recommended 1-day regimen dose, safety was evaluated for 139 patients receiving the 1-day regimen of FOSAPREPITANT. In the same analysis, safety was evaluated for 199 patients receiving either HEC or MEC and a single dose of FOSAPREPITANT at or above the recommended 3-day regimen of FOSAPREPITANT. Safety data following the administration of the 3-day IV/oral/oral regimen were also included.

No data are available following the administration of a 3-day IV fosaprepitant regimen in paediatric patients. The safety profile of the 3-day IV fosaprepitant regimen in paediatric patients is expected to be similar to that of the 1-day fosaprepitant regimen as the low daily trough levels do not significantly increase the exposures on subsequent days.

The safety profile of fosaprepitant in adult and paediatric patients was generally similar to that observed with aprepitant.

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. The frequency categories in the table are based on studies in adults; the observed frequencies in the paediatric studies were similar or lower. Some adverse reactions that are commonly observed in the adult population were not observed in the paediatric studies. Infusion site reactions (ISRs) have been reported with the use of FOSAPREPITANT (see section 4.4).

Frequencies are defined as: very common (?1/10); common (?1/100 to <1/10); uncommon (?1/1,000 to <1/100); rare (?1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 6: Tabulated list of adverse reactions ? fosaprepitant

System organ classAdverse reactionFrequency
Vascular disordersflushing, thrombophlebitis (predominantly, infusion-site thrombophlebitis)uncommon
Skin and subcutaneous tissue disorderserythemauncommon
General disorders and administration site conditionsinfusion site erythema, infusion site pain, infusion site pruritusuncommon
infusion site indurationrare
immediate hypersensitivity reactions including flushing, erythema, dyspnoea, anaphylactic reactions/anaphylactic shocknot known
Investigationsblood pressure increaseduncommon

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.

4.9 Overdose

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.

5.PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants,

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 (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 was shown to be non-inferior to that of the 3-day regimen of aprepitant. A summary of the primary and secondary endpoints is shown in Table 7.

Table 7: Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase ? Cycle 1
ENDPOINTS*Fosaprepitant regimen

(N =1,106) **

%

Aprepitant regimen
(N =1,134) **%
Difference?

(95 % CI)

Complete response?
Overall?71.972.3-0.4 (-4.1, 3.3)
Delayed phase??74.374.20.1 (-3.5, 3.7)
No vomiting
Overall?72.974.6-1.7 (-5.3, 2.0)

*Primary endpoint is bolded.

**N: Number of adult 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 post-initiation of cisplatin chemotherapy.
  • ?Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.

Moderately Emetogenic Chemotherapy (MEC)

In a randomized, parallel, double-blind, placebo-controlled study, Fosaprepitant (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 consisted 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 8 and was shown to be superior to the control regimen with regard to complete response in the delayed and overall phases.

Table 8: Percent of adult patients receiving Moderately Emetogenic Chemotherapy responding by treatment group and phase
ENDPOINTS*Fosaprepitant regimen

(N =502) **

%

Control regimen
(N =498) **%
P-Value
Complete response?
Delayed phase?78.968.5<0.001
Complete response?
Overall?77.166.9<0.001
Acute phase??93.2910.184

*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.

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 patients 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 EMEND capsules and EMEND powder for oral suspension for complete clinical information regarding studies performed with oral aprepitant.

5.2 Pharmacokinetic properties

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 adult volunteers, the mean AUC0-??of aprepitant was 35.0 ?g?hr/ml and the mean maximal aprepitant concentration was 4.01 ?g/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 AUC0-??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 9.

Table 9: Pharmacokinetic parameters of aprepitant for 3-day IV fosaprepitant regimen in paediatric patients

Population3-day IV/IV/IV doseAUC?0-24 hr.

(ng*hr/mL)

Cmax

(ng/mL)

C24

(ng/mL)

C48

(ng/mL)

C72

(ng/mL)

12 – 17 years old115mg, 80mg, 80mg211722475454424417
6 – < 12 years old3mg/kg, 2mg/kg, 2mg/kg259012719518438418
2 – < 6 years old205682335336248232
6 months ? < 2 years old169791916256179167

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 10.

Table 10: Pharmacokinetic parameters of aprepitant for 1-day IV fosaprepitant regimen in paediatric patients

Population1-day IV

dose

AUC?0-24 hr.

(ng*hr/mL)

Cmax

(ng/mL)

C24

(ng/mL)

C48

(ng/mL)

C72

(ng/mL)

12 – 17 years old150 mg304003500735NR*NR*
6 – < 12 years old4 mg/kg35766363774622769.2
2 – < 6 years old28655315049410823.5
6 months ? <2 years old5 mg/kg30484319152211224.4

*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.

5.3 Preclinical safety data

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium edetate
Polysorbate 80
Lactose anhydrous
Sodium hydroxide (for pH adjustment) and/or
Hydrochloric acid diluted (for pH adjustment)

6.2 Incompatibilities

FOSAPREPITANT 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.

6.3 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 point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8?C.

6.4 Special precautions for storage

Store in a refrigerator (2?C – 8?C).

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

6.5 Nature and contents of container

10 ml Type I clear glass vial with a chlorobutyl or bromobutyl rubber stopper and an aluminum seal with a grey plastic flip off cap.

Pack sizes: 1 or 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

FOSAPREPITANT must be reconstituted and then diluted prior to administration.

Preparation of Fosaprepitant 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 and final concentration of 1 mg/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).

  1. 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).

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)

Fosaprepitant Dimeglumine For Injection IP 150mg Taj Pharma
Package leaflet: Information for the patient

Fosaprepitant

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Fosaprepitant is and what it is used for
  2. What you need to know before you take Fosaprepitant
  3. How to take Fosaprepitant
  4. Possible side effects
  5. How to store Fosaprepitant
  6. Contents of the pack and other information
1 WHAT FOSAPREPITANT IS AND WHAT IT IS USED FOR

Fosaprepitant Inj contains the active substance fosaprepitant which is converted to aprepitant in your body. It belongs to a group of medicines called “neurokinin 1 (NK1) receptor antagonists”. The brain has a specific area that controls nausea and vomiting. Fosaprepitant Inj works by blocking signals to that area, thereby reducing nausea and vomiting. Fosaprepitant Inj is used in adults, adolescents, and children aged 6 months or older?in combination with other medicines?to prevent nausea and vomiting caused by chemotherapy (cancer treatment) that is a strong or moderate trigger of nausea and vomiting.

2 WHAT YOU NEED TO KNOW BEFORE YOU TAKE FOSAPREPITANT

Do not use Fosaprepitant Inj:

  • if you are allergic to fosaprepitant, aprepitant, or to polysorbate 80 or any of the other ingredients (listed in section 6).
  • with medicines containing pimozide (used to treat psychiatric illnesses), terfenadine and astemizole (used for hay fever and other allergic conditions), cisapride (used for treating digestive problems). Tell your doctor if you are taking these medicines since the treatment must be modified before you start using Fosaprepitant Inj.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before using Fosaprepitant Inj.

Before treatment with this medicine, tell your doctor if you have liver disease because the liver is important in breaking down the medicine in the body. Your doctor may therefore have to monitor the condition of your liver.

Children and adolescents

Do not give Fosaprepitant Inj to children under 6 months of age or who weigh less than 6 kg, because it has not been studied in this population.

Other medicines and Fosaprepitant Inj

Fosaprepitant Inj can affect other medicines both during and after treatment with Fosaprepitant Inj. There are some medicines that should not be taken with Fosaprepitant Inj (such as pimozide, terfenadine, astemizole, and cisapride) or that require a dose adjustment (see also ?Do not use Fosaprepitant Inj?).

The effects of Fosaprepitant Inj or other medicines might be influenced if you take Fosaprepitant Inj together with other medicines including those listed below. Please talk to your doctor or pharmacist if you are taking any of the following medicines:

  • birth control medicines which can include birth control pills, skin patches, implants, and certain Intrauterine devices (IUDs) that release hormones may not work adequately when taken together with Fosaprepitant Inj. Another or additional non-hormonal form of birth control should be used during treatment with Fosaprepitant Inj and for up to 2 months after using Fosaprepitant Inj,
  • cyclosporine, tacrolimus, sirolimus, everolimus (immunosuppressants),
  • alfentanil, fentanyl (used to treat pain),
  • quinidine (used to treat an irregular heart beat),
  • irinotecan, etoposide, vinorelbine, ifosfamide (medicines used to treat cancer),
  • medicines containing ergot alkaloid derivatives such as ergotamine and diergotamine (used for treating migraines),
  • warfarin, acenocoumarol (blood thinners; blood tests may be required),
  • rifampicin, clarithromycin, telithromycin (antibiotics used to treat infections),
  • phenytoin (a medicine used to treat seizures),
  • carbamazepine (used to treat depression and epilepsy),
  • midazolam, triazolam, phenobarbital (medicines used to produce calmness or help you sleep),
  • John?s Wort (an herbal preparation used to treat depression),
  • protease inhibitors (used to treat HIV infections),
  • ketoconazole except shampoo (used to treat Cushing?s syndrome ? when the body produces an excess of cortisol),
  • itraconazole, voriconazole, posaconazole (antifungals),
  • nefazodone (used to treat depression),
  • diltiazem (a medicine used to treat high blood pressure),
  • corticosteroids (such as dexamethasone),
  • anti-anxiety medicines (such as alprazolam),
  • tolbutamide (a medicine used to treat diabetes)

Tell your doctor about any other medicines or herbal medicines you are taking, have recently taken, or might take.

Pregnancy and breast-feeding

This medicine should not be used during pregnancy unless clearly necessary. If you are pregnant or breast-feeding, may be pregnant or are planning to have a baby, ask your doctor for advice before receiving this medicine.

For information regarding birth control, see ?Other medicines and Fosaprepitant Inj?.

It is not known whether Fosaprepitant Inj is excreted in human milk; therefore, breast-feeding is not recommended during treatment with this medicine. It is important to tell your doctor if you are breast-feeding or are planning to breast-feed before receiving this medicine.

Driving and using machines

It should be taken into account that some people get dizzy and get sleepy after using Fosaprepitant Inj. If you get dizzy or get sleepy, avoid driving or using machines after using this medicine (see ?Possible side effects?).

Fosaprepitant Inj contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ?sodium- free?.

3 HOW TO TAKE FOSAPREPITANT

Always take this medicine exactly as your doctor In adults (18 years of age and older), the recommended dose of Fosaprepitant Inj is 150 mg fosaprepitant on Day 1 (day of chemotherapy).

In children and adolescents (6 months to 17 years of age), the recommended dose of Fosaprepitant Inj is based on the patient?s age and weight. Depending on the chemotherapy treatment, there are two ways Fosaprepitant Inj may be given:

Fosaprepitant Inj is given only on Day 1 (single day of chemotherapy)

Fosaprepitant Inj is given on Day 1, 2, and 3 (single or multiple days of chemotherapy)

  • Oral formulations of aprepitant may be prescribed on Days 2 and 3 instead of Fosaprepitant Inj.

The powder is reconstituted and diluted before use. The solution for infusion is given to you by a health care professional, such as a doctor or nurse, via an intravenous infusion (a drip) approximately 30 minutes before you start the chemotherapy treatment in adults or 30 ? 60 minutes before you start the chemotherapy treatment in children and adolescents. Your doctor may ask you to take other medicines including a corticosteroid (such as dexamethasone) and a ?5HT3?antagonist? (such as ondansetron) for preventing nausea and vomiting. Check with your doctor or pharmacist if you are not sure.

4 POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Fosaprepitant Inj and see a doctor immediately if you notice any of the following side effects, which may be serious, and for which you may need urgent medical treatment:

  • Hives, rash, itching, difficulty breathing or swallowing, or a serious decrease of blood pressure (frequency not known, cannot be estimated from the available data); these are signs of a serious allergic reaction.

Other side effects that have been reported are listed below.

Common side effects (may affect up to 1 in 10 people) are:

  • constipation, indigestion,
  • headache,
  • tiredness,
  • loss of appetite,
  • hiccups,
  • increased amount of liver enzymes in your blood.

Uncommon side effects (may affect up to 1 in 100 people) are:

  • dizziness, sleepiness,
  • acne, rash,
  • anxiousness,
  • burping, nausea, vomiting, heartburn, stomach pain, dry mouth, passing wind,
  • increased painful or burning urination,
  • weakness, generally feeling unwell,
  • reddening of the face/skin, hot flush,
  • fast or irregular heartbeats, blood pressure increased,
  • fever with increased risk of infection, lowering of red blood cells,
  • infusion site pain, infusion-site redness, infusion-site itching, infusion site vein inflammation.

Rare side effects (may affect up to 1 in 1,000 people) are:

  • difficulty thinking, lack of energy, taste disturbance,
  • sensitivity of the skin to sun, excessive sweating, oily skin, sores on skin, itching rash, Stevens-Johnson syndrome/toxic epidermal necrolysis (rare severe skin reaction),
  • euphoria (feeling of extreme happiness), disorientation,
  • bacterial infection, fungal infection,
  • severe constipation, stomach ulcer, inflammation of the small intestine and colon, sores in mouth, bloating,
  • frequent urination, passing more urine than normal, presence of sugar or blood in urine,
  • chest discomfort, swelling, change in the manner of walking,
  • cough, mucus in back of throat, throat irritation, sneezing, sore throat,
  • eye discharge and itching,
  • ringing in the ear,
  • muscle spasms, muscle weakness,
  • excessive thirst,
  • slow heartbeat, heart and blood vessel disease,
  • lowering of white blood cells, low sodium levels in the blood, weight loss,
  • hardening of site of infusion.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5 HOW TO STOREFOSAPREPITANT

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and vial after EXP. The first 2 numbers indicate the month; the next 4 numbers indicate the year.

Store in a refrigerator (2?C – 8?C).

The reconstituted and diluted solution is stable for 24 hours at 25?C.

Do not throw away any medicines via wastewater or house hold waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6 CONTENTS OF THE PACK AND OTHER INFORMATION

What Fosaprepitant contains

The active substance is fosaprepitant.

Each lyophilized vial contains:
Fosaprepitant Dimeglumine??? IP
Equivalent to Fosaprepitant????? 150mg
Excipients???????????????????????????? q.s.

After reconstitution and dilution 1 ml of solution contains 1 mg fosaprepitant (1 mg/ml).
The other ingredients are: disodium edetate (E386), polysorbate 80 (E433), lactose anhydrous, sodium hydroxide? (for pH adjustment) and/or hydrochloric acid diluted (E507) (for pH adjustment).

Contents of the pack

Fosaprepitant Inj is a white to off-white powder for solution for infusion.

The powder is contained in a clear glass vial with a rubber stopper and an aluminum seal with a grey plastic flip off cap.

Each vial contains 150 mg of fosaprepitant. Pack sizes: 1 or 10 vials.

Not all pack sizes may be marketed.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
Mumbai, India
at SURVEY NO. 188/1, 190/1TO 4, ATHIYAWAD , DABHEL,
DAMAN- 396210 (INDIA)

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