1. Name of the medicinal product

Fosaprepitant Dimegluminefor Injection USP 150mg Taj Pharma

  1. Qualitative and quantitative composition

Fosaprepitant Dimegluminefor Injection USP 150mg Taj Pharma
Each vial contains:
Fosaprepitant DimeglumineUSP
Equivalent to Fosaprepitant Taj Pharma 150mg
Excipients: Q.S.

Which corresponds to 130.5mg of Fosaprepitant Taj Pharma. After reconstitution and dilution 1ml of solution contains 1mgFosaprepitant Taj Pharma (1mg/ml) (see section 6.6).

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Powder for solution for infusion. White to off-white amorphous powder.

  1. Clinical particulars
    • 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 Taj Pharma Dimeglumine150mg is given as part of a combination therapy (see section 4.2).

  • Posology and method of administration

Posology

Adults

The recommended dose is 150mg administered as an infusion over 20-30 minutes on Day 1, initiated approximately 30 minutes prior to chemotherapy (see section 6.6). Fosaprepitant Taj Pharma Dimeglumine 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 1 Day 2 Day 3 Day 4
 Fosaprepitant Taj Pharma Dimeglumine 150mg intravenously none none none
Dexamethasone 12mg orally 8mg orally 8mg orally twice daily 8mg orally twice daily
5-HT3 antagonists Standard dose of 5-HT3 antagonists. See the product information for the selected 5-HTantagonist for appropriate dosing information none none none

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
 Fosaprepitant Taj Pharma Dimeglumine 150mg intravenously
Dexamethasone 12mg orally
5-HT3 antagonists Standard dose of 5-HT3 antagonists. See the product information for the selected 5-HTantagonist 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 Taj Pharma Dimeglumine, 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 Taj Pharma Dimeglumine 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 Taj Pharma Dimeglumine, 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

Population Day 1 Day 2 Day 3
 Fosaprepitant Taj Pharma Dimeglumine * Paediatric patients 12 years and older 115mg intravenously 80mg intravenously

OR

80mg orally

(EMEND capsules)

80mg intravenously

OR

80mg orally

(EMEND capsules)

Paediatric patients 6 months to less than 12 years and not less than 6 kg 3mg/kg intravenously

Maximum dose 115mg

2mg/kg intravenously

OR

2mg/kg orally

(EMEND oral suspension)

Maximum dose 80mg

2mg/kg intravenously

OR

2mg/kg orally

(EMEND oral suspension)

Maximum dose 80mg

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

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

Population Day 1
 Fosaprepitant Taj Pharma Dimeglumine * Paediatric patients 12 years and older 150mg intravenously
Paediatric patients 2 to less than 12 years 4mg/kg intravenously

Maximum dose 150mg

Paediatric patients 6 months to less than 2 years and not less than 6 kg 5mg/kg intravenously

Maximum dose 150mg

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

* For paediatric patients 12 years and older, administer Fosaprepitant Taj Pharma Dimeglumine intravenously over 30 minutes, completing the infusion approximately 30 minutes prior to chemotherapy. For paediatric patients less than 12 years, administer Fosaprepitant Taj Pharma Dimeglumine 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 Taj Pharma Dimeglumine 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 Taj Pharma Dimeglumine should be used with caution in these patients (see sections 4.4 and 5.2).

Method of administration

Fosaprepitant Taj Pharma Dimeglumine 150mg 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 Taj Pharma Dimeglumine as a bolus injection or undiluted solution.

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

  • 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).

  • 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 Taj Pharma Dimeglumine should be used with caution in these patients (see section 5.2).

CYP3A4 interactions

Fosaprepitant Taj Pharma Dimeglumine 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 Taj Pharma  (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 Taj Pharma . Alternative non-hormonal back-up methods of contraception should be used during treatment withFosaprepitant Taj Pharma and for 2 months following the use of Fosaprepitant Taj Pharma  (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 Taj Pharma . 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 Taj Pharma Dimeglumine (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 Taj Pharma Dimeglumine 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 Taj Pharma Dimeglumine 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.

  • Interaction with other medicinal products and other forms of interaction

When administered intravenouslyFosaprepitant Taj Pharma is rapidly converted to  Fosaprepitant Taj Pharma.

Fosaprepitant Taj Pharma 150mg, given as a single dose, is a weak inhibitor of CYP3A4. Fosaprepitant Taj Pharma does not seem to interact with the P-glycoprotein transporter, as demonstrated by the lack of interaction of oral  Fosaprepitant Taj Pharma with digoxin. It is anticipated thatFosaprepitant Taj Pharma would cause less or no greater induction of CYP2C9, CYP3A4 and glucuronidation than that caused by the administration of oral  Fosaprepitant Taj Pharma. Data are lacking regarding effects on CYP2C8 and CYP2C19.

Interactions with other medicinal products following administration of intravenousFosaprepitant Taj Pharma are likely to occur with active substances that interact with oral  Fosaprepitant Taj Pharma. The potential for interactions with multi-dayFosaprepitant Taj Pharma regimens are anticipated to be no greater than those for oral  Fosaprepitant Taj Pharma regimens. Therefore, the recommendations for use of Fosaprepitant Taj Pharma Dimeglumine with other medicinal products in paediatric patients are based upon adult data fromFosaprepitant Taj Pharma and  Fosaprepitant Taj Pharma studies. When using combined Fosaprepitant Taj Pharma Dimeglumine 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  Fosaprepitant Taj Pharma and studies conducted with intravenous single-doseFosaprepitant Taj Pharma co-administered with dexamethasone, midazolam, or diltiazem.

Effect of Fosaprepitant Taj Pharma  on the pharmacokinetics of other active substances

CYP3A4 inhibition

As a weak inhibitor of CYP3A4, the Fosaprepitant Taj Pharma 150mg 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 150mgFosaprepitant Taj Pharma dose. Fosaprepitant Taj Pharma must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 byFosaprepitant Taj Pharma 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 Taj Pharma  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 withFosaprepitant Taj Pharma (see section 4.2). Fosaprepitant Taj Pharma 150mg 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 8mg oral dose on Days 1, 2, and 3.

Chemotherapeutic medicinal products

Interaction studies withFosaprepitant Taj Pharma 150mg and chemotherapeutic medicinal products have not been conducted; however, based on studies with oral  Fosaprepitant Taj Pharma and docetaxel and vinorelbine, FOSAPREPITANT DIMEGLUMINE TAJ PHARMA 150mg 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  Fosaprepitant Taj Pharma and ifosfamide co-administration.

Immunosuppressants

Following a single 150mgFosaprepitant Taj Pharma 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 Taj Pharma Dimeglumine .

Midazolam

Fosaprepitant Taj Pharma 150mg 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 2mg on Days 1 and 4. Fosaprepitant Taj Pharma 150mg 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 Taj Pharma Dimeglumine .

Diltiazem

Interaction studies withFosaprepitant Taj Pharma 150mg and diltiazem have not been conducted; however, the following study with 100mg of Fosaprepitant Taj Pharma  should be considered when using FOSAPREPITANT DIMEGLUMINE TAJ PHARMA 150mg with diltiazem. In patients with mild to moderate hypertension, infusion of 100mg of Fosaprepitant Taj Pharma  over 15 minutes with diltiazem 120mg 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 Taj Pharma 150mg single dose did not induce CYP3A4 on Days 1 and 4 in the midazolam interaction study. It is anticipated that Fosaprepitant Taj Pharma Dimeglumine would cause less or no greater induction of CYP2C9, CYP3A4, and glucuronidation than that caused by the administration of the 3-day oral  Fosaprepitant Taj Pharma regimen, for which a transient induction with its maximum effect 6-8 days after first  Fosaprepitant Taj Pharma dose has been observed. The 3-day oral  Fosaprepitant Taj Pharma 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 Taj Pharma Dimeglumine .

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 Taj Pharma Dimeglumine 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 Taj Pharma . Alternative non-hormonal back-up methods of contraception should be used during treatment withFosaprepitant Taj Pharma and for 2 months following the use of Fosaprepitant Taj Pharma .

5-HT3 antagonists

Interaction studies withFosaprepitant Taj Pharma 150mg and 5-HT3 antagonists have not been conducted; however, in clinical interaction studies, the oral  Fosaprepitant Taj Pharma 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 Taj Pharma Dimeglumine 150mg and 5-HT3 antagonists.

Effect of other medicinal products on the pharmacokinetics of  Fosaprepitant Taj Pharma resulting from administration of Fosaprepitant Taj Pharma  150mg

Concomitant administration of Fosaprepitant Taj Pharma  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  Fosaprepitant Taj Pharma (see section 4.4). Ketoconazole increased the terminal half-life of oral  Fosaprepitant Taj Pharma about 3-fold.

Concomitant administration of Fosaprepitant Taj Pharma  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  Fosaprepitant Taj Pharma that may result in decreased efficacy. Concomitant administration of Fosaprepitant Taj Pharma  with herbal preparations containing St. John’s Wort (Hypericum perforatum) is not recommended. Rifampicin decreased the mean terminal half-life of oral  Fosaprepitant Taj Pharma by 68 %.

Diltiazem

Interaction studies withFosaprepitant Taj Pharma 150mg and diltiazem have not been conducted; however, the following study with 100mg of Fosaprepitant Taj Pharma  should be considered when using Fosaprepitant Taj Pharma Dimeglumine 150mg with diltiazem. Infusion of 100mgFosaprepitant Taj Pharma over 15 minutes with diltiazem 120mg 3 times daily, resulted in a 1.5-fold increase of  Fosaprepitant Taj Pharma AUC. This effect was not considered clinically important.

Paediatric population

Interaction studies have only been performed in adults.

  • 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 Taj Pharma . Alternative non-hormonal back-up methods of contraception should be used during treatment withFosaprepitant Taj Pharma and for 2 months following the last dose of Fosaprepitant Taj Pharma  (see sections 4.4 and 4.5).

Pregnancy

ForFosaprepitant Taj Pharma and  Fosaprepitant Taj Pharma no clinical data on exposed pregnancies are available. The potential for reproductive toxicities of Fosaprepitant Taj Pharma  and  Fosaprepitant Taj Pharma 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 Taj Pharma Dimeglumine should not be used during pregnancy unless clearly necessary.

Breast-feeding

Fosaprepitant Taj Pharma is excreted in the milk of lactating rats after intravenous administration of Fosaprepitant Taj Pharma  as well as after oral administration of  Fosaprepitant Taj PharmaIt is not known whether  Fosaprepitant Taj Pharma is excreted in human milk. Therefore, breast-feeding is not recommended during treatment with Fosaprepitant Taj Pharma Dimeglumine .

Fertility

The potential for effects of Fosaprepitant Taj Pharma  and  Fosaprepitant Taj Pharma 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).

  • Effects on ability to drive and use machines

Fosaprepitant Taj Pharma Dimeglumine may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of FOSAPREPITANT DIMEGLUMINE TAJ PHARMA (see section 4.8).

  • Undesirable effects

Summary of the safety profile

In clinical studies, various formulations of Fosaprepitant Taj Pharma  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). SinceFosaprepitant Taj Pharma is converted to  Fosaprepitant Taj Pharma, those adverse reactions associated with  Fosaprepitant Taj Pharma are expected to occur withFosaprepitant Taj Pharma. The safety profile of  Fosaprepitant Taj Pharma was evaluated in approximately 6,500 adults and 184 children and adolescents.

Oral  Fosaprepitant Taj Pharma

The most common adverse reactions reported at a greater incidence in adults treated with the  Fosaprepitant Taj Pharma 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  Fosaprepitant Taj Pharma 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  Fosaprepitant Taj Pharma 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 –  Fosaprepitant Taj Pharma

The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with oral  Fosaprepitant Taj Pharma 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 –  Fosaprepitant Taj Pharma

System organ class Adverse reaction Frequency
Infection and infestations candidiasis, staphylococcal infection rare
Blood and lymphatic system disorders febrile neutropenia, anaemia uncommon
Immune system disorders hypersensitivity reactions including anaphylactic reactions not known
Metabolism and nutrition disorders decreased appetite common
polydipsia rare
Psychiatric disorders anxiety uncommon
disorientation, euphoric mood rare
Nervous system disorders headache common
dizziness, somnolence uncommon
cognitive disorder, lethargy, dysgeusia rare
Eye disorders conjunctivitis rare
Ear and labyrinth disorders tinnitus rare
Cardiac disorders palpitations uncommon
bradycardia, cardiovascular disorder rare
Vascular disorders hot flush/flushing uncommon
Respiratory, thoracic and mediastinal disorders hiccups common
oropharyngeal pain, sneezing, cough, postnasal drip, throat irritation rare
Gastrointestinal disorders constipation, dyspepsia common
eructation, nausea*, vomiting*, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence uncommon
duodenal ulcer perforation, stomatitis, abdominal distension, faeces hard, neutropenic colitis rare
Skin and subcutaneous tissue disorders rash, acne uncommon
photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysis rare
pruritus, urticaria not known
Musculoskeletal and connective tissue disorders muscular weakness, muscle spasms rare
Renal and urinary disorders dysuria uncommon
pollakisuria rare
General disorders and administration site conditions fatigue common
asthaenia, malaise uncommon
oedema, chest discomfort, gait disturbance rare
Investigations ALT increased common
AST increased, blood alkaline phosphatase increased uncommon
red blood cells urine positive, blood sodium decreased, weight decreased, neutrophil count decreased, glucose urine present, urine output increased rare

*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  Fosaprepitant Taj Pharma and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with  Fosaprepitant Taj Pharma.

Additional adverse reactions were observed in adult patients treated with  Fosaprepitant Taj Pharma 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  Fosaprepitant Taj Pharma.

Fosaprepitant Taj Pharma

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 Taj Pharma Dimeglumine 150mg compared to 1,169 patients receiving the 3-day regimen of  Fosaprepitant Taj Pharma. Additionally, in a placebo-controlled clinical trial in adult patients receiving MEC, safety was evaluated for 504 patients receiving a single dose of Fosaprepitant Taj Pharma Dimeglumine 150mg 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 Taj Pharma Dimeglumine at or above the recommended 1-day regimen dose, safety was evaluated for 139 patients receiving the 1-day regimen of Fosaprepitant Taj Pharma Dimeglumine . In the same analysis, safety was evaluated for 199 patients receiving either HEC or MEC and a single dose of Fosaprepitant Taj Pharma Dimeglumine at or above the recommended 3-day regimen of Fosaprepitant Taj Pharma Dimeglumine . 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 IVFosaprepitant Taj Pharma regimen in paediatric patients. The safety profile of the 3-day IVFosaprepitant Taj Pharma regimen in paediatric patients is expected to be similar to that of the 1-dayFosaprepitant Taj Pharma regimen as the low daily trough levels do not significantly increase the exposures on subsequent days.

The safety profile of Fosaprepitant Taj Pharma  in adult and paediatric patients was generally similar to that observed with  Fosaprepitant Taj Pharma.

Tabulated list of adverse reactions –Fosaprepitant Taj Pharma

The following are adverse reactions reported in adult patients receivingFosaprepitant Taj Pharma in clinical studies or postmarketing that have not been reported with  Fosaprepitant Taj Pharma 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 Taj Pharma Dimeglumine (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 Taj Pharma

System organ class Adverse reaction Frequency
Vascular disorders flushing, thrombophlebitis (predominantly, infusion-site thrombophlebitis) uncommon
Skin and subcutaneous tissue disorders erythema uncommon
General disorders and administration site conditions infusion site erythema, infusion site pain, infusion site pruritus uncommon
infusion site induration rare
immediate hypersensitivity reactions including flushing, erythema, dyspnoea, anaphylactic reactions/anaphylactic shock not known
Investigations blood pressure increased uncommon

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.

  • Overdose

In the event of overdose,Fosaprepitant Taj Pharma should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of  Fosaprepitant Taj Pharma, emesis induced by a medicinal product may not be effective.

Fosaprepitant Taj Pharma cannot be removed by haemodialysis.

  1. Pharmacological properties
    • Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants.

Fosaprepitant Taj Pharma is the prodrug of  Fosaprepitant Taj Pharma and when administered intravenously is converted rapidly to  Fosaprepitant Taj Pharma (see section 5.2). The contribution of Fosaprepitant Taj Pharma  to the overall antiemetic effect has not fully been characterised, but a transient contribution during the initial phase cannot be ruled out.  Fosaprepitant Taj Pharma is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1) receptors. The pharmacological effect of Fosaprepitant Taj Pharma  is attributed to  Fosaprepitant Taj Pharma.

1-Day Regimen of Fosaprepitant Taj Pharma  in Adults

Highly Emetogenic Chemotherapy (HEC)

In a randomized, parallel, double-blind, active-controlled study, Fosaprepitant Taj Pharma Dimeglumine 150mg (N=1,147) was compared with a 3-day  Fosaprepitant Taj Pharma regimen (N=1,175) in adult patients receiving a HEC regimen that included cisplatin (≥70mg/m2). The Fosaprepitant Taj Pharma regimen consisted of Fosaprepitant Taj Pharma  150mg on Day 1 in combination with ondansetron 32mg IV on Day 1 and dexamethasone 12mg on Day 1, 8mg on Day 2, and 8mg twice daily on Days 3 and 4. The  Fosaprepitant Taj Pharma regimen consisted of  Fosaprepitant Taj Pharma 125mg on Day 1 and 80mg/day on Days 2 and 3 in combination with ondansetron 32mg IV on Day 1 and dexamethasone 12mg on Day 1 and 8mg daily on Days 2 through 4. Fosaprepitant Taj Pharma placebo,  Fosaprepitant Taj Pharma placebo, and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding (see section 4.2). Although a 32mg 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 Taj Pharma Dimeglumine 150mg was shown to be non-inferior to that of the 3-day regimen of  Fosaprepitant Taj Pharma. 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 Taj Pharma regimen

(N =1,106) **

%

 Fosaprepitant Taj Pharma regimen
(N =1,134) **%
Difference

(95 % CI)

Complete response
Overall§ 71.9 72.3 -0.4 (-4.1, 3.3)
Delayed phase§§ 74.3 74.2 0.1 (-3.5, 3.7)
No vomiting
Overall§ 72.9 74.6 -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 Taj Pharma Dimeglumine150mg (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 Taj Pharma regimen consisted of Fosaprepitant Taj Pharma  150mg on Day 1 in combination with oral ondansetron 8mg for 2 doses and oral dexamethasone 12mg. On Days 2 and 3, patients in the Fosaprepitant Taj Pharma group received placebo for ondansetron every 12 hours. The control regimen consisted of Fosaprepitant Taj Pharma placebo 150mg IV on Day 1 in combination with oral ondansetron 8mg for 2 doses and oral dexamethasone 20mg. On Days 2 and 3, patients in the control group received 8mg oral ondansetron every 12 hours. Fosaprepitant Taj Pharma placebo and dexamethasone placebo (on Day 1) were used to maintain blinding.

The efficacy of Fosaprepitant Taj Pharma 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 Taj Pharma regimen

(N =502) **

%

Control regimen
(N =498) **%
P-Value
Complete response
Delayed phase‡ 78.9 68.5 <0.001
Complete response†
Overall§ 77.1 66.9 <0.001
Acute phase§§ 93.2 91 0.184

*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.

Figure 1:

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

Paediatric population

In 3 active-controlled, open-label clinical studies, paediatric patients aged 6 months to 17 years received either highly or moderately emetogenic chemotherapy and a single dose of Fosaprepitant Taj Pharma  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-DayFosaprepitant Taj Pharma Regimen

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

The efficacy of a 1-dayFosaprepitant Taj Pharma regimen in paediatric patients is expected to be similar to that of the 1-day adultFosaprepitant Taj Pharma regimen.

Paediatric Patients Receiving 3-DayFosaprepitant Taj Pharma Regimen

The efficacy of the 3-dayFosaprepitant Taj Pharma regimen in paediatric patients was based on that demonstrated in paediatric patients receiving the 3-day oral Fosaprepitant Taj Pharma regimen.

The efficacy of a 3-dayFosaprepitant Taj Pharma regimen in paediatric patients is expected to be similar to that of the 3-day oral Fosaprepitant Taj Pharma 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 Fosaprepitant Taj Pharma.

  • Pharmacokinetic properties

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

 Fosaprepitant Taj Pharma afterFosaprepitant Taj Pharma administration

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

Distribution

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

Biotransformation

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

Fosaprepitant Taj Pharma undergoes extensive metabolism. In healthy young adults,  Fosaprepitant Taj Pharma accounts for approximately 19 % of the radioactivity in plasma over 72 hours following a single intravenous administration 100mg dose of [14C]-Fosaprepitant Taj Pharma, a prodrug for  Fosaprepitant Taj Pharma, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of Fosaprepitant Taj Pharma have been identified in human plasma. The metabolism of Fosaprepitant Taj Pharma 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 Fosaprepitant Taj Pharma 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 100mg [14C]- Fosaprepitant Taj Pharma dose were also observed following an oral dose of [14C]- Fosaprepitant Taj Pharma. Upon conversion of 245.3mg of Fosaprepitant Taj Pharma Dimeglumine (equivalent to 150mgFosaprepitant Taj Pharma) to Fosaprepitant Taj Pharma, 23.9mg of phosphoric acid and 95.3mg of meglumine are liberated.

Elimination

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

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

Pharmacokinetics in special populations

Hepatic impairment:Fosaprepitant Taj Pharma is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of Fosaprepitant Taj Pharma  to  Fosaprepitant Taj Pharma. Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of Fosaprepitant Taj Pharma 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 Fosaprepitant Taj Pharma 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 240mg dose of oral Fosaprepitant Taj Pharma was administered to patients with severe renal impairment (CrCl< 30ml/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis.

In patients with severe renal impairment, the AUC0-¥ of total Fosaprepitant Taj Pharma (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 Fosaprepitant Taj Pharma decreased by 42 % and Cmax decreased by 32 %. Due to modest decreases in protein binding of Fosaprepitant Taj Pharma in patients with renal disease, the AUC of pharmacologically active unbound Fosaprepitant Taj Pharma 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 Fosaprepitant Taj Pharma ; 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  Fosaprepitant Taj Pharma 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 Fosaprepitant Taj Pharma for 3-day IVFosaprepitant Taj Pharma regimen in paediatric patients

Population 3-day IV/IV/IV dose AUC 0-24 hr.

(ng*hr/mL)

Cmax

(ng/mL)

C24

(ng/mL)

C48

(ng/mL)

C72

(ng/mL)

12 – 17 years old 115mg, 80mg, 80mg 21172 2475 454 424 417
6 – < 12 years old 3mg/kg, 2mg/kg, 2mg/kg 25901 2719 518 438 418
2 – < 6 years old 20568 2335 336 248 232
6 months – < 2 years old 16979 1916 256 179 167

In the 1-day IVFosaprepitant Taj Pharma setting, simulated median AUC0-24hr of  Fosaprepitant Taj Pharma 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  Fosaprepitant Taj Pharma for 1-day IVFosaprepitant Taj Pharma regimen in paediatric patients

Population 1-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 old 150mg 30400 3500 735 NR* NR*
6 – < 12 years old 4mg/kg 35766 3637 746 227 69.2
2 – < 6 years old 28655 3150 494 108 23.5
6 months – <2 years old 5mg/kg 30484 3191 522 112 24.4

*NR = Not Reported

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

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 150mgFosaprepitant Taj Pharma (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  Fosaprepitant Taj Pharma plasma concentrations.

  • Preclinical safety data

Pre-clinical data obtained with intravenous administration of Fosaprepitant Taj Pharma and oral administration of  Fosaprepitant Taj Pharma 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  Fosaprepitant Taj Pharma. 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 toFosaprepitant Taj Pharma and  Fosaprepitant Taj Pharma 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 Taj Pharma Cmax and  Fosaprepitant Taj Pharma AUC values were up to 3 times and 40 times, respectively, higher than clinical values.

In a toxicity study in juvenile dogs treated withFosaprepitant Taj Pharma from postnatal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4mg/kg/day. In a juvenile toxicity study in rats treated with Fosaprepitant Taj Pharma from postnatal day 10 to day 63, earlier vaginal opening in females from 250mg/kg b.i.d. and delayed preputial separation in males from 10mg/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  Fosaprepitant Taj Pharma. For short term treatment, these findings are considered unlikely to be clinically relevant.

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

In rabbits, Fosaprepitant Taj Pharma 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.

  1. Pharmaceutical particulars
    • List of excipients

Disodium edetate

Polysorbate 80

Lactose anhydrous

Sodium hydroxide (for pH adjustment) and/or

Hydrochloric acid diluted (for pH adjustment)

  • Incompatibilities

Fosaprepitant Taj Pharma Dimeglumine 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.

  • 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.

  • Nature and contents of container

10ml 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.

  • Special precautions for disposal and other handling

Fosaprepitant Taj Pharma Dimeglumine must be reconstituted and then diluted prior to administration.

Preparation of Fosaprepitant Taj Pharma Dimeglumine 150mg for intravenous administration:

  1. Inject 5ml sodium chloride 9mg/ml (0.9 %) solution for injection into the vial. Assure that sodium chloride 9mg/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 9mg/ml (0.9 %) solution for injection into the vial.
  2. Prepare an infusion bag filled with 145ml of sodium chloride 9mg/ml (0.9 %) solution for injection (for example, by removing 105ml of sodium chloride 9mg/ml (0.9 %) solution for injection from a 250ml sodium chloride 9mg/ml (0.9 %) solution for injection infusion bag).
  3. Withdraw the entire volume from the vial and transfer it into an infusion bag containing 145ml of sodium chloride 9mg/ml (0.9 %) solution for injection to yield a total volume of 150ml and final concentration of 1mg/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 (150ml) 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)

Note: Do not exceed maximum doses (see section 4.2).

  1. If necessary, for volumes less than 150ml, 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).

Manufactured in India By:

TAJ PHARMACEUTICALS LIMITED
At SURVEY NO.188/1 TO 189/1,190/1 TO
4, ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)

Fosaprepitant Dimeglumine for Injection USP 150mg Taj Pharma

Package leaflet: Information for the user

Fosaprepitant Dimeglumine for Injection USP 150mg Taj Pharma

Read all of this leaflet carefully before you start using 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, pharmacist, or nurse.
  • If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Fosaprepitant Dimeglumine Taj Pharma is and what it is used for
  2. What you need to know before you use Fosaprepitant Dimeglumine Taj Pharma
  3. How to use Fosaprepitant Dimeglumine Taj Pharma
  4. Possible side effects
  5. How to store Fosaprepitant Dimeglumine Taj Pharma
  6. Contents of the pack and other information
  7. What Fosaprepitant Dimeglumine Taj Pharma is and what it is used for

Fosaprepitant Dimeglumine Taj Pharma 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 Dimeglumine Taj Pharma works by blocking signals to that area, thereby reducing nausea and vomiting. Fosaprepitant Dimeglumine Taj Pharma 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.

  1. What you need to know before you use FOSAPREPITANT DIMEGLUMINE Taj Pharma

Do not use Fosaprepitant Dimeglumine Taj Pharma:

  • 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 Dimeglumine Taj Pharma.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before using Fosaprepitant Dimeglumine Taj Pharma.

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 Dimeglumine Taj Pharma 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 Dimeglumine Taj Pharma

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

The effects of Fosaprepitant Dimeglumine Taj Pharma or other medicines might be influenced if you take Fosaprepitant Dimeglumine Taj Pharma 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 Dimeglumine Taj Pharma. Another or additional non-hormonal form of birth control should be used during treatment with Fosaprepitant Dimeglumine Taj Pharma and for up to 2 months after using Fosaprepitant Dimeglumine Taj Pharma,

  • 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 Dimeglumine Taj Pharma’.

It is not known whether Fosaprepitant Dimeglumine Taj Pharma 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 breastfeeding 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 Dimeglumine Taj Pharma. If you get dizzy or get sleepy, avoid driving or using machines after using this medicine (see ‘Possible side effects’).

Fosaprepitant Dimeglumine Taj Pharma contains sodium

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

  1. How to use Fosaprepitant Dimeglumine Taj Pharma

In adults (18 years of age and older), the recommended dose of Fosaprepitant Dimeglumine Taj Pharma is 150mg fosaprepitant on Day 1 (day of chemotherapy).

In children and adolescents (6 months to 17 years of age), the recommended dose of Fosaprepitant Dimeglumine Taj Pharma is based on the patient’s age and weight. Depending on the chemotherapy treatment, there are two ways

Fosaprepitant Dimeglumine Taj Pharma may be given:

Fosaprepitant Dimeglumine Taj Pharma is given only on Day 1 (single day of chemotherapy)

Fosaprepitant Dimeglumine Taj Pharma 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 Dimeglumine Taj Pharma.

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 60 – 90 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.

  1. Possible side effects

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

Stop taking Fosaprepitant Dimeglumine Taj Pharma 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.
  • Infusion site reactions (ISR) at or near the infusion site. Most severe ISR have happened with a certain type of chemotherapy medicine that can burn or blister your skin (vesicant) with side effects, including pain, swelling and redness. Death of skin tissue (necrosis) has happened in some people getting this type of chemotherapy medicine.

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.

  1. How to store Fosaprepitant Dimeglumine Taj Pharma

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.

  1. Contents of the pack and other information

What Fosaprepitant Dimeglumine Taj Pharma contains

  • The active substance is fosaprepitant. Each vial contains FOSAPREPITANT DIMEGLUMINE Taj Pharma equivalent to 150mg fosaprepitant. After reconstitution and dilution 1ml of solution contains 1mg fosaprepitant (1mg/ml).
  • The other ingredients are: disodium edetate, polysorbate 80, lactose anhydrous,
  • sodium hydroxide (for pH adjustment) and/or hydrochloric acid diluted (for pH adjustment).
What Fosaprepitant Dimeglumine Taj Pharma looks like and contents of the pack

Fosaprepitant Dimeglumine Taj Pharma 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 Each vial contains 150mg of fosaprepitant.

Pack sizes: 1 or 10 vials.

Not all pack sizes may be marketed.

Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
At SURVEY NO.188/1 TO 189/1,190/1 TO 4, ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)