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Ivemend(福沙吡坦二甲葡胺注射剂)

2013-04-30 15:22:59  作者:新特药房  来源:互联网  浏览次数:353  文字大小:【】【】【
简介:药品名称: 中文药名:福沙吡坦二甲葡胺注射剂商品药名:美国:Emend,在瑞典、捷克、葡萄牙和英国商品名为Ivemend英文别名:Fosaprepitant dimeglumine [USAN]; Fosaprepitant dimeglumine; Ivemend; MK-0517; ...

药品名称:
中文药名:福沙吡坦二甲葡胺注射剂
商品药名:美国:Emend,在瑞典、捷克、葡萄牙和英国商品名为Ivemend
英文别名:Fosaprepitant dimeglumine [USAN]; Fosaprepitant dimeglumine; Ivemend; MK-0517; UNII-D35FM8T64X; D-Glucitol, 1-deoxy-1-(methylamino)-, (3-(((2R,3S)-2-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4- morpholinyl)methyl)-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)phosphonate (2:1) (salt); Phosphonic acid, (3-(((2R,3S)-2-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)-4-morpholinyl)methyl)-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)-, compd. with 1-deoxy-1-(methylamino)-D-glucitol (1:2)
结构式:
国外上市: 2008年6月在美国获批上市。
适 应 症:
与其它止吐药联用静脉注射防治中等催吐和大剂量催吐的抗癌药化疗(包括大剂量顺铂)初始和反复用药引起的急性和迟后的恶心和呕吐。
用法用量:
本品推荐剂量为115mg,给药方法为静脉注射(15分钟)。
药 理:
本品是阿瑞匹坦(aprepitant)口服制剂的前体药物,注射后在体内迅速转化成阿瑞吡坦。福沙匹坦二甲葡胺与阿瑞匹坦属于称作人P物质/神经激肽1(NK-1)选择性高亲和性受体阻断剂,主要通过阻断大脑恶心和呕吐信号新颖的作用机制发挥作用。阿瑞匹坦对5-羟色胺(5-HT3)、多巴胺和糖皮质激素受体极微弱或无亲和性,用于治疗化疗诱导的恶心和呕吐及术后恶心和呕吐。
临床研究:
美国FDA批准默克公司的福沙吡坦二甲葡胺注射剂(fosaprepitant dimeglumine,Emend)上市,与其它止吐药联用静脉注射防治中等催吐和大剂量催吐的药化疗(包括大剂量顺铂)初始和反复用药引起的急性和迟后的恶心和呕吐。本品是阿瑞吡坦(aprepitant)口服制剂的前体药物,注射后在体内迅速转化成阿瑞吡坦。
美国FDA批准福沙吡坦二甲葡胺注射剂上市是基于临床研究显示,本品115 mg注射后与口服阿瑞吡坦125 mg呈生物等效性。在研究中报道的不良反应为输注部位疼痛(7.6%)、输注部位硬结(1.5%)和头痛(3%)。由于福沙吡坦二甲葡胺注射后在体内转化成阿瑞吡坦,因此口服制剂出现的不良反应在注射剂中也会发生,如倦困、恶心、打呃、便秘、腹泻、食欲减退、头痛和掉发。
福沙吡坦二甲葡胺与阿瑞吡坦属于称作人P物质/神经激肽1(NK-1)选择性高亲和性受体阻断剂,主要通过阻断大脑恶心和呕吐信号新颖的作用机制发挥作用。瑞吡阿坦对5-羟色胺(5-HT3)、多巴胺和糖皮质激素受体极微弱或无亲和性,用于治疗化疗诱导的恶心和呕吐及术后恶心和呕吐。
阿瑞吡坦在动物模型上显示通过中枢神经作用抑制诸如顺铂等细胞毒化疗药物诱导的呕吐。阿瑞吡坦以动物和人正电子发射断层照相术(PET)研究表明,药物穿过血脑屏障并占据了脑NK-1受体。对动物和人的研究显示,阿瑞吡坦增大5-HT3受体阻断剂昂丹司琼和糖皮质激素地塞米松的止吐作用,抑制顺铂诱导的急性期和迟后期呕吐。


IVEMEND 150 mg powder for solution for infusion
1. NAME OF THE MEDICINAL PRODUCT
IVEMEND 150 mg powder for solution for infusion.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains fosaprepitant dimeglumine 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 acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy in adults.
Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults.
IVEMEND 150 mg is given as part of a combination therapy (see section 4.2).
4.2 Posology and method of administration
Posology
The recommended dose is 150 mg administered as an infusion over 20-30 minutes on Day 1, initiated approximately 30 minutes prior to chemotherapy (see section 6.6). IVEMEND 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.
Highly Emetogenic Chemotherapy Regimen

Day 1

Day 2

Day 3

Day 4

IVEMEND

150 mg intravenously

none

none

none

Dexamethasone

12 mg orally

8 mg orally

8 mg orally twice daily

8 mg orally twice daily

5-HT3 antagonists

Standard dose of 5-HT3 antagonists. See the product information for the selected 5-HT3 antagonist 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.
Moderately Emetogenic Chemotherapy Regimen

Day 1

IVEMEND

150 mg intravenously

Dexamethasone

12 mg orally

5-HT3 antagonists

Standard 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.
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. IVEMEND should be used with caution in these patients (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of IVEMEND in children and adolescents below 18 years of age has not yet been established. No data are available.
Method of administration
IVEMEND 150 mg should be administered intravenously and should not be given by the intramuscular or subcutaneous route. Intravenous administration occurs preferably through a running intravenous infusion over 20-30 minutes (see section 6.6). Do not administer IVEMEND 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. IVEMEND should be used with caution in these patients (see section 5.2).
CYP3A4 interactions
IVEMEND 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, diergotamine, ergotamine, 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 of fosaprepitant with ergot alkaloid derivatives, which are CYP3A4 substrates, may result in elevated plasma concentrations of these active substances. Therefore, caution is advised due to the potential risk of ergot-related toxicity.
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 (see section 4.5). Concomitant administration of fosaprepitant with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended.
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 increased plasma concentrations of aprepitant (see section 4.5).
Co-admnistration with warfarin (a CYP2C9 substrate)
Co-administration of oral aprepitant with warfarin results in decreased prothrombin time, reported as International Normalised Ratio (INR). In patients on chronic warfarin therapy, the INR should be monitored closely for 14 days following the use of fosaprepitant (see section 4.5).
Co-administration with hormonal contraceptives
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of fosaprepitant. Alternative non-hormonal back-up methods of contraception should be used during treatment with fosaprepitant and for 2 months following the use of fosaprepitant (see section 4.5).
Hypersensitivity reactions
Isolated reports of immediate hypersensitivity reactions including flushing, erythema, and dyspnoea have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who experience hypersensitivity reactions.
Administration and infusion site reactions
IVEMEND should not be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see section 4.2). IVEMEND should not be administered intramuscularly or subcutaneously (see section 5.3). Mild injection site thrombosis has been observed at higher doses. If signs or symptoms of local irritation occur, the injection or infusion should be terminated and restarted in another vein.
4.5 Interaction with other medicinal products and other forms of interaction
When administered intravenously fosaprepitant is rapidly converted to aprepitant.
Interactions with other medicinal products following administration of intravenous fosaprepitant are likely to occur with active substances that interact with oral aprepitant. The following information was derived from studies conducted with oral aprepitant and studies conducted with intravenous fosaprepitant co-administered with dexamethasone, midazolam, or diltiazem.
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.
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 on Days 1 and 2 should be reduced by approximately 50 % when co-administered with fosaprepitant 150 mg on Day 1 to achieve exposures of dexamethasone similar to those obtained when given without fosaprepitant 150 mg. Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-24hr of dexamethasone, a CYP3A4 substrate, by 100 % on Day 1 86 % on Day 2 and 18 % on Day 3 when dexamethasone was co-administered as a single 8 mg oral dose on Days 1, 2, and 3.
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, IVEMEND 150 mg is not expected to have a clinically relevant interaction with intravenously administered docetaxel and vinorelbine. An interaction with orally administered chemotherapeutic medicinal products metabolised primarily or in part by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving such medicinal products (see section 4.4).
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 IVEMEND.
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 IVEMEND.
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 IVEMEND 150 mg with diltiazem. In patients with mild to moderate hypertension, infusion of 100 mg of fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.4-fold increase in diltiazem AUC and a small but clinically meaningful decrease in blood pressure, but did not result in a clinically meaningful change in heart rate, or PR interval.
Induction
The fosaprepitant 150 mg single dose did not induce CYP3A4 on Days 1 and 4 in the midazolam interaction study. It is anticipated that IVEMEND 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 IVEMEND.
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 IVEMEND 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 IVEMEND 150 mg and 5-HT3 antagonists.
Effect of other medicinal products on the pharmacokinetics of aprepitant resulting from administration of fosaprepitant 150 mg
Concomitant administration of fosaprepitant with active substances that inhibit CYP3A4 activity (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors) should be approached cautiously, as the combination is expected to result in several-fold increased plasma concentrations of aprepitant (see section 4.4). Ketoconazole increased the terminal half-life of oral aprepitant about 3-fold.
Concomitant administration of fosaprepitant with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, 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 IVEMEND 150 mg 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.
4.6 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. IVEMEND 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 IVEMEND.
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
IVEMEND may have minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of IVEMEND (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
Since fosaprepitant is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with fosaprepitant. Prior to approval of fosaprepitant 150 mg, the safety profiles of fosaprepitant and aprepitant were evaluated in approximately 1,100 individuals and 6,500 individuals, respectively. In clinical studies, various formulations of fosaprepitant have been administered to a total of 2,183 individuals including 371 healthy subjects and 1,579 patients with chemotherapy induced nausea and vomiting (CINV).
Oral aprepitant
The most common adverse reactions reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC) were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving Moderately Emetogenic Chemotherapy (MEC) was fatigue (1.4 % versus 0.9 %).
Tabulated list of adverse reactions - aprepitant
The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with oral aprepitant than with standard therapy or in postmarketing use:
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).

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

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

pollakiuria

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 for up to 6 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.
In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant.
Additional adverse reactions were observed in patients treated with aprepitant for postoperative nausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, constipation*, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, sub-ileus*, visual acuity reduced, wheezing.
*Reported in patients taking a higher dose of aprepitant.
Fosapepitant
In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of IVEMEND 150 mg compared to 1,169 patients receiving the 3-day regimen of aprepitant. The safety profile was generally similar to that seen in the aprepitant table above.
Tabulated list of adverse reactions - fosaprepitant
The following are adverse reactions reported in patients receiving fosaprepitant in clinical studies or postmarketing that have not been reported with aprepitant as described above:
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).

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

not known

Investigations

blood pressure increased

uncommon


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, ATC code: A04AD12.
Fosaprepitant is the prodrug of aprepitant and when administered intravenously is converted rapidly to aprepitant (see section 5.2). The contribution of fosaprepitant to the overall antiemetic effect has not fully been characterised, but a transient contribution during the initial phase cannot be ruled out. Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1) receptors. The pharmacological effect of fosaprepitant is attributed to aprepitant
3-day regimen of aprepitant
In 2 randomised, double-blind studies encompassing a total of 1,094 patients receiving chemotherapy that included cisplatin ≥70 mg/m2, aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with a standard regimen (placebo plus ondansetron 32 mg intravenously administered on Day 1 plus dexamethasone 20 mg orally on Day 1 and 8 mg orally twice daily on Days 2 to 4). 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 measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. The results were evaluated for each individual study and for the 2 studies combined.
A summary of the key study results from the combined analysis is shown in Table 1.
Table 1
Percent of patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase — Cycle 1

COMPOSITE MEASURES

Aprepitant regimen

Standard therapy

Differences*

(N= 521)

(N= 524)

%

%

%

(95 % CI)

Complete response (no emesis and no rescue therapy)

Overall (0-120 hours)

0-24 hours

25-120 hours

67.7

86.0

71.5

47.8

73.2

51.2

19.9

12.7

20.3

(14.0, 25.8)

(7.9, 17.6)

(14.5, 26.1)

INDIVIDUAL MEASURES

No emesis (no emetic episodes regardless of use of rescue therapy)

Overall (0-120 hours)

0-24 hours

25-120 hours

71.9

86.8

76.2

49.7

74.0

53.5

22.2

12.7

22.6

(16.4, 28.0)

(8.0, 17.5)

(17.0, 28.2)

No significant nausea (maximum VAS <25 mm on a scale of 0-100 mm)

Overall (0-120 hours)

25-120 hours

72.1

74.0

64.9

66.9

7.2

7.1

(1.6, 12.8)

(1.5, 12.6)

* The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which were included in the primary analysis of odds ratios and logistic models.
† One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses; one patient in the Standard regimen only had data in the delayed phase and was excluded from the overall and acute phase analyses.
The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1.
Figure 1


Percent of patients receiving Highly Emetogenic Chemotherapy who remain emesis free over time – Cycle 1
Statistically significant differences in efficacy were also observed in each of the 2 individual studies.
In the same 2 clinical studies, 851 patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was maintained during all cycles.
In a randomised, double-blind study in a total of 866 patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1,500 mg/m2; or cyclophosphamide 500-1,500 mg/m2 and doxorubicin (≤60 mg/m2) or epirubicin (≤100 mg/m2), aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).
Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1.
A summary of the key study results is shown in Table 2.
Table 2
Percent of patients responding by treatment group and phase —Cycle 1
Moderately Emetogenic Chemotherapy

COMPOSITE MEASURES

Aprepitant regimen

Standard therapy

Differences*

(N= 433)

(N= 424)

%

%

%

(95 % CI)

Complete response (no emesis and no rescue therapy)

Overall (0-120 hours)

0-24 hours

25-120 hours

50.8

75.7

55.4

42.5

69.0

49.1

8.3

6.7

6.3

(1.6, 15.0)

(0.7, 12.7)

(-0.4, 13.0)

INDIVIDUAL MEASURES

 

No emesis (no emetic episodes regardless of use of rescue therapy)

Overall (0-120 hours)

0-24 hours

25-120 hours

75.7

87.5

80.8

58.7

77.3

69.1

17.0

10.2

11.7

(10.8, 23.2)

(5.1, 15.3)

(5.9, 17.5)

No significant nausea (maximum VAS <25 mm on a scale of 0-100 mm)

Overall (0-120 hours)

0-24 hours

25-120 hours

60.9

79.5

65.3

55.7

78.3

61.5

5.3

1.3

3.9

(-1.3, 11.9)

(-4.2, 6.8)

(-2.6, 10.3)


* The confidence intervals were calculated with no adjustment for age category (<55 years, ≥55 years) and investigator group, which were included in the primary analysis of odds ratios and logistic models.
† One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses.
In the same clinical study, 744 patients continued into the Multiple-Cycle extension for up to 3 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was maintained during all cycles.
In a second multicenter, randomized, double-blind, parallel-group, clinical study, the aprepitant regimen was compared with standard therapy in 848 patients (652 females, 196 males) receiving a chemotherapy regimen that included any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide IV (<1,500 mg/m2); or cytarabine IV (>1 g/m2). Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumour types including 52 % with breast cancer, 21 % with gastrointestinal cancers including colorectal cancer, 13 % with lung cancer and 6 % with gynaecological cancers. The aprepitant regimen in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo in combination with ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).
Efficacy was based on the evaluation of the following primary and key secondary endpoints: No vomiting in the overall period (0 to 120 hours post-chemotherapy), evaluation of safety and tolerability of the aprepitant regimen for CINV, and complete response (defined as no vomiting and no use of rescue therapy) in the overall period (0 to 120 hours post-chemotherapy). Additionally, no significant nausea in the overall period (0 to 120 hours post-chemotherapy) was evaluated as an exploratory endpoint, and in the acute and delayed phases as a post-hoc analysis.
A summary of the key study results is shown in Table 3.
Table 3
Percent of patients responding by treatment group and phase for Study 2 – Cycle 1
Moderately Emetogenic Chemotherapy

Aprepitant regimen

Standard therapy

Differences*

(N= 425)

(N= 406)

%

%

%

(95 % CI)

Complete response (no emesis and no rescue therapy)

Overall (0-120 hours)

0-24 hours

25-120 hours

68.7

89.2

70.8

56.3

80.3

60.9

12.4

8.9

9.9

(5.9, 18.9)

(4.0, 13.8)

(3.5, 16.3)

No emesis (no emetic episodes regardless of use of rescue therapy)

Overall (0-120 hours)

0-24 hours

25-120 hours

76.2

92.0

77.9

62.1

83.7

66.8

14.1

8.3

11.1

(7.9, 20.3)

(3.9, 12.7)

(5.1, 17.1)

No significant nausea (maximum VAS <25 mm on a scale of 0-100 mm)

Overall (0-120 hours)

0-24 hours

25-120 hours

73.6

90.9

74.9

66.4

86.3

69.5

7.2

4.6

5.4

(1.0, 13.4)

(0.2, 9.0)

(-0.7, 11.5)


*The confidence intervals were calculated with no adjustment for gender and region, which were included in the primary analysis using logistic models.
The benefit of aprepitant combination therapy in the full study population was mainly driven by the results observed in patients with poor control with the standard regimen such as in women, even though the results were numerically better regardless of age, tumour type or gender. Complete response to the aprepitant regimen and standard therapy, respectively, was reached in 209/324 (65 %) and 161/320 (50 %) in women and 83/101 (82 %) and 68/87 (78 %) of men.
1-day regimen of IVEMEND 150 mg
In a randomized, parallel, double-blind, active-controlled study, IVEMEND 150 mg (N=1,147) was compared with a 3-day aprepitant regimen (N=1,175) in 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. IVEMEND 150 mg 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 4.
Table 4
Percent of patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase — Cycle 1

ENDPOINTS*

Fosaprepitant regimen

Aprepitant regimen

Difference

 

(N =1,106) **

(N =1,134) **

 

 

%

%

(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 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.
Paediatric population
Studies evaluating the use of fosaprepitant in paediatric patients are on-going (see section 4.2 for information on paediatric use).
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 volunteers, the mean AUC0-∞ of aprepitant was 35.0 µg•hr/ml and the mean maximal aprepitant concentration was 4.01 µg/ml.
Distribution
Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean volume of distribution at steady state (Vdss) of aprepitant estimated from a single 150 mg intravenous dose of fosaprepitant is approximately 82 l in humans.
Biotransformation
Fosaprepitant was rapidly converted to aprepitant in in vitro incubations with liver preparations from humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9 preparations from other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple tissues. In humans, fosaprepitant administered intravenously was rapidly converted to aprepitant within 30 minutes following the end of infusion.
Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19 % of the radioactivity in plasma over 72 hours following a single intravenous administration 100 mg dose of [14C]- fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19.
All metabolites observed in urine, faeces and plasma following an intravenous 100 mg [14C]-fosaprepitant dose were also observed following an oral dose of [14C]-aprepitant. Upon conversion of 245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of meglumine are liberated.
Elimination
Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [14C]- fosaprepitant to healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces.
The pharmacokinetics of aprepitant is non-linear across the clinical dose range. The terminal half-life of aprepitant following a 150 mg intravenous dose of fosaprepitant was approximately 11 hours. The geometric mean plasma clearance of aprepitant following a 150 mg intravenous dose of fosaprepitant was approximately 73 ml/min.
Pharmacokinetics in special populations
Fosaprepitant pharmacokinetics has not been evaluated in special populations. No clinically relevant differences in aprepitant pharmacokinetics is expected due to age and gender.
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.
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. 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.
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, rabbit and monkey, including the reproduction toxicity studies, are limited since systemic exposures to fosaprepitant and aprepitant were only similar or even lower than therapeutic exposure in 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 rabbits, IVEMEND 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 excipient(s)
 Disodium edetate (E386)
Polysorbate 80 (E433)
Lactose anhydrous
Sodium hydroxide (E524) (for pH adjustment) and/or
Hydrochloric acid diluted (E507) (for pH adjustment)
6.2 Incompatibilities
 IVEMEND 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 of the reconstituted and diluted 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
IVEMEND must be reconstituted and then diluted prior to administration.
Preparation of IVEMEND 150 mg for intravenous administration:
1. Inject 5 ml sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial. Assure that sodium chloride 9 mg/ml (0.9 %) solution for injection is added to the vial along the vial wall in order to prevent foaming. Swirl the vial gently. Avoid shaking and jetting sodium chloride 9 mg/ml (0.9 %) solution for injection into the vial.
2. Prepare an infusion bag filled with 145 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection (for example, by removing 105 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection from a 250 ml sodium chloride 9 mg/ml (0.9 %) solution for injection infusion bag).
3. Withdraw the entire volume from the vial and transfer it into an infusion bag containing 145 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection to yield a total volume of 150 ml. Gently invert the bag 2-3 times.
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).
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.
No special requirements for disposal.
7. MARKETING AUTHORISATION HOLDER
 Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN 11 9BU
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
 EU/1/07/437/003
EU/1/07/437/004
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
 Date of first authorisation: 11 January 2008
Date of latest renewal: 11 January 2013
10. DATE OF REVISION OF THE TEXT
22 March 2013

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