Aprepitant

Prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and adolescents from the age of 12. 2).

Posology Adults Aprepitant is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose is 125mg orally once daily one hour before start of chemotherapy on Day 1 and 80 mg orally once daily on Days 2 and 3 in the morning.

The following regimens are recommended in adults for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy: Highly Emetogenic Chemotherapy Regimen Day 1 Day 2 Day 3 Day 4 Aprepitant 125mg orally 80mg orally 80mg orally none Dexamethasone 12mg orally 8mg orally 8mg orally 8mg orally 5-HT3 antagonists Standard dose of 5-HT3 antagonists.

See the product information for 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 Day 2 to 4. The dose of dexamethasone accounts for active substance interactions.

Moderately Emetogenic Chemotherapy Regimen Day 1 Day 2 Day 3 Aprepitant 125mg orally 80mg orally 80mg orally Dexamethasone 12mg orally None None 5-HT3 antagonists Standard dose of 5-HT3 antagonists. See the product information for selected 5-HT3 antagonist for appropriate dosing information None None Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1.

The dose of dexamethasone accounts for active substance interactions. Paediatric population Adolescents (aged 12 through 17 years) Aprepitant is given for 3 days as part of a regimen that includes a 5-HT3 antagonist. The recommended dose of capsules of aprepitant is 125mg orally on Days 1 and 80 mg orally on Days 2 and 3.

Aprepitant is administered orally 1 hours prior to chemotherapy on Days 1, 2 and 3. If no chemotherapy is given on Days 2 and 3, aprepitant should be administered in the morning. See the Summary of Product Characteristics (SmPC) for the selected 5-HT3 antagonist for appropriate dosing information.

1). The safety and efficacy of the 80 mg and 125mg capsules have not been demonstrated in children less than 12 years of age. No data are available. General Efficacy data in combination with other corticosteroids and 5-HT3 antagonists are limited.

5. Please refer to the SmPC of co-administered 5-HT3 antagonist medicinal products. 2). 2). 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.

2). Method of administration For oral use. The hard capsule should be swallowed whole. Aprepitant may be taken with or without food.

Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials. 5 %). 9 %). 0 %). Tabulated list of adverse reactions The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy in adults or paediatric patients or in post-marketing 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). 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 Decreased appetite CommonMetabolism and nutrition disorders Polydipsia Rare Anxiety UncommonPsychiatric disorders Disorientation, euphoric mood Rare Headache Common Dizziness, somnolence Uncommon Nervous system disorders Cognitive disorder, lethargy, dysgeusia Rare Eye disorders Conjunctivitis Rare Ear and labyrinth disorders Tinnitus Rare Palpitations UncommonCardiac disorders Bradycardia, cardiovascular disorder Rare Vascular disorders Hot flushes/flushing Uncommon Respiratory, thoracic Hiccups Common and mediastinal disorders Oropharyngeal pain, sneezing, cough, postnasal drip, throat irritation Rare Constipation, dyspepsia Common Eructation, nausea†, vomiting†, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence Uncommon Gastrointestinal disorders Duodenal ulcer perforation, stomatitis, abdominal distention, faeces hard, neutropenic colitis Rare Rash, acne Uncommon Photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash prutitic, Stevens-Johnson syndrome/toxic epidermal necrolysis Rare Skin and subcutaneous tissue disorders Pruritus, urticarial Not known Musculoskeletal and connective tissue disorders Muscular weakness, muscle spasms Rare Renal and urinary disorders Dysuria Pollakiuria Uncommon Rare Fatigue Common Asthenia, malaise Uncommon General disorders and administration site conditions Oedema, chest discomfort, gait disturbance Rare ALT increase Common AST increase, blood alkaline phosphatase increased Uncommon Investigations 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 adults 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 adult patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant. Additional adverse reactions were observed in adult patients treated with aprepitant for postoperative nausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, constipation*, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, sub-ileus*, visual acuity reduced, wheezing.

*Reported in patients taking a higher dose of aprepitant. Reporting of suspected adverse reactions If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine

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38 EMEND® (aprepitant capsules) Page 3 of 40 EMEND® aprepitant capsules PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION INDICATIONS AND CLINICAL USE EMEND® (aprepitant), in combination with a 5-HT3 antagonist class of antiemetics and dexamethasone, is indicated for the: 1.

prevention of acute and delayed nausea and vomiting due to highly emetogenic cancer chemotherapy 2. prevention of nausea and vomiting in women due to treatment with moderately emetogenic cancer chemotherapy.

Geriatrics (≥65 years of age):

In clinical studies, the efficacy and safety of EMEND® in the elderly (≥65 years) were comparable to those seen in younger patients (<65 years). No dosage adjustment is necessary in elderly patients.

Pediatrics (<18 years of age):

No data available. CONTRAINDICATIONS Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph. EMEND® should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride.

Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life- threatening reactions (see DRUG INTERACTIONS). Route of Administration Dosage Form / Strength Clinically Relevant Non-Medicinal Ingredients oral Capsule/ 80 mg, 125 mg For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

EMEND® (aprepitant capsules) Page 4 of 40 WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Drug interactions with: Medicinal products, including chemotherapeutic agents, that are metabolized through CYP3A4 (see DRUG INTERACTIONS) Warfarin (see DRUG INTERACTIONS) Hormonal contraception (see DRUG INTERACTIONS) Drug Interactions CYP3A4 substrates: EMEND® is a moderate inhibitor of CYP3A4.

Caution should be used when EMEND® is co-administered with CYP3A4 substrates, including chemotherapeutic agents (see DRUG INTERACTIONS). Serious post-marketing reports of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported in patients after EMEND® and ifosfamide co-administration.

Caution and careful monitoring are advised. Refer to IFEX (ifosfamide for injection) product monograph. (see ADVERSE REACTIONS / Post-Market Adverse Drug Reactions and DRUG INTERACTIONS).

Warfarin:

Co-administration of EMEND® with warfarin may cause a clinically significant decrease in the INR. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND® with each chemotherapy cycle (see DRUG INTERACTIONS).

Hormonal contraception:

EMEND® may reduce the efficacy of hormonal contraception. Alternative or backup methods should be used during and for 1 month following the last dose of EMEND® (see DRUG INTERACTIONS). 5 times the systemic exposure at the adult human dose and have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant.

However, there are no adequate and well-controlled studies in pregnant women; therefore, EMEND® is not recommended for use during pregnancy unless clearly necessary.

Nursing Women:

Aprepitant is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk; therefore, breastfeeding is not recommended during treatment with EMEND®.

Pediatrics (<18 years of age):

Safety and effectiveness of EMEND® in pediatric patients have not been established.

EMEND® (aprepitant capsules) Page 5 of 40 Geriatrics (≥65 years of age):

In 2 well-controlled clinical studies, of the total number of patients (N=544) treated with EMEND®, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Greater sensitivity of some older individuals cannot be ruled out. […]

Prevention nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and adolescents from the age of 12. 2).

Posology Adults EMEND is given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose is 125 mg orally once daily one hour before start of chemotherapy on Day 1 and 80 mg orally once daily on Days 2 and 3 in the morning.

3 The following regimens are recommended in adults for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy: Highly Emetogenic Chemotherapy Regimen Day 1 Day 2 Day 3 Day 4 EMEND 125 mg orally 80 mg orally 80 mg orally none Dexamethasone 12 mg orally 8 mg orally 8 mg orally 8 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 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.

The dose of dexamethasone accounts for active substance interactions. Moderately Emetogenic Chemotherapy Regimen Day 1 Day 2 Day 3 EMEND 125 mg orally 80 mg orally 80 mg orally Dexamethasone 12 mg orally none none 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 Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for active substance interactions.

Paediatric population Adolescents (aged 12 through 17 years) EMEND is given for 3 days as part of a regimen that includes a 5-HT3 antagonist. The recommended dose of capsules of EMEND is 125 mg orally on Day 1 and 80 mg orally on Days 2 and 3.

EMEND is administered orally 1 hour prior to chemotherapy on Days 1, 2 and 3. If no chemotherapy is given on Days 2 and 3, EMEND should be administered in the morning. See the Summary of Product Characteristics (SmPC) for the selected 5-HT3 antagonist for appropriate dosing information.

1). The safety and efficacy of the 80 mg and 125 mg capsules have not been demonstrated in children less than 12 years of age. No data are available. Refer to the powder for oral suspension SmPC for appropriate dosing in infants, toddlers and children aged 6 months to less than 12 years.

General Efficacy data in combination with other corticosteroids and 5-HT3 antagonists are limited. 5. Please refer to the SmPC of co-administered 5-HT3 antagonist medicinal products. 2). 2). 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. 2). Method of administration The hard capsule should be swallowed whole. EMEND may be taken with or without food.

Summary of the safety profile The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials. 5 %). 9 %). 0 %). Tabulated list of adverse reactions The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy in adults or paediatric patients or in post- marketing 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). 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 9 System organ class Adverse reaction Frequency 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 pollakiuria rare 10 System organ class Adverse reaction Frequency General disorders and administration site conditions fatigue common asthenia, 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 adults 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 adult patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant. Non-CINV studies Additional adverse reactions were observed in adult patients treated with a single 40 mg dose of aprepitant for postoperative nausea and vomiting (PONV) with 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. 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.

Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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