Active ingredients: Apripitant
EMEND 125 mg hard capsules
EMEND 80 mg hard capsules
Emend package inserts are available for pack sizes: - EMEND 125 mg hard capsules, EMEND 80 mg hard capsules
- EMEND 125 mg powder for oral suspension
Why is Emend used? What is it for?
EMEND contains the active substance aprepitant and belongs to a group of medicines called 'neurokinin 1 (NK1) receptor antagonists'. The brain has a specific "area that controls nausea and vomiting. EMEND works by blocking the signals sent to that area, thereby reducing nausea and vomiting. EMEND capsules are used in adults and adolescents aged 12 and over together with others. medicines to prevent nausea and vomiting caused by chemotherapy treatments (cancer treatments) which are strong and moderate inducers of nausea and vomiting (e.g. cisplatin, cyclophosphamide, doxorubicin or epirubicin).
Contraindications When Emend should not be used
Do not take EMEND:
- if you or the child are allergic to aprepitant or any of the other ingredients of this medicine
- with medicines containing pimozide (a substance used to treat psychiatric diseases), terfenadine and astemizole (used for hay fever and other allergies), cisapride (used to treat digestive problems). Tell the doctor if you or the child are taking these medicines as the therapy needs to be changed before you or the child starts taking EMEND.
Precautions for use What you need to know before taking Emend
Talk to your doctor, pharmacist or nurse before taking EMEND or giving this medicine to your child.
Before treatment with this medicine, tell your doctor if you or the child have liver disease because the liver is important in breaking down the medicine in the body. Your doctor may therefore need to check the condition of your liver or than that of the child.
Children and adolescents
Do not give EMEND 80 mg capsules to children under 12 years of age, as the 80 mg capsules have not been studied in this population.
Interactions Which drugs or foods can modify the effect of Emend
EMEND can affect other medicines both during and after treatment with EMEND. There are some medicines that must not be taken with EMEND (such as pimozide, terfenadine, astemizole, and cisapride) or that require dose adjustment (see also: "Do not take EMEND").
The effects of EMEND or other medicines could be influenced if you or your child take EMEND together with other medicines including those listed below. Tell your doctor or pharmacist if you or your child are taking any of the following medicines:
- birth control medicines which may include birth control pills, skin patches, implants, and some hormone-releasing intrauterine devices (IUDs) may not work properly when taken together with EMEND. Another or additional non-hormonal method of birth control should be used during treatment with EMEND and for up to 2 months after use of EMEND.
- cyclosporine, tacrolimus, sirolimus, everolimus (immunosuppressants)
- alfentanil, fentanyl (used to treat pain)
- quinidine (used to treat an irregular heartbeat)
- irinotecan, etoposide, vinorelbine, ifosfamide (medicines used to treat cancer)
- medicines containing ergot-derived alkaloids such as ergotamine and diergotamine (used to treat migraine)
- warfarin, acenocoumarol (anticoagulants; 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 calm or help you sleep)
- St. John's wort (a herbal preparation used to treat depression)
- protease inhibitors (used to treat HIV infections)
- ketoconazole except shampoo (used to treat Cushing's syndrome, which is characterized by the body making too much cortisol)
- itraconazole, voriconazole, posaconazole (antifungals)
- nefazodone (used to treat depression)
- corticosteroids (such as dexamethasone and methylprednisolone)
- anti anxiety medicines (such as alprazolam)
- tolbutamide (a medicine used to treat diabetes) Tell your doctor or pharmacist if you or your child are taking, have recently taken, or might take any other medicines.
Tell your doctor or pharmacist if you or your child are taking, have recently taken, or might take any other medicines.
Warnings It is important to know that:
Pregnancy and breastfeeding
This medicine should not be used during pregnancy unless clearly needed. If you or the baby are pregnant, think you may be pregnant or are planning to have a baby or are breast-feeding, ask your doctor for advice before taking this medicine.
For information on birth control, see "Other medicines and EMEND".
It is not known whether EMEND is excreted in human milk; Breastfeeding is therefore not recommended during treatment with this medicine. Before taking this medicine it is important to tell your doctor if you or the baby are breastfeeding or thinking of breastfeeding.
Driving and using machines
It should be taken into account that some people feel dizzy and sleepy after taking EMEND. If you or your child feel dizzy or sleepy, avoid driving, cycling or using machines or tools after taking this. medicine (see "Possible side effects").
EMEND contains sucrose
EMEND capsules contain sucrose. If you have been told by your doctor that you or the child have an intolerance to some sugars, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Emend: Posology
Always take this medicine or give this medicine to your child exactly as your doctor, pharmacist or nurse has told you. If you are unsure, ask your doctor, pharmacist or nurse. Always take EMEND together with other medicines to prevent nausea and vomiting. After treatment with EMEND, your doctor may ask you or your child to continue taking other medicines including a corticosteroid (such as dexamethasone) and a "5-HT3 antagonist" (such as "ondansetron) to prevent nausea and vomiting. Consult your doctor, pharmacist or nurse if you are not sure.
The recommended oral dose of EMEND is:
- Day 1:
- one 125 mg capsule 1 hour before starting the chemotherapy session
- Days 2 and 3:
- one 80 mg capsule each day.
- If chemotherapy is not given, take EMEND in the morning.
- If chemotherapy is given, take
EMEND 1 hour before starting the chemotherapy session. EMEND can be taken with or without food.
Swallow the capsule whole with liquid.
If you forget to take EMEND
If you or the child miss a dose, ask your doctor for advice.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Emend
Do not take more capsules than recommended by your doctor. If you or the child have taken too many capsules, call your doctor immediately.
Side Effects What are the side effects of Emend
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking EMEND and see a doctor immediately if you or your child notice any of the following side effects, which can be serious and for which you or your child may need urgent medical treatment:
- hives, rash, itching, difficulty in breathing or swallowing (frequency not known, cannot be estimated from the available data); these are signs of an allergic reaction.
Other side effects that have been reported are listed below.
Common side effects (may affect up to 1 in 10 people) are:
- constipation, indigestion
- headache
- tiredness
- loss of appetite
- hiccup
- increase in the amount of liver enzymes in the blood.
Uncommon side effects (may affect up to 1 in 100 people) are:
- dizziness, sleepiness,
- acne, rash
- anxiety,
- belching
- nausea, vomiting, heartburn, stomach pain, dry mouth, wind
- increased pain or burning when urinating
- weakness, general feeling of being unwell
- flushing / redness of the face or skin
- rapid or irregular heartbeats
- fever with increased risk of infection, lowering of red blood cells.
Rare side effects (may affect up to 1 in 1,000 people) are:
- difficulty thinking, lack of energy, altered taste
- sensitivity of the skin to the sun, excessive sweating, oily skin, skin lesions, itchy rash, Stevens-Johnson syndrome / toxic epidermal necrolysis (a rare serious skin reaction)
- euphoria (feeling of extreme happiness), disorientation
- bacterial infection, fungal infection
- severe constipation, stomach ulcer, inflammation of the small intestine and colon, lesions in the mouth, intestinal gas
- frequent urination, passing more urine than normal, having sugar or blood in the urine
- chest discomfort, swelling, change in the way you walk
- cough, mucous discharge in the back of the throat, throat irritation, sneezing, sore throat
- ocular discharge and itching
- ringing in the ears
- muscle spasms, muscle weakness
- excessive thirst
- slow heart rate, heart and blood vessel disease
- lowering of white blood cells, lowering of sodium levels in the blood, weight loss.
Reporting of side effects
If you or the child get any side effects, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system.
By reporting side effects you can help provide more information on the safety of this medicine.
<Other Information
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 after EXP. The expiry date refers to the last day of the month.
Store in the original package to keep it away from moisture.
Do not remove the capsule from the blister until you are about to take it.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other "> Other Information
What EMEND contains
EMED 80 mg hard capsules:
- The active ingredient is aprepitant. Each capsule contains 80 mg of aprepitant.
- The other ingredients are: sucrose, microcrystalline cellulose (E 460), hydroxypropylcellulose (E 463), sodium lauryl sulfate, gelatin, titanium dioxide (E 171), shellac, potassium hydroxide and black iron oxide (E 172).
EMED 125 mg hard capsules:
- The active ingredient is aprepitant. Each 125 mg hard capsule contains 125 mg of aprepitant.
- The other ingredients are: sucrose, microcrystalline cellulose (E 460), hydroxypropylcellulose (E 463), sodium lauryl sulfate, gelatin, titanium dioxide (E 171), shellac, potassium hydroxide, black iron oxide (E 172), red iron oxide (E 172) and yellow iron oxide (E 172).
Description of what EMEND looks like and contents of the pack
EMED 80 mg hard capsules:
The 80 mg hard capsule is opaque with white cap and body with "461" and "80 mg" printed radially on the body in black ink.
EMEND 80 mg hard capsules are available in the following pack sizes:
- Aluminum blister containing one 80 mg capsule
- 2-day treatment pack containing two 80 mg capsules
- 5 aluminum blisters each containing one 80 mg capsule
Not all pack sizes may be marketed.
EMED 125 mg hard capsules:
The 125 mg hard capsule is opaque with a white body and pink cap with "462" and "125 mg" printed radially on the body in black ink.
EMEND 125 mg hard capsules are available in the following pack sizes:
- Aluminum blister pack containing one 125 mg capsule
- 5 aluminum blisters each containing one 125 mg capsule
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
EMEND HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 125 mg capsule contains 125 mg of aprepitant. Each 80 mg capsule contains 80 mg of aprepitant.
Excipient with known effect
Each capsule contains 125 mg of sucrose (in the 125 mg capsule).
Excipient with known effect
Each capsule contains 80 mg of sucrose (in the 80 mg capsule).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsule.
The 125 mg capsules are opaque with a white body and pink cap with "462" and "125 mg" printed radially on the body in black ink. The 80 mg capsules are opaque with a white body and cap with "461" and "80 mg" printed radially on the body in black ink.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and adolescents from 12 years.
EMEND 125 mg / 80 mg is given as part of a combination therapy (see section 4.2).
04.2 Posology and method of administration
Dosage
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 starting 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
Dexamethasone should be administered 30 minutes before chemotherapy treatment on day 1 and in the morning on days 2 to 4. The dose of dexamethasone takes into account drug interactions.
Moderately emetogenic chemotherapy regimen
Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on day 1. The dose of dexamethasone takes into account drug interactions.
Pediatric population
Teenagers (12 to 17 years of age)
EMEND is given for 3 days as part of a regimen that includes a 5-HT3 antagonist. The recommended dose for EMEND capsules is 125 mg orally on Day 1 and 80 mg orally on Days 2 and 3. EMEND is given orally 1 hour before chemotherapy on Days 1, 2 and 3. If chemotherapy is not given on days 2 and 3, EMEND should be given in the morning. See the Summary of Product Characteristics (SmPC) of the selected 5-HT3 antagonist for information on the appropriate dosage. If a corticosteroid, such as dexamethasone, is co-administered with EMEND, the corticosteroid dose should be administered at 50% of the usual dose (see sections 4.5 and 5.1).
The safety and efficacy of the 80 mg capsule and 125 mg capsule have not been demonstrated in children under the age of 12. No data are available. For information on appropriate dosing in infants, toddlers and in children from 6 months to less than 12 years of age, see the summary of product characteristics for the powder for oral suspension.
General
Efficacy data on combination with other corticosteroids and 5-HT3 antagonists are limited. For more information on co-administration with corticosteroids, see section 4.5. Refer to the Summary of Product Characteristics of 5-HT3 antagonist medicinal products. administered.
Special populations
Elderly (≥ 65 years old)
No dose adjustment is required for the elderly (see section 5.2).
Sex
No dose adjustment is required based on gender (see section 5.2).
Impaired renal function
No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing hemodialysis (see section 5.2).
Impaired liver function
No dose adjustment is necessary for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and there is no data in patients with severe hepatic impairment. Apripitant should be used with caution in these patients (see sections 4.4 and 5.2).
Method of administration
The hard capsules must be swallowed whole.
EMEND can be taken with or without food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).
04.4 Special warnings and appropriate 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. EMEND should be used with caution in these patients (see section 5.2).
Interactions with CYP3A4
EMEND should be used with caution in patients on concomitant oral therapy with active substances metabolised primarily by CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, ergot-derived alkaloids, fentanyl and quinidine (see section 4.5 Furthermore, concomitant administration with irinotecan must be approached with great caution as the combination may result in increased toxicity.
Concomitant administration with warfarin (a CYP2C9 substrate)
In patients on chronic warfarin therapy, the International Normalized Ratio (INR) should be closely monitored during treatment with EMEND and for 14 days after each 3-day course of EMEND (see section 4.5).
Concomitant administration with hormonal contraceptives
The efficacy of hormonal contraceptives may be reduced during and 28 days after administration of EMEND. During treatment with EMEND and for 2 months after the administration of the last dose of EMEND, alternative non-hormonal replacement methods of contraception should be used (see paragraph 4.5).
Excipients
EMEND capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
L "aprepitant (125 mg / 80 mg) is a substrate, moderate inhibitor and inducer of CYP3A4. L" aprepitant is also an inducer of CYP2C9. There is inhibition of CYP3A4 during treatment with EMEND. Upon termination of treatment, EMEND causes a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Aperpitant does not appear to interact with transport P-glycoprotein, as suggested by the lack of interaction between aprepitant and digoxin.
Effect of aprepitant on the pharmacokinetics of other active substances
CYP3A4 inhibition
As a moderate inhibitor of CYP3A4, aprepitant (125 mg / 80 mg) may increase plasma concentrations of concomitantly administered CYP3A4 metabolised active substances. Total exposure of concomitantly administered CYP3A4 substrates may increase to approximately 3 times during the 3 day treatment with EMEND; the expected effect of aprepitant on plasma concentrations of CYP3A4 substrates administered intravenously is expected to be lower. EMEND must not be used concomitantly with pimozide, terfenadine, astemizole or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant may result in elevated plasma concentrations of these active substances, potentially causing serious and life-threatening reactions. Caution is advised during concomitant administration of EMEND and orally administered active substances metabolised primarily by 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 usual oral dose of dexamethasone should be reduced by approximately 50% when co-administered with a therapeutic regimen with EMEND 125 mg / 80 mg. The dose of dexamethasone in chemotherapy induced nausea and vomiting clinical studies was chosen taking into account drug interactions (see section 4.2). EMEND, given as a regimen of 125 mg with 20 mg dexamethasone in combination orally on day 1, and EMEND given at a dose of 80 mg / day with 8 mg dexamethasone in combination orally on days 2 to 5 , increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on days 1 and 5.
Methylprednisolone: The usual intravenous methylprednisolone dose should be reduced by approximately 25% and the usual oral methylprednisolone dose should be reduced by approximately 50% when co-administered with a therapeutic regimen with EMEND 125 mg / 80 mg. When given as part of a 125 mg regimen on day 1 and 80 mg / day on days 2 and 3, EMEND increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3 times on day 1 and 2.5 times on day 3, when methylprednisolone was administered concomitantly intravenously at doses of 125 mg on day 1 and orally at doses of 40 mg on days 2 and 3.
During continued treatment with methylprednisolone, the AUC of methylprednisolone may decline late within 2 weeks after initiation of the dose of EMEND, due to the inducing effect of aprepitant on CYP3A4. This effect is expected to be more pronounced. with the administration of oral methylprednisolone.
Chemotherapy medicines
In the pharmacokinetic studies EMEND, when administered with a regimen of 125 mg / day on day 1 and 80 mg / day on days 2 and 3, did not change the pharmacokinetics of docetaxel administered intravenously on day 1 or of vinorelbine administered intravenously to day 1 or day 8. Because the effect of EMEND on the pharmacokinetics of orally administered CYP3A4 substrates is superior to the effect of EMEND on the pharmacokinetics of intravenous CYP3A4 substrates, an interaction with chemotherapy medicinal products administered to Orally metabolised mainly or partly by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is advised and further monitoring is appropriate in patients receiving medicinal products metabolised mainly or partly by CYP3A4 (see section 4.4) Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported dop or concomitant administration of aprepitant and ifosfamide.
Immunosuppressants
During the 3-day regimen for the treatment of CINV, a moderate transient increase followed by a slight decrease in exposure of CYP3A4 metabolised immunosuppressants (eg cyclosporine, tacrolimus, everolimus and sirolimus) is expected. duration of the 3-day regimen and limited time-dependent changes in exposure, no dose reduction of immunosuppressants is recommended during the 3-day co-administration with EMEND.
Midazolam
The potential effects of increased concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when these medicinal products are co-administered with EMEND (125 mg / 80 mg).
EMEND increased the AUC of midazolam, a sensitive substrate of CYP3A4, by 2.3 times on day 1 and 3.3 times on day 5 when a single 2 mg dose of midazolam was administered on day 1 and day 5 of a course of therapy with EMEND 125 mg on day 1 and 80 mg / day on days 2 to 5.
In another study with intravenous administration of midazolam, EMEND was administered at a dose of 125 mg on day 1 and 80 mg / day on days 2 and 3, and 2 mg of midazolam was administered intravenously prior to administration of the 3-day therapy cycle with EMEND and on days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on day 4 and decreased the AUC of midazolam by 19% on day 8 and 4% on day 15 These effects were not considered clinically important.
In a third study with intravenous and oral midazolam administration, EMEND was administered at a dose of 125 mg on day 1 and 80 mg / day on days 2 and 3 together with ondansetron 32 mg on day 1, dexamethasone 12 mg on day 1 and 8 mg on days 2-4. This combination (EMEND, ondansetron and dexamethasone) decreased the AUC of oral midazolam by 16% on day 6, 9% on day 8, 7% on day 15, and 17% on day 22. These effects did not were considered clinically important.
A further study was completed with intravenous administration of midazolam and EMEND.
2 mg intravenous midazolam was administered 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam increased 1.5-fold. This effect was not considered clinically important.
Induction
As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant may decrease the plasma concentrations of substrates cleared by these metabolic pathways within two weeks of initiation of treatment. This effect may only become evident after the 3-day treatment with EMEND has ended. For CYP2C9 and CYP3A4 substrates, induction is transient with maximum effect 3-5 days after the 3-day treatment with EMEND is finished. The effect is maintained for a few days, then slowly diminishes and is clinically insignificant. after two weeks after stopping treatment with EMEND. A mild induction of glucuronidation is also observed with 80 mg of orally aprepitant administered for 7 days. There is a lack of data regarding the effects on CYP2C8 and CYP2C19. Caution is advised when administering warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances known to be metabolised by CYP2C9 within this time interval.
Warfarin
In patients on chronic warfarin therapy, prothrombin time (INR) should be closely monitored during treatment with EMEND and for 2 weeks following each 3-day course of EMEND for chemotherapy-induced nausea and vomiting (see section 4.4). . When a single 125 mg dose of EMEND was given on day 1 and a dose of 80 mg / day was given on days 2 and 3 in healthy people stabilized on chronic warfarin therapy, there was no effect of EMEND on Plasma AUC of R (+) or "(S-) warfarin determined on day 3; c" was however a 34% decrease in trough concentration of S (-) warfarin (a CYP2C9 substrate), accompanied by a 14% decrease in INR 5 days after stopping treatment with EMEND.
Tolbutamide
When given at a dose of 125 mg on day 1 and 80 mg / day on days 2 and 3, EMEND decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on day 4, by 28% on day 8, and 15% on day 15, when a single dose of 500 mg tolbutamide was administered orally prior to administration of the 3-day course of EMEND and on days 4, 8 and 15.
Hormonal contraceptives
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. Alternative non-hormonal replacement methods of contraception should be used during treatment with EMEND and for 2 months after administration of the last dose of EMEND. .
In a clinical study, single doses of an oral contraceptive containing ethinylestradiol and norethindrone were administered on day 1 through day 21 with EMEND, in a regimen of 125 mg on day 8 and 80 mg / day on days 9 and 10 with ondansetron 32. intravenous mg on day 8 and oral dexamethasone given in doses of 12 mg on day 8 and 8 mg / day on days 9, 10 and 11. During days 9 through 21 in this study there was a decrease up to 64 % of the trough concentrations of ethinylestradiol and decrease of up to 60% of the trough concentrations of norethindrone.
5-HT3 antagonists
In clinical interaction studies, aprepitant had no clinically relevant effect on the pharmacokinetics of ondansetron, granisetron or hydrodolasetron (the active metabolite of dolasetron).
Effects of other medicinal products on the pharmacokinetics of aprepitant
Concomitant administration of EMEND with active substances inhibiting CYP3A4 activity (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors) should be considered with caution, as the combination is expected results in a several-fold increase in the plasma concentrations of aprepitant (see section 4.4).
Concomitant administration of EMEND with active substances strong inducers of CYP3A4 activity (eg rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided since the combination results in reductions in plasma concentrations of aprepitant which may result in decreased efficacy. of EMEND. The concomitant administration of EMEND with herbal preparations containing St. John's wort (Hypericum perforatum) is not recommended.
Ketoconazole
With administration of a single 125 mg dose of aprepitant on day 5 of a 10-day course of therapy with ketoconazole, a strong CYP3A4 inhibitor, at a dose of 400 mg / day, the AUC of aprepitant increased by approximately 5. and the mean terminal half-life of aprepitant increased approximately 3-fold.
Rifampicin
When administering a single 375 mg dose of aprepitant on day 9 of a 14-day course of therapy with 600 mg / day of rifampicin, a strong CYP3A4 inducer, the "aprepitant AUC decreased by 91% and" mean terminal half-life decreased by 68%.
Pediatric population
Interaction studies have only been conducted in adults.
04.6 Pregnancy and breastfeeding
Contraception in males and females
The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of EMEND. During treatment with EMEND and for 2 months after the administration of the last dose of EMEND, alternative non-hormonal replacement methods of contraception should be used ( see sections 4.4 and 4.5).
Pregnancy
No clinical data on the use of aprepitant during pregnancy are available. The potential for reproductive toxicity of aprepitant has not been fully characterized as exposure levels above therapeutic exposure at the 125 mg dose could not be achieved in animal studies. / 80 mg in humans. These studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryo-fetal development, parturition or postnatal development (see section 5.3). The potential effects on reproduction of alterations in neurokine regulation are unknown. EMEND should not be used during pregnancy unless clearly needed.
Feeding time
Aperpitant is excreted in the milk of rats during lactation. It is not known whether aprepitant is excreted in human milk; breastfeeding is therefore not recommended during therapy with EMEND.
Fertility
The potential for the effects of aprepitant on fertility was not fully characterized as higher than therapeutic exposure levels in humans could not be achieved in animal studies. These fertility studies did not indicate direct or indirect harmful effects in relation to mating performance, fertility, embryo / fetal development, or sperm count and motility (see section 5.3).
04.7 Effects on ability to drive and use machines
EMEND may slightly affect the ability to drive, cycle or use machines. Dizziness and fatigue may occur after administration of EMEND (see section 4.8).
04.8 Undesirable effects
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 pilot pediatric clinical studies.
The most common adverse reactions reported at a higher incidence in adults treated with aprepitant than with standard therapy in patients receiving highly emetogenic chemotherapy (HEC) were: hiccups (4.6% versus 2.9%), increased alanine amino transferase (ALT) (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 with higher incidence in patients treated with aprepitant than with standard therapy in patients receiving moderately emetogenic chemotherapy ( MEC) was fatigue (1.4% versus 0.9%).
The most common adverse reactions reported with a higher incidence in pediatric patients treated with aprepitant than in the control regimen concurrently with the administration of emetogenic cancer chemotherapy were hiccups (3.3% vs. 0.0%) and flushing (1.1%). vs. 0.0%).
Table with list of adverse reactions
The following adverse reactions were observed in an analysis from HEC and MEC studies with a higher incidence with aprepitant than that reported with standard therapy in adults or pediatric patients or in post-marketing use. The frequency categories given in the table are based on studies and performed in adults; frequencies observed in pediatric studies were similar or lower, unless stated in the table. Some less common ADRs in the adult population were not observed in pediatric studies.
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100,
† Nausea and vomiting were efficacy parameters in the first 5 days following chemotherapy treatment and were only reported as adverse events thereafter.
Description of selected adverse reactions
The adverse reaction profile in adults in the multiple-cycle extension of studies with HEC and MEC up to 6 additional cycles of chemotherapy was generally similar to that observed in cycle 1.
In an additional active controlled clinical study in 1169 adult patients receiving aprepitant and HEC, the adverse reaction profile was generally similar to that seen in other HEC studies with aprepitant.
Additional adverse reactions were observed in adult patients treated with aprepitant for postoperative nausea and vomiting (PONV) at an incidence higher than that reported with ondansetron: upper abdominal pain, abdominal auscultatory abnormality, constipation *, dysarthria, dyspnoea, hypoesthesia, insomnia, miosis, nausea, sensory disturbances, gastric discomfort, sub occlusion *, decreased visual acuity, wheezing.
* Reported in patients taking a higher dose of aprepitant.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In the event of an overdose, treatment with EMEND should be discontinued, the patient monitored and general supportive measures taken. Due to the antiemetic effects of aprepitant, drug-induced emesis may not be effective.
Apripitant cannot be removed by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiemetics and antinauseants, ATC code: A04AD12
Aperpitant is a selective human substance P antagonist with high affinity for neurokinin 1 (NK1) receptors.
3-day treatment with aprepitant in adults
In 2 randomized, double-blind studies involving a total of 1,094 adult patients treated with chemotherapy including cisplatin ≥ 70 mg / m2, aprepitant in combination with ondansetron / dexamethasone treatment (see section 4.2) was compared to standard (placebo plus ondansetron 32 mg intravenously given on day 1 plus dexamethasone 20 mg orally on day 1 and 8 mg twice daily on days 2 and 4). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See product information for selected 5-HT3 antagonist for appropriate dose information.
Efficacy was based on assessment of the following composite measure: complete response (defined as no episodes of emesis and no use of rescue therapy) mainly during cycle 1.Results were evaluated for each individual study and for the 2 combined studies.
A summary of the main study results based on the combined analysis is shown in Table 1.
Table 1
Percentage of adult patients receiving highly emetogenic chemotherapy treatment
and who responded to treatment by treatment group and phase - Cycle 1
* Confidence intervals were calculated without the adjustments for gender and concomitant chemotherapy previously included in the primary analysis of odds ratios and logistic models.
† One patient in the Apripitant treatment group had data in the acute phase only and was excluded from the overall and delayed phase analyzes; one patient in the Standard treatment group had data in the delayed phase only and was excluded from the global analysis and from the acute phase analysis.
Statistically significant differences in efficacy were also observed in each of the 2 individual studies.
In the same 2 clinical studies, 851 adult patients continued in the multiple-cycle extension for up to 5 additional courses of chemotherapy. The efficacy of aprepitant therapy was apparently maintained throughout all courses.
In a double-blind, randomized study of a total of 866 adult patients (864 women and 2 men) receiving chemotherapy treatment with 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 ondansetron / dexamethasone (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 assessed on the basis of a composite measure: complete response (defined as no episodes of emesis and no use of rescue therapy) mainly during cycle 1.
A summary of the key study results is shown in Table 2.
Table 2
Percentage of adult patients receiving moderately emetogenic chemotherapy treatment and responding to treatment by treatment group and phase - Cycle 1
* Confidence intervals were calculated without age category adjustments (
† One patient in the Apripitant treatment group had only acute phase data and was excluded from the overall and delayed phase analyzes.
In the same clinical study, 744 adult patients continued the multiple-cycle extension for up to 3 further courses of chemotherapy. The efficacy of aprepitant therapy was apparently maintained throughout all courses.
In a second multicenter, randomized, double-blind, parallel-group clinical trial, treatment with aprepitant was compared with standard therapy in 848 adult patients (652 women, 196 men) receiving chemotherapy treatment with any intravenous dose of oxaliplatin. , carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; intravenous cyclophosphamide; or intravenous cytarabine (> 1 g / m2). Patients treated with aprepitant received chemotherapy for various types of cancer comprising 52% of patients with breast cancer, 21% with various types of gastrointestinal cancer including colorectal cancer, 13% with lung cancer and 6%. with various types of gynecological cancer. Aperpitant in combination with ondansetron / dexamethasone (see section 4.2) was compared with standard therapy [placebo 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 assessment of the following primary and key secondary endpoints: absence of vomiting in the total period (0 to 120 hours post-chemotherapy), assessment of the safety and tolerability of treatment of chemotherapy-induced nausea and vomiting ( CINV) with aprepitant, and complete response (defined as absence of vomiting and rescue therapy) in the total period (0 to 120 hours post-chemotherapy). Furthermore, the absence of significant nausea in the total period (0 to 120 hours). hours post-chemotherapy) was evaluated as an exploratory endpoint, both in the acute and in the delayed phase as a post-hoc analysis.
A summary of the key study results is shown in Table 3.
Table 3
Percentage of Adult Patients Responding by Treatment Group and Phase for Study 2 - Cycle 1 Moderately Emetogenic Chemotherapy
* Confidence intervals were calculated without adjustments for gender and region, which were included in the primary analysis using logistic models.
The benefit of the combination therapy with aprepitant in the full study population was mainly guided by the results observed in patients with poor control with standard therapy as well as in women, although the results were numerically superior regardless of age, tumor type or gender. . Complete response to aprepitant and standard therapy treatment was achieved in 209 of 324 (65%) and 161 of 320 (50%) women and 83 of 101 (82%) and 68 of 87 (78%), respectively. men.
Pediatric population
In a randomized, double-blind, active-controlled clinical trial in 302 children and adolescents (aged 6 months to 17 years) treated with moderately or highly emetogenic chemotherapy, the aprepitant regimen was compared with an control regime for the prevention of CINV. The efficacy of the aprepitant regimen was assessed in a single cycle (cycle 1). Patients had the opportunity to receive open-label aprepitant in subsequent cycles (optional cycles 2-6); in these optional cycles, however, efficacy has not been evaluated. The aprepitant regimen for adolescents aged 12 to 17 years (n = 47) involved administration of EMEND 125 mg capsules orally on day 1 and administration of 80 mg / day on days 2 and 3 in combination with ondansetron on day 1. The aprepitant regimen for children 6 months to less than 12 years of age (n = 105) consisted of the administration of EMEND powder for suspension oral 3.0 mg / kg (up to 125 mg) orally on day 1 and 2.0 mg / kg (up to 80 mg) orally on days 2 and 3 in combination with ondansetron on day 1. The regimen control in adolescents aged 12-17 years (n = 48) and children aged 6 months to less than 12 years (n = 102) consisted of the administration of placebo instead of aprepitant on days 1, 2 and 3 in combination with ondansetron on day 1. EMEND or placebo and ondansetron were given 1 hour and 30 minutes respectively before at the start of chemotherapy. Intravenous dexamethasone administration was permitted in the context of the antiemetic regimen for pediatric patients of both age groups, at the physician's discretion. A reduction (50%) of the dexamethasone dose was required for pediatric patients treated with aprepitant. No dose reductions were planned for pediatric patients treated with the control regimen. Of pediatric patients, 29% in the aprepitant regimen and 28% in the control regimen used dexamethasone as a component of the cycle 1 regimen.
The antiemetic activity of EMEND was assessed for a period of 5 days (120 hours) after initiation of chemotherapy on day 1. The primary endpoint was complete response during the delayed phase (25-120 hours after initiation). of chemotherapy) in cycle 1. A summary of the main results of the study is shown in Table 4.
Table 4
Number (%) of pediatric patients with complete response and no vomiting by treatment group and phase - Cycle 1 (intent-to-treat population)
Estimated time to first episode of vomiting after initiation of chemotherapy was longer with aprepitant (estimated median time to first vomiting episode of 94.5 hours) than in the control group (estimated median time to first vomiting episode of 26, 0 hours).
An "efficacy analysis in the subpopulations in cycle 1 showed that, regardless of age category, gender, use of dexamethasone for antiemetic prophylaxis and" emetogenicity of chemotherapy, the aprepitant regimen allowed for better control. compared to the control regimen for complete response endpoints.
05.2 Pharmacokinetic properties
Aperpitant exhibits non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose.
Absorption
The mean absolute oral bioavailability of aprepitant is 67% for the 80 mg capsule and 59% for the 125 mg capsule. The mean peak plasma concentration (Cmax) of aprepitant occurred at approximately 4 hours (tmax). Oral administration of the capsule with a standard breakfast of approximately 800 Kcal resulted in an increase of up to 40% in the AUC of aprepitant. This increase is not considered clinically relevant.
The pharmacokinetics of aprepitant are non-linear over the entire clinical dose range. In healthy young adults, the increase in AUC0-? between 80 mg and 125 mg in single doses administered to fed individuals was 26% higher than dose proportionality.
After oral administration of a single 125 mg dose of EMEND on day 1 and 80 mg once daily on days 2 and 3, the AUC0-24h (mean ± SD) was 19.6 ± 2, 5 mcg • hr / mL and 21.2 ± 6.3 mcg • hr / mL on days 1 and 3, respectively. Cmax was 1.6 ± 0.36 mcg / mL and 1.4 ± 0 , 22 mcg / mL on days 1 and 3, respectively.
Distribution
Aperpitant is highly protein bound, averaging 97%. The geometric mean apparent steady-state volume of distribution (Vdss) is approximately 66 L in humans.
Biotransformation
Aperpitant is extensively metabolised. In healthy young adults, approximately 19% of the radioactivity present in plasma is attributable to aprepitant within 72 hours following administration of a 100 mg dose of [14C] -fosaprepitant, a prodrug of aprepitant. , indicating a substantial presence of metabolites in plasma. Twelve metabolites of aprepitant have been identified in human plasma. only faint evidence of activity in vitro with human liver microsomes indicate that aprepitant is metabolised primarily via CYP3A4 with potential minor contributions from CYP1A2 and CYP2C19.
Elimination
Aperpitant is not excreted unchanged in the urine. The metabolites are excreted in the urine and faeces via biliary excretion. After a single 100 mg intravenous dose of [14C] -fosaprepitant, a prodrug of aprepitant, to healthy people, 57% of the radioactivity was recovered in the urine and 45% in the faecal.
Plasma clearance of aprepitant is dose dependent, decreases with increasing dose and ranges from approximately 60 to 72 mL / min within the therapeutic window. The terminal half-life is approximately 9 to 13 hours.
Pharmacokinetics in special populations
Senior citizens: Following oral administration of 125 mg single dose aprepitant on day 1 and 80 mg once daily on days 2 to 5, the AUC0-24h of aprepitant was 21% higher on day 1 and 36% on day 5 in elderly (≥ 65 years) compared to young adults.Cmax was 10% higher on day 1 and 24% higher on day 5 in elderly than in young adults These differences are not considered clinically significant. No dose adjustment of EMEND is required in elderly patients.
Sex: Following oral administration of a single 125 mg dose of aprepitant, the Cmax of aprepitant was 16% higher in females than in males. The half-life of aprepitant is 25% shorter in women than in men and its tmax is reached at approximately the same time. These differences are not considered clinically significant. No dose adjustment of EMEND is necessary based on gender.
Hepatic impairment: Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is required for patients with mild hepatic impairment. Based on currently available data it is not possible to conclude on the effect of moderate hepatic impairment (Child-Pugh class B) on the pharmacokinetics of aprepitant. 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 aprepitant was administered to patients with severe renal impairment (CrCl
In patients with severe renal impairment the AUC of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32% compared to healthy people. In patients with ESRD undergoing hemodialysis, 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 the unbound pharmacologically active drug was not significantly changed in patients with renal impairment compared to healthy people. Hemodialysis treatment conducted 4 or 48 hours after administration had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.
No dose adjustment of EMEND is required for patients with renal impairment or for patients with ESRD undergoing hemodialysis.
Pediatric population: In the context of a 3-day course, administration of aprepitant capsules (125/80/80-mg) to adolescent patients (aged 12-17 years) resulted in an AUC0-24 h greater than 17 mcg • h / mL on day 1 with concentrations (Cmin) at the end of days 2 and 3 above 0.4 mcg / mL in the majority of patients. The median peak plasma concentration (Cmax) was approximately 1.3 mcg / mL on day 1 and was reached after approximately 4 hours. In the context of a 3-day course, administration of aprepitant powder for oral suspension (3/2/2-mg / kg) in patients 6 months to less than 12 years of age resulted in a higher AUC0-24 h at 17 mcg • h / mL on day 1 with concentrations (Cmin) at the end of days 2 and 3 above 0.1 mcg / mL in the majority of patients. The median peak plasma concentration (Cmax) was approximately 1.2 mcg / mL on day 1 and was reached between 5 and 7 hours.
A population pharmacokinetic analysis of the administration of aprepitant to pediatric patients (aged 6 months to 17 years) suggests that gender and race do not have a clinically significant effect on the pharmacokinetics of aprepitant.
Relationship between concentration and effect
Studies with positron emission tomography (PET) imaging of healthy young men using highly specific tracers for NK1 receptors have shown that aprepitant penetrates the brain and occupies the NK1 receptors to a dose and concentration-dependent extent in plasma. calculates that the plasma concentrations of aprepitant achieved with the 3-day course of EMEND in adults result in an occupancy of brain NK1 receptors greater than 95%.
05.3 Preclinical safety data
Non-clinical data reveal no hazard to humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity and developmental toxicity. It should be noted, however, that systemic exposure in rodents is was similar or even lower than the therapeutic exposure in humans at the dose of 125 mg / 80 mg. In particular, although no adverse effects on human exposure levels were observed in reproductive studies, animal exposures are not sufficient to make an adequate human risk assessment.
In a juvenile toxicity study in rats treated from postnatal day 10 to day 63, aprepitant induced an "early vaginal opening in female specimens starting at 250 mg / kg bid and delayed foreskin separation in specimens of male sex from 10 mg / kg bid There was no margin for clinically relevant exposure. No treatment-related effects on mating, fertility or embryo-fetal survival were found, nor were there any pathological changes in the reproductive organs. In a juvenile toxicity study in dogs treated from postnatal day 14 to day 42, a reduction in testicular weight and Leydig cell size was observed in males at a dose of 6 mg / kg / day and Weight gain of the uterus, hypertrophy of the uterus and cervix and edema of the vaginal tissues were observed in female specimens starting from 4 mg / kg / day. There was no "margin for" clinically relevant exposure of aprepitant. For short-term treatment according to the recommended dosing regimen, these data are considered unlikely to be of clinical relevance.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule contents
Sucrose
Microcrystalline cellulose (E 460)
Hydroxypropylcellulose (E 463)
Sodium lauryl sulfate
Capsule shell (125 mg)
Jelly
Titanium dioxide (E 171)
Red iron oxide (E 172)
Yellow iron oxide (E 172)
Capsule shell (80 mg)
Jelly
Titanium dioxide (E 171)
Printing ink
Shellac
Potassium hydroxide
Black iron oxide (E 172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
4 years.
06.4 Special precautions for storage
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
Different types of packaging are available including different formulations.
Aluminum blister with one 80 mg capsule.
Aluminum blister with two 80 mg capsules.
5 aluminum blisters each with one 80 mg capsule.
Aluminum blister with one 125 mg capsule.
5 aluminum blisters each with one 125 mg capsule.
Aluminum blister with one 125 mg capsule and two 80 mg capsules.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/03/262/001
EU / 1/03/262/002
EU / 1/03/262/003
EU / 1/03/262/004
EU / 1/03/262/005
EU / 1/03/262/006
036167043
036167068
036167017
036167029
036167056
036167031
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 11 November 2003
Date of most recent renewal: 22 September 2008
10.0 DATE OF REVISION OF THE TEXT
23 March 2016
