H-1051 Budapest, Zrínyi utca 3.

1372 P.O. Box 450

Tel.: +36 1 886 9300, Fax: +36 1 886 9460
E-mail: [email protected]
Web: www.ogyei.gov.hu

Public Assessment Report

Name of the Product:

Aprepitant-Q Pharma

80 mg, 125 mg and

(80+125) mg

hard capsules

(aprepitant)
Procedure number: HU/H/0624/001-003/DC

Marketing authorisation holder: Q PHARMA Gyógyszerkereskedelmi és

Szolgáltató Kft.

Date: 26th February 2021

 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

CONTENT

LAY SUMMARY ................................................................................................................................... 3

SCIENTIFIC DISCUSSION ................................................................................................................... 9
I. INTRODUCTION ......................................................................................................................... 10
II. Quality aspects .............................................................................................................................. 11
II.1 Introduction ........................................................................................................................... 11
II.2 Drug substance ...................................................................................................................... 11
II.3 Medicinal product.................................................................................................................. 12
II.4 Discussion on chemical, pharmaceutical and biological aspects .......................................... 13
III. NON-CLINICAL ASPECTS .................................................................................................... 14
III.1 Introduction ........................................................................................................................... 14
III.2 Pharmacology ........................................................................................................................ 14
III.3 Pharmacokinetics................................................................................................................... 14
III.4 Toxicology ............................................................................................................................ 14
III.5 Ecotoxicology/environmnetal risk assessment (ERA) .......................................................... 14
III.6 Discussion onthe non-clinical aspects ................................................................................... 14
IV. CLINICAL ASPECTS .............................................................................................................. 15
IV.1 Introduction ........................................................................................................................... 15
IV.2 Pharmacokinetics................................................................................................................... 15
IV.3 Pharmacodynamics ................................................................................................................ 17
IV.4 Clinical efficacy .................................................................................................................... 17
IV.5 Clinical safety ........................................................................................................................ 18
IV.6 Pharmacovigilance ................................................................................................................ 18
IV.6.1 Summary of the Pharmacovigilance System ................................................................. 18
IV.6.2 Risk Management Plan .................................................................................................. 18
IV.6.3 Periodic Safety Update Reports..................................................................................... 19
IV.7 Discussion on the clinical aspects ......................................................................................... 19
V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION .. 21
V.1 Summary ............................................................................................................................... 21
V.2 Classification ......................................................................................................................... 21
V.3 Package Leaflet and user consultation .................................................................................. 21
VI. Upgrade: steps taken after the initial procedure with an influence on the Public Assessment
Report 22

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

LAY SUMMARY

After careful assessment of its quality and therapeutic benefit/risk ratio, the member states have
granted the marketing authorisation of the Aprepitant-Q Pharma 80 mg, 125 mg and
(80+125) mg hard capsules. The holder of the marketing authorisation is Q PHARMA Gyógy-
szerkereskedelmi és Szolgáltató Kft.

The active substance is aprepitant.

Aprepitant-Q Pharma 80 mg hard capsules

Each hard capsule contains 80 mg of aprepitant.

Aprepitant-Q Pharma 125 mg hard capsules

Each hard capsule contains 125 mg of aprepitant.

The other ingredients are:

sucrose, cellulose microcrystalline (sphere 500) (E 460), hydroxypropylcellulose (HPC-SL) (E

463), sodium laurilsulfate, gelatin, titanium dioxide (E 171); the 125 mg hard capsule also
contains red iron oxide (E 172).

The appearance of the tablets is:

Aprepitant-Q Pharma 80 mg hard capsules

Opaque with a white body and cap, containing white to off-white pellets.

Aprepitant-Q Pharma 80 mg hard capsules are supplied in the following pack sizes:
- OPA/Al/PVC//Al blister containing one 80 mg capsule
- OPA/Al/PVC//Al blister containing two 80 mg capsules
- 3 OPA/Al/PVC//Al blisters each containing one 80 mg capsule
- 5 OPA/Al/PVC//Al blisters each containing one 80 mg capsule

Aprepitant-Q Pharma 125 mg hard capsules

Opaque with a white body and cap, containing white to off-white pellets.

Aprepitant-Q Pharma 125 mg hard capsules are supplied in the following pack sizes:
- OPA/Al/PVC//Al blister containing one 125 mg capsule
- OPA/Al/PVC//Al blister containing two 125 mg capsules
- 3 OPA/Al/PVC//Al blisters each containing one 125 mg capsule
- 5 OPA/Al/PVC//Al blisters each containing one 125 mg capsule

Aprepitant-Q Pharma 125 mg hard capsules + Aprepitant-Q Pharma 80 mg hard capsules are
supplied in the following pack size:
- 3-day treatment pack containing one blister of 125 mg capsule and one blister of 80 mg
capsules

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

Not all pack sizes may be marketed.

Aprepitant-Q Pharma 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. Aprepitant-Q Pharma works by blocking signals to that area,
thereby reducing nausea and vomiting. Aprepitant-Q Pharma are used in adults and adolescents
from the age of 12 years in combination with other medicines to prevent nausea and vomiting
caused by chemotherapy (cancer treatment) that are strong and moderate triggers of nausea and
vomiting (such as cisplatin, cyclophosphamide, doxorubicin or epirubicin).

What patients need to know before using Aprepitant-Q Pharma

Patients should not take Aprepitant-Q Pharma
- if the patient or the child is allergic to aprepitant or any of the other ingredients of this
medicine.
- with medicines containing pimozide (used to treat psychiatric illnesses), terfenadine and
astemizole (used for hay fever and other allergic conditions), cisapride (used for treating
digestive problems) . Patients should tell their doctor if they or their child is taking these
medicines since the treatment must be modified before they or the child start taking Aprepitant-
Q Pharma.

Warnings and precautions

Patients should talk to their doctor, pharmacist before they take Aprepitant-Q Pharma or give
this medicine to their child.
Before treatment with Aprepitant-Q Pharma, patients should tell their doctor if they have liver
disease because the liver is important in breaking down the medicine in the body. The doctor
may therefore have to monitor the condition of patient’s liver.

Children and adolescents

Aprepitant-Q Pharma 80 mg and Aprepitant-Q Pharma 125 mg should not be given to chil-
dren under 12 years of age, because the Aprepitant-Q Pharma 80 mg and Aprepitant-Q
Pharma 125 mg capsules have not been studied in this population.

Other medicines and Aprepitant-Q Pharma

Aprepitant-Q Pharma can affect other medicines both during and after treatment with aprep-
itant, the active substance of Aprepitant-Q Pharma. There are some medicines that should
not be taken with Aprepitant-Q Pharma (such as pimozide, terfenadine, astemizole, and cis-
apride) or that require a dose adjustment.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

The effects of Aprepitant-Q Pharma or other medicines might be influenced if the patient or
the child take Aprepitant-Q Pharmatogether with other medicines including those listed be-
low. Patients should talk to the doctor or pharmacist if they or their child is taking any of the
following medicines:

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

Patients should tell their doctor if they or the child are taking, have recently taken, or might
take any other medicines.

Pregnancy and breast-feeding

This medicine should not be used during pregnancy unless clearly necessary. If the patient is
pregnant or breast-feeding, thinks she may be pregnant or is planning to have a baby, she
should ask her doctor for advice before taking this medicine.
For information regarding birth control, see ‘Other medicines and Aprepitant-Q Pharma’.
It is not known whether Aprepitant-Q Pharma is excreted in human milk; therefore, breast-
feeding is not recommended during treatment with this medicine. It is important to tell the
doctor if the patient is breast-feeding or is planning to breast-feed before taking this medi-
cine.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

Driving and using machines

It should be taken into account that some people feel dizzy and sleepy after taking Aprepitant-
Q Pharma. If the patient or the child feels dizzy or sleepy, avoid driving, riding a bicycle or
using machines or tools after taking Aprepitant-Q Pharma (see ‘Possible side effects’).

Aprepitant-Q Pharma contains sucrose

Aprepitant-Q Pharma capsules contain sucrose. If the patient or the child have been told by
their doctor that he/she or the child have an intolerance to some sugars, they should contact
the doctor before taking this medicine.

How to use Aprepitant-Q Pharma?

Patients should always take this medicine or give this medicine to the child exactly as the
doctor, pharmacist or nurse has told them. They should check with the doctor, pharmacist or
nurse if they are not sure. Aprepitant-Q Pharma should be always taken together with other
medicines, to prevent nausea and vomiting. After treatment with Aprepitant-Q Pharma, the
doctor may ask the patient or the child to continue taking other medicines including a
corticosteroid (such as dexamethasone) and a ‘5HT3 antagonist’ (such as ondansetron) for
preventing nausea and vomiting. Patients should check with the doctor, pharmacist or nurse if
they are not sure.

The recommended oral dose of Aprepitant-Q Pharma is Day 1:

- one Aprepitant-Q Pharma125 mg capsule 1 hour before the patient starts his/her
chemotherapy session

and

Days 2 and 3:
- one Aprepitant-Q Pharma80 mg capsule each day
- If no chemotherapy is given, patients should take Aprepitant-Q Pharmain the morning.
- If chemotherapy is given, take Aprepitant-Q Pharma1 hour before the patient starts
his/her chemotherapy session.

Aprepitant-Q Pharma can be taken with or without food. Swallow the capsule whole with some
liquid.

What to do if more Aprepitant-Q Pharma was taken that it should have been?

Patients should not take more Aprepitant-Q Pharma than the doctor recommends. If the pa-
tient or the child has taken too many capsules, they should contact their doctor immediately.

What to do if taking Aprepitant-Q Pharma was forgotten?

If the patient or the child has missed a dose, they should contact their doctor for advice.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

If patients have any further questions on the use of this medicine, they should ask their doctor
or pharmacist.

Possible side effects

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

Patients should stop taking Aprepitant-Q Pharma and see a doctor immediately if the
patient or the child notice any of the following side effects, which may be serious, and for
which he/she or the child may need urgent medical treatment:
- Hives, rash, itching, difficulty 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):
- constipation, indigestion,
- headache,
- tiredness,
- loss of appetite,
- hiccups,
- increased amount of liver enzymes in the patient’s blood.

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

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

Rare side effects (may affect up to1 in 1,000 people):

- difficulty thinking, lack of energy, taste disturbance,
- sensitivity of the skin to sun, excessive sweating, oily skin, sores on skin, itching
rash, Stevens-Johnson syndrome/toxic epidermal necrolysis (rare severe skin reac-
tion),
- euphoria (feeling of extreme happiness), disorientation,
- bacterial infection, fungal infection,
- severe constipation, stomach ulcer, inflammation of the small intestine and co-
lon, sores in mouth, bloating,
- frequent urination, passing more urine than normal, presence of sugar or blood in
urine,
- chest discomfort, swelling, change in the manner of walking,
- cough, mucus in back of throat, throat irritation, sneezing, sore throat,

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

- eye discharge and itching,

- ringing in the ear,
- muscle spasms, muscle weakness,
- excessive thirst,
- slow heartbeat, heart and blood vessel disease,
- lowering of white blood cells, low sodium levels in the blood, weight loss.

Reporting of side effects

If the patient or the child gets any side effects, he/she should talk to his/her doctor, pharma-
cist, or nurse. This includes any possible side effects not listed in this leaflet. Side effects can
also be reported directly via the national reporting system. By reporting side effects the pa-
tients can help provide more information on the safety of this medicine.

How to store Aprepitant-Q Pharma?

This medicine should be kept out of the sight and reach of children.

This medicine should not be used after the expiry date which is stated on the carton after EXP.
The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

The capsule should not be removed from its blister until the patient is ready to take it.

Patients should not throw away any medicines via wastewater or household waste. Their phar-
macist should be asked how to throw away medicines they no longer use. These measures will
help protect the environment.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

SCIENTIFIC DISCUSSION

This module reflects the scientific discussion for the approval of Aprepitant-Q Pharma 80 mg, 125
mg and (80+125) mg hard capsules. The procedure was finalised on 04-03-2020 (day210). For
information on changes after this date please refer to the module ‘Update’.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Aprepitant-Q Pharma 80 mg, 125 mg, (80 + 125) mg hard cap-
sules from Q Pharma GmbH.

The product is indicated for: prevention of nausea and vomiting associated with highly and
moderately emetogenic cancer chemotherapy in adults and adolescents from the age of 12.

A comprehensive description of the indications and posology is given in the SmPC.

The marketing authorisation has been granted pursuant to Article 10(1) generic of Directive
2001/83/EC.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

II. QUALITY ASPECTS

II.1 Introduction

The chemical-pharmaceutical assessment report concerns the application of Aprepitant Q

Pharma 80 mg, 125 mg hard capsules and Aprepitant Q Pharma 80 mg+125 mg hard capsules
via a decentralized procedure according to Article 10.1 of Directive 2001/83/EC (i.e a generic
application). The products have been developed by Rontis Hellas Medical and Pharmaceutical
Products S.A.
Reference products are Emend 80 mg, 125 mg, 80 mg&125 mg hard capsules (containing 80
mg and 125 mg aprepitant as active ingredient) which were the original products of Merck
Sharp & Dohme Ltd. UK.

II.2 Drug substance

Data on the quality and manufacture of the active substance were provided in the applicant’s
submission using the CEP procedure with additional data in the marketing authorization dos-
sier. The Quality Overall Summary is adequate.

INN name: aprepitant

Chemical name: 5-[[ (2R,3S)-2-[ (1R)-1-[3 ,5-Bis(trifluoromethyl)phenyl] ethoxy]-3-(4-fluor-
ophenyl)-4-morpholinyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one
Structure:

The active substance is white to cream coloured crystalline powder. Soluble in methanol,
slightly soluble in acetonitrile, practically insoluble in water. It shows polymorphism, the man-
ufacturers consistently produce the correct isomer and the same polymorphic form.

Description of the manufacturing process of the active pharmaceutical ingredient (API) is ade-
quate.

Evidence of the structure has been confirmed. The impurity profile of the API contains detailed
information about genotoxic impurities, residual solvents and catalysts.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

The substance is specified according to the requirements of the current Ph.Eur. monograph,
additional specifications have been set for residual solvents, particle size distribution, polymor-
phism, impurities and microbial impurities.

The presented specification is in accordance with the Ph.Eur. general monograph on Substances
for Pharmaceutical Use and the ICH Q6A guideline. The specification reflects all relevant
quality attributes of the active substance and was found to be adequate to control the quality of
the drug substance. The limits set are properly justified.

Testing methods not described in details in the Pharmacopoeia are adequately drawn up and
sufficiently validated. Reference materials used by the active substance manufacturer and the
drug product manufacturer for the control of the substance are adequately characterised.
The substance complies with the requirements of the EMA guideline on genotoxic impurities.

Batch analysis data justify the limits, indicate the good performance of testing methods and
demonstrate the batch to batch consistency of the production.

Stability studies have been performed with the drug substance. According to the presented sta-
bility data the proposed re-test period is acceptable with the proposed storage condition.

Good Manufacturing Practice (GMP) compliance of the API manufacture is demonstrated by

the applicant.

II.3 Medicinal product

The aim was to develop hard capsules containing aprepitant as drug substance in 80 mg and
125 mg doses bioequivalent and pharmaceutically equivalent to the reference medicinal product
Emend 80 mg and 125 mg hard capsules, the branded original products of Merck Sharp &
Dohme Ltd. UK.
A satisfactory package of data on development pharmaceutics has been presented. Brief discus-
sion on reasons for inclusion and quantity of excipients has been provided.
As regards dissolution and impurity profile the product is shown to be similar to the reference
product.

The compositions and the pharmaceutical tests evaluated during development of the final for-
mulation are included in the documentation. As a result of development studies product with
the following appearance, composition and packaging was obtained.

80 mg: size 2, opaque hard gelatin capsule with a white body and cap containing white to off-
white pellets.
125 mg: size 1, opaque hard gelatin capsule with a white body and pink cap containing white
to off-white pellets.

The excipients used in the finished product are sucrose, microcrystalline cellulose (Spheres
500), hydroxypropylcellulose (HPC-SL), sodium laurilsulfate and capsule shell (titanium diox-
ide (E171), talc, red iron oxide (E172) (only for 125 mg) and gelatin). All excipients used com-
ply with their respective European Pharmacopoeia monograph. Compliance of the product with

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

the general monograph of the European Pharmacopoeia on the Products with the risk of TSE
has been demonstrated by the applicant.

A description and flow chart of the manufacturing method has been provided. Appropriate in-
process controls are included in the manufacturing process. Satisfactory batch formulae were
also presented. GMP compliance of the manufacturing site has been demonstrated.

The finished product specification is satisfactory. Acceptance criteria have been justified with
respect to conventional pharmaceutical requirements as prescribed in the relevant dosage form
monograph of the Ph.Eur. and the ICH Q6A guideline. Appropriate control strategy was se-
lected. The test methods have been described and have been adequately validated, as appropri-
ate. Batch data have been provided and complied with the specification. Certificates of analysis
for the batches involved in the bioequivalence study are presented.

The container closure system of the product is OPA/Al/PVC//Al blister. Specifications and
quality certificates for all packaging components are enclosed.

Finished product stability studies have been conducted in accordance with the current guide-
lines. Based on the results, a shelf-life of 4 years with no special storage conditions is ap-
proved.
The Summary of Product Characteristics, patient Information Leaflet and label texts are phar-
maceutically acceptable.

II.4 Discussion on chemical, pharmaceutical and biological aspects

Conclusion: The product has been shown to meet the current regulatory requirements with
regards to its quality and content of the active substance as well as dosage-form characteristics
until the end of the approved shelf-life consistently. The manufacture and the quality standards
applied adequately support the safe use and efficacy of the product.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

III. NON-CLINICAL ASPECTS

III.1 Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of aprepitant are well

known, no further non-clinical studies are required in support of this marketing authorisation.
The Applicant submitted a nonclinical overview based on a literature review of the pre clinical
pharmacology, pharmacokinetic and toxicology characteristics of aprepitant which is
considered adequate. No further studies are required.

III.2 Pharmacology

No new non-clinical pharmacological studies were conducted by the Applicant.

Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1)
receptors.

III.3 Pharmacokinetics

No new non-clinical pharmacokinetic studies were conducted by the Applicant.

III.4 Toxicology

Published information on toxicological studies with aprepitant was the basis for the evaluation.
No new toxicity studies were submitted by the Applicant for the product, which is acceptable
for this type of application.

III.5 Ecotoxicology/environmnetal risk assessment (ERA)

Since Aprepitant-Q Pharma 80 mg, 125 mg, (80 + 125) mg hard capsules are intended for ge-
neric substitution, this will not lead to an increased exposure to the environment. An environ-
mental risk assessment is therefore not deemed necessary.

III.6 Discussion onthe non-clinical aspects

The dossier concerned an abridged application that avoids the need for repetitive tests on ani-
mals and humans.
Aprepitant-Q Pharma 80 mg, 125 mg, (80 & 125) mg hard capsules are considered essentially
similar to the innovator products are registered throughout the European Union under the brand
name Emend® 80 mg, 125 mg, (80 & 125) mg hard capsules, marketed in Europe by Merck
Sharp & Dohme Ltd, UK. Emend® has been centrally authorized in the European community
since 13/11/2003.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

IV. CLINICAL ASPECTS

IV.1 Introduction

Applicant has not conducted any clinical studies with Aprepitant-Q Pharma 80 mg, 125 mg,
(80 & 125) mg hard capsules and all the relevant Clinical information provided in Clinical
overview is based on literature.

Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1)

receptors.
The vomiting reflex involves activation of neuronal nuclei in the brainstem by both peripheral
(glosophararyngeal and vagal nerves) and central (cortical and cerebellar) pathways that trig-
gers a sequence of events. Incoming signals from the chemoreceptor trigger zone, gastrointes-
tinal tract, cerebral cortex and other areas are coordinated in the emetic center in the CNS. The
main neurotransmitter receptors involved in this signaling are 5-HT3, neurokinin-1 (NK-1) and
dopamine receptors. Other receptors include corticosteroid, histamine, cannabinoid, acetylcho-
line, GABA-containing and opiate receptors. This central site of action is the likely explanation
for the unique broad antiemetic pharmacological profile of the SPAs.

IV.2 Pharmacokinetics

To support the application, the applicant has submitted as report one pilot and two pivotal (fast-
ing and fed) bioequivalence studies.

• Pilot study was performed between Aprepitant Capsules 125 mg (Test 1), Aprepitant Capsules
125 mg (Test 2) manufactured by Rontis Hellas S.A. Greece) and Emend® 125 mg Capsules
(125 mg aprepitant) (Reference) manufactured by Merck Sharp & Dohme Ltd., Netherland.
• The first pivotal study was conducted between Aprepitant Capsules 125 mg (manufactured by
Rontis Hellas S.A., Greece) and Emend® 125 mg hard capsules (manufactured by Merck Sharp
& Dohme Ltd., UK, from the Netherlands market) in healthy adult volunteers under fasting
conditions.
• The second pivotal study was conducted between Aprepitant Capsules 125 mg (manufactured
by Rontis Hellas S.A., Greece) and Emend® 125 mg hard capsules (manufactured by Merck
Sharp & Dohme Ltd., UK, from the Netherlands market) in healthy adult volunteers under fed
conditions.

Bioequivalence studies:

• Fasting study:
Design: randomized, open label, balanced, two-treatment, two-period, two-sequence, single-
dose, crossover, bioequivalence study in 40 healthy volunteers under fasting conditions with a
9 days wash-out period. For each subject, a total of 24 blood samples were collected in each
period, pre-dose sample (within one hour before dosing) and post-dose samples were taken at
0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.33, 3.67, 4.00, 4.33, 4.67, 5.00, 5.33, 5.67, 6.00, 7.00, 9.00,
12.00, 16.00, 24.00, 36.00, 48.00 and 72.00 hours after dosing. Blood samples were collected
in pre-labelled vacutainer containing K3EDTA as anticoagulant.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

Bioequivalence criteria:
was based on the 90% confidence intervals for the ratios of geometric least squares means
(Test/Reference), from the ln-transformed parameters Cmax and AUC0-t. The acceptance
range for bioequivalence is 80.00-125.00% for the 90% confidence intervals of the geometric
least squares means ratio (T/R) for the primary pharmacokinetic parameters Cmax and AUC0-
t.

Safety results: no death or serious adverse event occurred during the study. The test and refer-
ence products were comparable in their safety and tolerability.

Results:

The 90% confidence intervals of the ratios of LSM derived from analyses on the ln-transformed
PK parameters AUC0-t and Cmax for aprepitant in plasma were within the predefined protocol
limits (80% to 125%) indicating bioequivalence with the reference product.

 Fed study:
Design: randomized, open label, balanced, two-treatment, two-period, two-sequence, single-
dose, crossover, bioequivalence study in 62 healthy volunteers under fed conditions with an 11
days wash-out period. For each subject, a total of 24 blood samples (3.2mL) were collected in
each period, pre-dose sample (within one hour before dosing) and post-dose samples were taken
at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.33, 3.67, 4.00, 4.33, 4.67, 5.00, 5.33, 5.67, 6.00, 7.00,
9.00, 12.00, 16.00, 24.00, 36.00, 48.00 and 72.00 hours after dosing. Blood samples were col-
lected in pre-labelled vacutainer containing K3EDTA as anticoagulant.

Bioequivalence criteria:
the acceptance range for bioequivalence was 80.00-125.00% for the 90% confidence intervals
of the geometric least squares means ratio (T/R) for the primary pharmacokinetic parameters
Cmax and AUC0-t.

Safety results: no death, serious or clinically significant, unexpected adverse drug reaction ad-
verse events occurred during the study.

Results:

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

The 90% confidence intervals of the ratios of LSM derived from analyses on the ln-transformed
pharmacokinetic parameters AUC0-t and Cmax for aprepitant in plasma were within the prede-
fined protocol limits (80.00% to 125.00%) indicating bioequivalence with the reference product
in fed conditions.

Biowaiver:
The bioequivalence studies were performed with the highest strength (125 mg), and according
to the Bioequivalence Guideline the applicant submitted biowaiver request for the lower
strength (80 mg) which was based on the following conditions:
 the pharmaceutical products are manufactured by the same manufacturing process,
 qualitative composition of the different strengths is the same,
 composition of the strengths are quantitatively proportional,
 appropriate in vitro dissolution data confirm the adequacy of waiving additional in vivo bioe-
quivalence testing.

Since all criteria of general biowaiver claim were satisfied for the claimed dose strength (80
mg) according to the bioequivalence guideline (CPMP/EWP/QWP/1401/98 Rev.1 Corr**) and
similarity of dissolution profiles of the 80 and 125 mg dose strengths was justified, the bio-
waiver claim for the 80 mg dose strength is acceptable.

Conclusion on bioequivalence studies:

Based on the submitted pivotal bioequivalence studies Aprepitant 1 A Pharma 125 mg hard
capsules is considered bioequivalent with Emend® 125 mg capsules (manufactured by Merck
Sharp & Dohme Ltd., UK, from the Netherlands market) in healthy adult volunteers under fast-
ing and fed conditions.

The results of bioequivalence studies with 125 mg hard capsules can be extrapolated to the
other 80 mg strength, according to conditions in Guideline on the Investigation of Bioequiva-
lence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), section 4.1.6.

IV.3 Pharmacodynamics

No new data have been submitted. No data are required for an abridged application provided
bioequivalence has been satisfactorily demonstrated.

IV.4 Clinical efficacy

No new clinical efficacy studies were presented and no such studies are required for this appli-
cation. The applicant has provided an adequate review of clinical trials published in the litera-
ture, describing the efficacy profile of aprepitant.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

IV.5 Clinical safety

With the exception of the data generated during the bioequivalence study, no new safety data
were submitted and none were required for this application. No new or unexpected safety issues
were raised by the bioequivalence data.

No new clinical safety studies were presented and no such studies are required for this applica-
tion. The applicant has provided an adequate review of clinical trials published in the literature,
describing the safety profile of aprepitant.

IV.6 Pharmacovigilance

IV.6.1 Summary of the Pharmacovigilance System

The applicant has submitted a signed Summary of the Applicant's Pharmacovigilance System.
Provided that the Pharmacovigilance System Master File fully complies with the new legal
requirements as set out in the Commission Implementing Regulation 520/2012 and as detailed
in the relevant Good Pharmacovigilance Practice module, the Summary is considered accepta-
ble.

IV.6.2 Risk Management Plan

Summary of safety concerns

Important identified risks Hypersensitivity
Drug interaction: hormonal contraceptives
Important potential risks Potential for medication errors
Missing information Use in pregnancy
Use in children less than 12 years of age.
Use in patients with moderate or severe hepatic
impairment

The safety concerns listed by the Applicant are in line with safety specification of the latest
accepted version of the originator’s RMP. (Version 4.1, dated on 01-July 2015; Assessment
report, Procedure No. EMEA/H/C/000527/X/0049/G, 22 October 2015, EMA/787667/2015,
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-
_Variation/human/000527/WC500200826.pdf).

There is only one difference that the missing information, “Use in patients < 6 months of age
or weighing <6 kg” has been changed to “Use in children less than 12 years of age”, since the
products under evaluation in this procedure are for treatment adults and adolescent from the
age of 12. EMEND 125 mg powder for oral suspension is adequate only for the treatment in
children, toddlers and infants from the age of 6 months to less than 12 years.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

Note: During the last PSUSA procedure (EMEA/H/C/PSUSA/00000229/201903), the Lead

member state recommended to update the RMP of the originator according to the new guidance
document but the originator has not submitted an updated RMP.

Q Pharma should continuously check EMA website to notice any change.

Pharmacovigilance plan: routine pharmacovigilance activities are considered sufficient to ma-

nage all of the safety concerns connected to the product. No additional activities are proposed.

Risk Minimisation Measures: Routine risk minimisation measures (i.e. wording in SmPC, PL
and classification as a prescription only medicine) are considered sufficient to manage all of
the safety concerns connected to the product.
No additional activities are proposed. For any further information on risk minimisation, please
refer to the product information.

IV.6.3 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for these medicinal products
are set out in the list of Union reference dates (EURD list) provided for un-der Article 107c(7)
of Directive 2001/83/EC and any subsequent updates published on the European medicines
web-portal.

IV.7 Discussion on the clinical aspects

The dossier concerned an abridged application that avoids the need for repetitive tests on ani-
mals and humans.
Aprepitant-Q Pharma 80 mg, 125 mg, (80 & 125) mg hard capsules is considered essentially
similar to the innovator products are registered throughout the European Union under the brand
name Emend® 80 mg, 125 mg, (80 & 125) mg hard capsules, marketed in Europe by Merck
Sharp & Dohme Ltd, UK.

The Applicant has adequately demonstrated bioequivalence between the products and reference
products.
Based on the submitted pivotal bioequivalence studies Aprepitant-Q Pharma 125 mg hard
capsules are considered bioequivalent with Emend® 125 mg capsules (manufactured by
Merck Sharp & Dohme Ltd., UK, from the Netherlands market) in healthy adult volunteers
under fasting and fed conditions.

The results of study with 125 mg hard capsules CAN be extrapolated to the other 80 mg
strength, according to conditions in Guideline on the Investigation of Bioequivalence
(CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), section 4.1.6.

All criteria of general biowaiver claim were satisfied for the claimed dose strength (80 mg)
according to the bioequivalence guideline (CPMP/EWP/1401/98 Rev.1 Corr** and
EMA/CHMP/600958/2010/Corr.*).

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

Similarity of dissolution profiles of the 80 and 125 mg dose strengths was justified; hence, the
biowaiver claim for the 80 mg dose strength can be acceptable.

Based on the review of the data on safety and efficacy, the Member State have granted a mar-
keting authorization for Aprepitant 80 mg, 125 mg, 80 + 125 mg hard capsules in the treatment
of prevention nausea and vomiting associated with highly and moderately emetogenic cancer
chemotherapy in adults and adolescents from the age of 12.

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 National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

V.1 Summary

Based on the submitted pivotal bioequivalence studies Aprepitant 1 A Pharma 125 mg hard
capsules is considered bioequivalent with Emend® 125 mg capsules (manufactured by
Merck Sharp & Dohme Ltd., UK, from the Netherlands market) in healthy adult volunteers
under fasting and fed conditions.

The results of study with 125 mg hard capsules CAN be extrapolated to the other 80 mg
strength, according to conditions in Guideline on the Investigation of Bioequivalence
(CPMP/EWP/QWP/1401/98 Rev. 1/Corr**), section 4.1.6.

All criteria of general biowaiver claim were satisfied for the claimed dose strength (80 mg)
according to the bioequivalence guideline (CPMP/EWP/1401/98 Rev.1 Corr** and
EMA/CHMP/600958/2010/Corr.*).
Similarity of dissolution profiles of the 80 and 125 mg dose strengths was justified; hence, the
biowaiver claim for the 80 mg dose strength can be acceptable.

Based on the review of the data on safety and efficacy, the RMS considers that the application
for Aprepitant 80 mg, 125 mg, 80 + 125 mg hard capsules in the treatment of prevention nausea
and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults
and adolescents from the age of 12, is approvable.

V.2 Classification

Product on restricted prescription.

V.3 Package Leaflet and user consultation

A user consultation with target patient groups on the package information leaflet (PIL) has
been performed on the basis of a bridging report making reference to EMEND 125 mg hard
capsules (content) and Darunavir 400 mg & 800 mg film coated tablets (layout). The
bridging report submitted by the applicant has been found acceptable.
.

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National Institute of Pharmacy - Aprepitant-Q Pharma
and Nutrition 80 mg, 125 mg and (80+125) mg hard capsules
HU/H/0624/001-003/DC
Budapest, Hungary Public Assessment Report

VI. UPGRADE: STEPS TAKEN AFTER THE INITIAL PROCEDURE WITH AN IN-
FLUENCE ON THE PUBLIC ASSESSMENT REPORT
This module reflects the procedural steps and scientific information after the finalisation of the initial procedure.

Product in-
Date of start of the pro- Date of end of Approval or non
Scope Procedure number formation
cedure procedure approval
affected

*Only procedure qualifier, chronological number and grouping qualifier (when applicable)