release tablets Yantil retard 50, 100, 150, 200, 250 mg prolonged

Bundesinstitut für Arzneimittel
und Medizinprodukte
Decentralised Procedure
Public Assessment Report
Palexia retard 50, 100, 150, 200, 250 mg prolongedrelease
tablets
Yantil retard 50, 100, 150, 200, 250 mg prolongedrelease
tablets
Tapentadol
DE/H/2020-2021/004-008/DC
Applicant: Grünenthal GmbH
Reference Member State DE
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/10 Public AR

TABLE OF CONTENTS
I. INTRODUCTION......................................................................................................................... 4
II. EXECUTIVE SUMMARY....................................................................................................... 4
II.1 Problem statement..................................................................................................................... 4
II.2 About the product ..................................................................................................................... 4
II.3 General comments on the submitted dossier .......................................................................... 4
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles..4
III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................... 5
III.1 Quality aspects....................................................................................................................... 5
III.2 Nonclinical aspects ................................................................................................................ 6
III.3 Clinical aspects ...................................................................................................................... 6
IV. BENEFIT RISK ASSESSMENT ........................................................................................... 10
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Proposed name of the medicinal
product in the RMS
INN (or common name) of the active
substance(s):
Pharmaco-therapeutic group
(ATC Code):
Pharmaceutical form(s) and
strength(s):
Reference Number for the
Decentralised Procedure
ADMINISTRATIVE INFORMATION
Palexia retard 50, 100, 150, 200, 250 mg Retardtabletten
Yantil retard 50, 100, 150, 200, 250 mg Retardtabletten
Tapentadol
N 02 AX 06
50, 100, 150, 200, 250 mg prolonged-release tablets
DE/H/2020-2021/004-008/DC
Reference Member State: DE
Member States concerned: BE, BG, CY, CZ, DK, EE, EL, ES, FI, HU, IE, IS, IT, LT,
LU, LV, MT, NO, PL, PT, RO, SE, SI, SK, UK
Applicant (name and address) Grünenthal GmbH
Zieglerstraße 6
D-52078 Aachen
Farmaceutici Formenti S.p.A.
Names and addresses of
Via Vittor Pisani 16,
manufacturers responsible for batch
20124 Milano, Italy
release in the EEA
alternatively
Grünenthal GmbH
Zieglerstr. 6
52078 Aachen, Germany
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I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the application for Palexia/Yantil 50,
100, 150, 200, 250 mg prolonged-release tablets, in the treatment of severe chronic pain requiring
opioid therapy is approved.
II. EXECUTIVE SUMMARY
II.1 Problem statement
Tapentadol is a new chemical entity developed for the treatment of moderate to severe pain of
different non-malignant and malignant origin. Currently, a variety of different analgesic substances are
on the market. Pharmacologically severe pain is mainly treated by opioids, but depending on the origin
of pain and its characteristics, also NSAIDS and other substances play an important role.
II.2 About the product
Tapentadol is a centrally active analgesic agent which acts as a µ-receptor agonist and an inhibitor of
norepinephrine reuptake. (Please refer to the Public Assessment Report of the IR formulation
(DE/H/2020/001-004/DC). The Anatomical Therapeutic Chemical (ATC) classification code is N02
AX 06. The claimed indication is “Tapentadol is indicated for the management of severe chronic pain
in adults, which can be adequately managed only with opioid analgesics.” The film coated prolonged
release tablets should be taken twice daily, approximately every 12 hours up to a maximal daily dose
of 500 mg. The treatment should be started with single doses of 50 mg b.i.d. and up-titrated every
three days in increments of 50 mg b.i.d. up to an optimal dose.
II.3 General comments on the submitted dossier
This application is submitted as a decentralised procedure according to Article 28(3) of Directive
2001/83/EC with Germany as Reference Member State. AT, BE, BG, CY, CZ, DK, EE, EL, ES, FI,
FR, HU, IE, IS, IT, LT, LU, LV, MT, NL, NO, PL, PT, RO, SE, SI, SK and UK were involved as
Concerned Member States. The applicant, however, withdrew in AT, FR and NL.
The application concerns a new active substance, tapentadol hydrochloride manufactured as a slow
release formulation, submitted under the tradename Palexia SR, which is not yet authorised by any of
the European Member States. A duplicate application under the product name Ixarto SR and the
application for the immediate release formulation have simultaneously been submitted. The immediate
release formulation Tapentadol IR was approved by the US Food and Drug Administration on 20 th
November 2008 for the relief of moderate to severe acute pain in adults.
Consideration of this application is also requested under the Article 10(1) of Directive 2001/83/EC /
Article 14(11) of Regulation (EC) No 726/2004 (one year of market exclusivity for a new indication).
According to Article 7 of the Paediatric Regulation this application includes a PIP (Decision Number
P/48/2009). Development in other special populations has not been performed.
A risk management plan has been provided.
This medicinal product has been given formal scientific advice by the CHMP
(EMEA/CPMP/SAWG/845/04, procedure No EMEA/H/SA/371/2/2003/II and EMEA/CPMP/SAWP/
363827/06, procedure No EMEA/H/SA/371/2/FU/1/2006/II). Member States UK (2001-11-19), FR
(2002-01-09), DE (2002-01-15) and SE (2005-10-17) have also given scientific advice. In addition,
pre-submission meetings were conducted with CZ, NL, DE, UK, SE, IT, FR and ES.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical
principles.
The RMS has been assured that acceptable standards of GMP are in place for these product types at all
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sites responsible for the manufacture and assembly of this product. For manufacturing sites within the
Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection
services of the competent authorities as certification that acceptable standards of GMP are in place at
those sites.
For all studies presented within this AR, the applicant declares that the study was conducted in
accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are
consistent with Good Clinical Practices and applicable regulatory requirements.
GCP inspections have been conducted in single sites involved in the phase III study KF5503/35 in
patients with post-operative pain after hysterectomy. Subsequent to GCP findings some of the
participating sites were excluded from the dataset. At Day 106 the Applicant provided an Addendum
to the clinical trial report of study KF5503/35 based on the reduced dataset. The data that were
presented in this Addendum are considered valid.
Relevant toxicological investigations were conducted in compliance with GLP standards. However,
not all safety pharmacology studies are conforming to GLP regulations, because they were performed
before ICH S7A and S7B came into force. Nonetheless, these studies are satisfactorily documented.
III. SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects
Drug substance
Tapentadol hydrochloride is a new chemical entity, not described in any pharmacopoeia. The content
of this ASMF follows the requirements of the note for guidance “Chemistry of New Active
Substance” (CPMP/QWP/130/96 Rev1). Letter of access has been provided.
Tapentadol hydrochloride drug substance is manufactured through a series of organic synthesis steps
starting from commercially available chemicals.
No major concerns raised during the assessment of the documentation regarding the ASMF provided.
The questions regarding the open part and restricted part have been sufficiently answered. The re-test
period of 36 months is accepted.
Drug Product
Tapentadol prolonged released tablets are film-coated, oblong shaped tablets. The conversion factor
from tapentadol free base to its hydrochloride salt is 1.1648 and reverse 0.8585.
The tablet cores of the different dosage strengths have the same qualitative excipient composition but
they vary in quantity, drug substance concentration, tablet core weight and diameter. The excipients
used for the tablet core, hypromellose 100,000 mPas, cellulose microcrystalline, colloidal anhydrous
silica, magnesium stearate and purified water are well known pharmaceutical ingredients and their
quality is described in Ph. Eur. monographs.
The dosage strength can be differentiated by using different colours for the film coating material.
The description of the product development and its proof of concept are comprehensible and supported
by dissolution data.
The ingredients and the manufacturing process of the prolonged release tablet, comprising standard
blending, compression, film coating processes, are considered suitable to produce a pharmaceutical
product of the proposed quality.
Sufficient process validation data is available, proving a robust and reproducible process.
All relevant quality characteristics of the drug product (release and shelf-life) are specified. The
proposed limits are justified. The description of the analytical methods used to analyse the drug
substance and drug product are adequate, the validation results are plausible. The stability data
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ecently available justifies a shelf-life of 36 months without label claim for the package proposed for
marketing.
III.2 Nonclinical aspects
The pharmacological and toxicological characteristics of tapentadol as evaluated in non-clinical
investigations are extensively described in the assessment report as well as in the Public Assessment
Report of the IR formulation (DE/H/2020/001-004/DC).
III.3 Clinical aspects
Pharmacokinetics
The initial development of tapentadol for clinical use was performed with an immediate release
formulation. For details please refer to the Preliminary Assessment of the dossier of the IR
formulation. Due to the relatively short half life of tapentadol (4-5 h) a prolonged-release formulation
was developed for the treatment of chronic pain.
Tapentadol PR tablets of 2 sizes are intended to be commercialized. For the lower dose strengths of 50
mg, 100 mg and 150 mg of tapentadol, a smaller tablet (designated PR2small) was developed to offer
a more convenient and easy to swallow tablet to the patient. The PR2 formulation was designed for the
upper dose strengths of 200 mg and 250 mg of tapentadol. The tablet cores of the different dose
strengths have an identical qualitative excipient composition but vary in their quantitative
composition, drug substance amount, tablet core weight and tablet size. Initial studies used an early
tapentadol PR formulation, referred to as PR1. Phase 3 studies have been performed with the PR 2
formulation, the equivalence of PR2small was assessed by comparative in-vitro dissolution testing at
all strengths and by bioequivalence studies for the 50 and 150 mg strengths.
The following table gives an overview of the key studies contributing to the biopharmaceutical
characterization of tepentadol PR:
Furthermore, pharmacokinetic data has been explored during the clinical efficacy studies (see below).
The pharmacokinetic study program is adequate. The applicant conducted studies with an early
formulation PR1 to explore bioavailability and food effect. Dose proportionality and food effect was
also explored with the PR2 formulation. Furthermore, studies to demonstrate bioequivalence of the to
be marketed PR2small formulation with the PR2 formulation, have been conducted.
The applicant demonstrated bioavailability comparable to the IR formulation. A slight food effect
could be shown, which is regarded not clinically relevant. Dose proportionality is assumed for doses
up to 200 mg tapentadol PR. Bioequivalence could be demonstrated between formulations.
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Pharmacodynamics
Please refer to the Assessment of the IR formulation.
It is not expected, that the pharmacodynamic profile differs from that of the IR formulation.
Clinical efficacy
The study programme consisted of Phase 2 and Phase 3 studies in adult subjects with chronic pain of
different etiologies (osteoarthritis, chronic low back pain and diabetic peripheral neuropathy) outlined
in the following table:
Tramadol SR (200-400 mg daily) and Oxycodone CR (20-40 mg) have been chosen as active
comparators during the phase IIb studies as they are well established to be effective and safe in the
treatment of moderate to severe pain conditions. Nevertheless, in the above described Phase IIb
studies, efficacy of these active comparators could not be confirmed.
No conclusions can be drawn from three of four Phase II dose finding studies, as neither the active
comparator nor the tested doses of tapentadol SR showed significant analgesic efficacy compared to
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placebo. Only KF5503/19 could show efficacy of tapentadol SR in the range 150 to 200 mg b.i.d.
However, the CHMP (EMEA/CHMP/SAWP/363827/2006) had no major objection to the dose range
chosen (see below) for use in the Phase 3 studies based on the above dose finding studies.
Four main Phase III studies have been conducted, three of them in a nearly identical design, using
oxycodone CR as the active comparator. Efficacy of tapentadol PR (100 mg to 250 mg twice daily) for
the treatment of moderate to severe chronic pain was studied in 3 pain conditions (chronic
osteoarthritis, chronic low back pain, and painful diabetic peripheral neuropathy). The majority of
subjects (≥ 80%) had severe pain at baseline. Statistical separation from placebo for the primary
efficacy endpoints was demonstrated in 2 of these 3 similar designed studies for a period of up to 12
weeks. The results of the third study showed effects of tapentadol PR that were in the same direction
as the other studies not reaching statistical significance. Furthermore an additional study in patients
with DPN has been performed in a withdrawal design. In total of 3260 patients have been included in
the main studies of whom 1174 were exposed to the study drug.
The design of the submitted studies has been discussed prior by the CHMP during a scientific advice
(EMEA/CPMP/SAWP/845/04 and EMEA/CHMP/SAWP/363827/2006): It was pointed out by the
CHMP that in Europe OA and LBP are not primarily treated with opioids but with NSAIDs, COX-2
inhibitors and non-pharmacological measures. OA and LBP are recommended as models for mild to
moderate pain conditions. Choosing these pain models, it is required to assure that a representative
number of patients is suffering from severe pain (NRS ≥6) and is not responding to first line
analgesics after a trial period of sufficient duration. This has been fulfilled.
The objections regarding study designs, conduct and results of the studies could be resolved and in
conclusion across studies clinical efficacy in the treatment of severe chronic pain can be regarded as
demonstrated.
Clinical safety
The applicant provided comprehensive safety documentation. Safety assessment has been performed
for every single clinical study. Additionally a pooled safety analysis has been presented in the clinical
safety summary and in a smaller proportion in the clinical overview.
3,420 patients received tapentadol within the placebo-controlled study program. 494 received
tapentadol for more than 6 month and 243 patients for more than 12 month. This fulfils the
requirements of ICH E1 and is acceptable.
The most commonly reported adverse events within the clinical studies were typical opioid induced
side effects like nausea, dizziness, constipation, headache, somnolence, and vomiting. The majority of
all reported TEAEs was mild to moderate in intensity. The incidence of respiratory depression, another
typical opioid induced side effect was very low (< 0.1%) in the tapentadol group. The side effect
profile was comparable to that of oxycodone but with lower frequency and intensity. The only
common TEAE that occurs as often in the tapentadol group as in the oxycodone group was headache.
The norepinephrine uptake inhibiting effect seems to cause no additional side effects not known as
typical opioid side effects. Deaths occurred primarily in subjects with progression of neoplasm and
were not related to the study drug.
The side effect profile of tapentadol is comparable to the side effect profile strong opioids. Incidence
of TEAEs increases with increasing doses. Typical withdrawal symptoms occur in some subjects
following abrupt cessation of treatment. Tapentadol should be classified as a substance with a relevant
drug abuse potential.
Pharmacovigilance system
The applicant has provided documents that set out a detailed description of the system of
pharmacovigilance (Version 3.0 dated 15 April 2010). A statement signed by the applicant and the
qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified
person responsible for pharmacovigilance and the necessary means for the notification of any adverse
reaction occurring either in the Community or in a third country has been provided.
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The Pharmacovigilance system as described by the applicant fulfils the requirements as described in
Volume 9A of the Rules Governing Medicinal Products in the European Union and provides adequate
evidence that the applicant has the services of a qualified person responsible for pharmacovigilance
and has the necessary means for the notification of any adverse reaction suspected of occurring either
in the Community or in a third country.
Risk Management Plan
Safety specification:
The following non-clinical safety concerns have been investigated: QT-prolongation, potential for
abuse, convulsion, reproductive toxicity. Convulsions and reproductive toxicity will be accounted for
in the SPC.
No risk of QT-prolongation was observed. Potential for abuse is acknowledged and regarded as
comparable to other opioids. Convulsions and reproductive toxicity will be accounted for in the SPC.
A list of adverse reactions grouped by frequency and SOC observed in clinical trials is presented for
both the immediate and the prolonged release formulation. Populations not studied or with limited data
include mainly patients below the age of 18, pregnant and lactating women, patients with severe renal
impairment, patients with clinically relevant hepatic impairment (Transaminases > 3 times ULN),
patients on MAO inhibitors and patients with a history of drug or alcohol abuse. These aspects will be
reflected in the relevant sections of the SPC.
As the product has not been launched prior to the finalization of this version of the RMP, no data on
post-authorization usage is available.
No clinically relevant interactions were observed in the drug-drug interaction studies. Additive CNS
depression is expected with other CNS depressants. Both will be stated in the SPC.
Pharmacological class effects of the group of µ-opioid receptor agonists include potential for abuse,
convulsion, respiratory depression and bowel hypomobility. Compared to other opiods the risk of
respiratory depression and bowel hypomobilty is regarded as low.
A summary tabulation of ongoing safety concerns can be found below:
Important identified risks Drug abuse and drug dependence
Convulsion
Important potential risks, Overdose
Off-label use in pediatric patients
Potential for medication errors
Accidental exposure
Diversion
Important missing information Use in pediatrics
Following the initial assessment the MAH agreed to replace the originally suggested important
identified risk “Potential for abuse” by the more exact wording “Drug abuse and drug dependence”.
Pharmacovigilance Plan:
Apart from routine pharmacovigilance practices no additional pharmacovigilance activities have been
suggested by the applicant. No additional studies are considered necessary by the applicant.
Risk minimization plan:
Apart from routine risk minimization activities (labeling, controlled drug status, inclusion into CCDS)
no additional risk minimization activities have been proposed for the identified safety concerns. Thus
no risk minimization plan is presented.
Summary of the risk management plan
Safety concern Proposed pharmacovigilance
activities (routine and
Proposed risk minimization
activities (routine and
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Drug abuse and drug
dependence
Overdose
Diversion
additional) additional)
Routine Pharmacovigilance
practices are considered to be
sufficient.
Convulsion Routine Pharmacovigilance
practices are considered to be
sufficient.
Potential for medication errors
Accidental exposure
Use in pediatrics
Off-label use in pediatric patients
Routine Pharmacovigilance
practices are considered to be
sufficient.
Routine Pharmacovigilance
practices are considered to be
sufficient.
IV. BENEFIT RISK ASSESSMENT
The benefit risk assessment is positive.
The application is approved.
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Appropriate labeling (Warning
in section 4.4 and description in
4.9of the CCDS) and the use of
legal status of the drug as a
controlled drug. No further risk
minimization activities are
identified as necessary or
requested to date.
Appropriate labeling (Warning
in section 4.4 of the CCDS). No
further risk-minimization
activities, other than labeling
has been conducted to date. No
further risk-minimization
activities are identified as
necessary or requested to date.
Appropriate labeling. No
further risk-minimization
activities, other than labeling
has been conducted to date. No
further riskminimization
activities are identified as
necessary or requested to date
Appropriate labeling. No
further risk-minimization
activities, other than labeling
has been conducted to date. No
further riskminimization
activities are identified as
necessary or requested to date.
A development program to
address the pediatric population
is defined in the agreed PIP.