Minutes for 269th Meeting Registration Board held on 27 ... Minutes for 269th Registration Board...
Transcript of Minutes for 269th Meeting Registration Board held on 27 ... Minutes for 269th Registration Board...
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Minutes for 269th
Registration Board Meeting 1
Minutes for 269th
Meeting Registration Board held on 27-28th
April, 2017.
Item No. Detail of Item Page No.
Item No.I Confirmation for minutes of 268th
Registration Board meeting 03
Item No.II Pharmaceutical Evaluation & Registration Division 04 –459
Item No.III Biological Drugs Division 460 – 520
Item No.VI Additional Agenda
A. Pharmaceutical Evaluation & Registration Division
521 – 533
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Minutes for 269th
Registration Board Meeting 2
269th
meeting of Registration Board was held on 27-28th
April, 2017 in the Committee
Room, Drug Regulatory Authority of Pakistan, G-9/4, Islamabad. The meeting was chaired
by Mr. Ghulam Rasool Dutani, Director, Pharmaceutical Evaluation & Registration Division,
DRAP. The meeting started with recitation of the Holy Verses. The meeting was attended by
the following:-
1. Dr.Rafeeq Alam Khan Meritorious Professor, Faculty of Pharmacy,
University of Karachi
Member
2. Maj.Gen.Dr. Tahir Mukhtar Syed Commandant AFIRM / Head Department of Medicine,
Army Medical College
Member
3. Prof.Dr.Ghulam Sarwar, Dean, Faculty of Pharmacy, Jinnah Women University, Karachi
Member
4. Dr.Qurban Ali, Director General National Veterinary Laboratory, Islamabad.
Member
5. Dr.Amanullah Khan Director, Drugs Testing Laboratory, Quetta
Govt. of Baluchistan
Member
6. Dr. Muhammad Shoaib Akhter Director, Drugs Testing Laboratory, Rawalpindi
Govt. of Punjab.
Member
7. Dr. Abid Hayat, Director, Drugs Testing Laboratory, Peshawar, Govt. of
Khyber Pakhtunkhwa
Member
8. Mr. Muhammad Aslam Assistant Draftsman-II, Ministry of Law & Justice
Member
9. Mr.Ghulam Mujtaba Representative IPO
Member
10. Dr.Noor-us-Saba Director, Biological Drugs Division, DRAP
Member
11. Dr.Abdur Rasheed Additional Director, QA< Division, DRAP
Member
12. Dr. Obaidullah, Additional Director (Reg.I) Secretary
Prof.Dr.Ghulam Sarwar and Dr.Qurban Ali, attended meeting on 28.04.2017.
The officers of relevant sections assisted their Directors with agenda and deliberation
during the meeting.
Mr.Khalid Muneer, Ehsan Naseer, Nadeem Hussain Alamgeer and Dr.Haider Ali
attended the meeting as observer on behalf of PPMA and Pharma Beauru respectively.
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Minutes for 269th
Registration Board Meeting 3
Item No.I: Confirmation of minutes of 268th
meeting Registration Board.
268th
meeting of Registration Board was held on 20-21st March, 2017. The draft
minutes were circulated among the members of meeting on 04th
April, 2017 with the request
to forward their comments (if any) within five days; but no comments were received.
However, during scrutiny of draft minutes, following correction was identified;
Details Name of Firm/ Product &
Composition
Recorded Decision Correct Decision
Case No. 02:
Registration
applications with
differential fee
submitted upto
September, 2015
(Sr.No.82)
M/s Gulf Pharmaceuticals.
Orthovis 500mg Capsules
Each capsule contains:-
Glucosamine Sulphate as KCl
………500mg
(Amino Acid)
Rejected as firm
has mentioned
wrong
pharmacological
group in Form 5
Deferred for evidence of
approval by reference
Regulatory Authorities &
clarification of
Pharmacological Group.
Minutes were approved after above correction in draft minutes.
Decision: Registration Board confirmed minutes for 268th
meeting.
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Minutes for 269th
Registration Board Meeting 4
Item No.II: Pharmaceutical Evaluation & Registration Division.
A. Pharmaceutrical Evaluation Cell:
Items Title of case No. of Cases
Case No.01 Review of formulations 2
Case No.02 Import cases
a. Import cases for priority consideration 5
b. Import cases List-II 4
c. Deferred cases of Import 7
Case No.03 Cases which require stability studies
a. New cases of stability studies 21
b. Deferred cases of stability studies 12
Case No.04 Verification of authenticity of stability study 40
Case No.05 Deferred cases of previous meetings of Registraion Board 41
Case No.06 Routine applications whose differential fee submitted upto 30th
September, 2015
56
Case No.07 Missing/ Anomaly applications which were missed and could not be
included in list I
1
Case No.08 Applications of List-II (Human) 213
Case No.09 Applications of List-II (Veterinary) 30
Case No.10 Applications of new sections
a. Remaining applications of new sections considered before 258
th meeting
23
b. Remaining applications of new sections considered after 258
th Meeting
68
c. Deferred cases of new sections 64
Case No.11 Miscellaneous Cases 6
Total 593
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Minutes for 269th
Registration Board Meeting 5
Case No.01: Review of formulations
1. Review of formulation of Diacerein capsule 50mg
Diacerein 50mg capsule formulations were deferred in various meeting of Registration
Board for review by review committee. The review committee finalized their comments and
the case was presented in 245th
meeting of Registration Board with following
comments/recommendations.
Approval by
International
Regulatory
Bodies
Status in Authentic
Textbooks
(Pharmacological
basis of
therapeutics-
Goodman &
Gilman, Basic &
Clinical
pharmacology-B G
Katzung, Current
Medical Diagnosis &
Treatment – 2013)
Research
published in
Reputed/
Authentic
Journals
Concluding Remarks &
Recommendation
Not approved
by FDA, TGA
& PMDA.
Approved by
EMA for use in
epidermolysis
bullosa only
Not mentioned in any
standard textbook
Some in vitro
studies on
chondrocytes have
been published.
Clinical trials have
reported slight but
statistically
significant
superiority over
placebo.
Diacerein is an anti-inflammatory drug
acting by inhibition of Interleukin-
1beta. It has been used in osteoarthritis
where it may produce slight
improvement. In limited number of
countries where it is available, it is
being reviewed and withdrawn due to
hepatotoxicity.
In view of the limited usefulness and
concerns of toxicity, diacerein is not
recommended for registration.
These cases were deferred as PPMA and Pharma Bureau requested that the Board
may also consider their views on these formulations. The Board acceded to the request and
advised both to forward their comments by 15.11.2014 for consideration of Registration
Board.
The formulation was again discussed with same comments/recommendations in 246th
meeting of Registration Board and it was again deferred with following comments.
Registration Board discussed comments of stakeholders for following formulations and
decided that Review Committee will review these comments for framing its final
recommendation. The Board also advised the committee to take assistance of any expert (if
required) and can also call any stakeholder for their views.
These formulations were again discussed in 250th
Registration Board meeting with the
following comments;
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Minutes for 269th
Registration Board Meeting 6
Diacerein 50mg Capsules
International
availability
Me too status Remarks
Available in EMA
with restrictions.
Diora Capsule 50
mg by Getz
On 19 March 2014, the Co-ordination Group for Mutual
Recognition and Decentralised Procedures – Human (CMDh)
endorsed recommendations to restrict the use of diacerein-
containing medicines in order to manage the risks of severe
diarrhoea and effects on the liver.
Due to the risks associated with severe diarrhoea, diacerein is
no longer recommended in patients aged 65 years and above.
It is also advised that patients start treatment on half the
normal dose (i.e. 50 mg daily instead of 100 mg) and should
stop taking diacerein if diarrhoea occurs.
In addition, diacerein-containing medicines must now not be
used in any patient with liver disease or a history of liver
disease, and doctors should be monitoring their patients for
early signs of liver problems.
Doctors should also note that, based on available data, the use
of diacerein is to be limited to treating symptoms of
osteoarthritis affecting the hip or knee. Treatment should
only be started by doctors experienced in treating
osteoarthritis.
These recommendations are based on the review of the
benefits and risks of diacerein conducted by the
EMA‘s Pharmacovigilance and Risk Assessment Committee
(PRAC) and follow concerns raised by the French medicines
agency (ANSM) about diacerein‘s gastro-intestinal and liver
effects. The CMDh endorsed the PRAC‘s final
recommendations to address these concerns and ensure that
diacerein‘s benefits continue to outweigh its known risks.
As the CMDh position on diacerein was adopted by majority
vote, it was sent to the European Commission which
endorsed it and issued a final legally binding decision valid
throughout the European Union (EU) on 4 September 2014.
(Ref: EMA)
N.B: (Review committee has not recommended the product
for regsitatrion in 246th meeting of registration board.
However, Registration Board discussed comments of
stakeholders in 246th meeting and decided that Review
Committee will review these comments for framing its final
recommendation).
Decision: Deferred for expert opinion for clarification as under:
i. Significance/ place of therapy
ii. Risk vs benefit ratio
iii. What are the alternates therapies available in Pakistan or Internationally
Experts:
i. Dr Khalid Aslam, QAU International Hospital Islamabad
ii. Brig. Mushtaq Military Hospital Rawalpindi
iii. Dr Abid Farooqi PIMS, Islamabad
The formulation is available in Austria and registered by Austrian Agency for Health and
Food Safety in the same strength and dosage form. The details of product registration are as
follows;
Brand Name: ARTROLYT 50 mg capsules
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Minutes for 269th
Registration Board Meeting 7
Market Authorization number: 1-24324
Composition Active ingredient: Each capsule contains Diacerein……………50mg
Additive:
Lactose monohydrate (214.3 mg), croscarmellose sodium, povidone, fumed silica,
Magnesium stearate, gelatin, quinoline yellow (E104), indigocarmine (E132), titanium
dioxide (E171), purified water
Marketing Authorization holder: TRB Chemedica (Austria) GmbH, A- 2355 Wr.
Neudorf, Strasse 7, Object 58 D / 1 / 2.OG
Link for reference:
https://aspregister.basg.gv.at/aspregister/faces/aspregister.jspx?_adf.ctrl-
state=mr1prvwog_4&_afrLoop=46931814654857739 (Accessed on 16-03-2017)
The following applications are hereby presented before the Board
S.
No. Name and
address of
manufacturer /
Applicant
Brand Name
(Proprietary name +
Dosage Form +
Strength)
Composition
Pharmacological
Group
Finished product
Specification
Type of Form
Initial date,
diary
Fee including
differential fee
Demanded
Price /
Pack size
Remarks on the
formulation (if
any) including
International
status in
stringent drug
regulatory
agencies /
authorities
Me-too status
Decision of
previous DRB
1. M/s Filix Pharmaceutical
s Rawat.
Dynfix 50mg Capsules
Each capsule contains:-
Diacerein (INN)
……50mg
(NSAID ANALGESIC)
17-05-2013
Dy.No.1460
Fee.
Rs.20,000
As Per SRO
Referred to the
review committee.
(M-238)
2. M/s. Novartana
Pharma
Lahore
Orthin 50mg Capsule
Each capule contains:-
Diacerein….50mg
22-5-2013
Rs.20,000/-
10‘s
DeferredforSubmis
sion of
correctsignedappli
cationon form
5,rawmaterialsandf
inishedproductspec
ifications and
decision ofreview
committee
(M-239)
3. M/s Hilton Pharma (Pvt).
Ltd. Karachi
Dicer Capsule
Each capsule contains:
Diacerein (M.S)..50mg
(for Treatment of
Osteoarthritis)
Form 5Routine
1.21-09-2010
133
Rs.8000/-
2.15-05-2013
Rs.12000/-
Rs.30/Capsule
Referred to review
committee for
review of
formulation.
(M-241)
4. M/s A‘RAF (Pvt) Ltd, 23-
Km, Raiwind
Road, Lahore.
(Formerly M/s.
Remedy
Diacerem Oral Capsule
Each capsule contains:-
Diacerein (M.S)…50mg
(NSAIDs)
Form 5
Fast Track
As per
SRO/30‘s
14-05-2013,
(3059)14.5.201
1.Manufacturer‘s
2. DIORA(GETZ
PHARMA
PAKISTAN
(PVT) LTD.)
[Diacerein:50mg]
Deferred for
review of
formulation by
Review Committee
(M-242)
https://aspregister.basg.gv.at/aspregister/faces/aspregister.jspx?_adf.ctrl-state=mr1prvwog_4&_afrLoop=46931814654857739https://aspregister.basg.gv.at/aspregister/faces/aspregister.jspx?_adf.ctrl-state=mr1prvwog_4&_afrLoop=46931814654857739
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Minutes for 269th
Registration Board Meeting 8
Pharmaceutical
(Pvt) Ltd, 23rd
KM Raiwind
Road, Lahore.)
3 (Rs.60000/-)
Cap
5. M/s Safina Pharmaceutical
s (Pvt) Limited,
17Km, Lahore
Sheikhupura
Road, Lahore.
DICE, MACIN, ICIN
Tablet
Each tablet contains
diacerein....50mg
For treatment in
osteoarthritis
Form 5
Fast Track
21/tablet 1x5‘s
2997
dated 13/05/13
11/10/2013
Rs.60,000/-
Me too exists in
capsule form.Firm
has been
conveyed the
same however no
reply submitted
Deferred as the
production has
beens stopped by
the area FID due to
non-GMP
compliance
(M-242)
6. M/s Genix Pharma (Pvt)
Ltd., 44,45-B,
Korangi Creek
Road, Karachi.
OSTEO-GCapsules
Each capsule contains:
Diacerein …... 50mg
Anti Osteoarthritis.
Form-5 Fast
Track
As per PRC
08-04-2013 293
(R&I)
Rs.60,000/-
Manufacturersspe
cifications.
Capsule General
section available
as per inspection
report dated
18/12/2013.
Inspection report
dated 21/12/2012
provided.
Deferrd for review
of formulation by
Review Committee
(M-242)
7. M/s Wellness Pharmaceutical
s Lahore
Diacerin 50mg Capsule
Each capsule contains
diacerein….50mg
Anthraquinone
derivative
Form 5
31-07-2013
Dy No 9427
Rs 20,000/-
As per SRO
1x 10‘s
Deferrd for review
of formulation by
Review Committee
(M-243)
8. M/s Aventek Pharmaceutical
s (Pvt)Ltd,44-
C,Sunder
Industrial
Estate, Lahore.
DIATEK Capsule
Each Capsulecontains:
Diacerein……50mg
Anti Osteoarthritis
Manufacturers
specifications
Form 5
Rs. 8,000/-
26-06-2012
Rs. 12,000/-
09-03-2015
Dy.No.1505R&
I
Price: Rs.810/-
Per pack
DIORA
50mg Capsules
M/s Getz
Deferred for
submission of
following:
1) Undertaking
thatlabel claim
andprescribinginfo
rmation shall
besame as
approved
byreference drug
agencies e.g.,
FDA,TGA,MHLW
, EMAand Health
Canada.
2)
Underrecommende
dclinicaluse
interactions
withother drugs
hasbeen
mentioned.
Indicationsand
dosageinformation
to besubmitted as
approvedby
reference
drugagencies
e.g.,FDA,
TGA,MHLW,
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Minutes for 269th
Registration Board Meeting 9
EMAand Health
Canada.
3) Evidence
ofapproval of
sameformulation
byreference
drugagencies
required.
4) Evidence
ofapproval of
technicalstaff by
licensingrequired.
(M-249)
1) Indications and
dosage information
to be submitted as
approved by
reference drug
agencies e.g.,
FDA, TGA,
MHLW, EMA and
Health Canada.
2) Evidence of
approval of same
formulation by
reference drug
agencies required.
(M-251)
Defered as the
Formulation is
underReview
(M-253)
9. M/s Venus Pharma, 23
Km,Multan
Road Lahore.
DIANEX Capsule
Each Capsulecontains:
Diacerein……50mg
Anti Arthritic
Manufacturers
specifications
Form 5
Rs. 20,000/-
05-03-2015
Dy.No.1396R&
I
Price: Rs.850/-
Per 30‘s
DIORA
50mg Capsules
M/s Getz
Deferred
forconfirmation
offormulation
inreference
drugagencies.
(M-249)
10. M/s Unipharma
(Pvt) Ltd.
4.5km Manga-
Raiwind Road
Lahore.
Priority #1113
Uviarein
Tablet
Each tablet contains.
Diacerein…….50mg
(NSAID,s)
(Manufacturer‘s Specs)
Form-5
Dy. No:1525
Rs.8000/-
08-06-2011
Rs.12,000/-
31-07-2013
Rs.270/1x10‘s
Artrodar by Proter
Pharma Itlay
(need to be
verified)
Diacerein by
Genome Pharma
(need to be
verified)
Deferred for
thesubmission
ofCommitment
asperdecision of theboard (M-256)
11. M/s Hygeia Pharmaceutical
s,295, Industrial
Triangles,
Kahuta Road,
Islamabad.
Priority # 1730
Capsule Direin 50mg
Each capsule contains
Diacerein……. 50 mg
Anthraquinone
Derivative
In-house specification
Form 5 with fee
Rs.20,000/-
Rs. 8000/- vide
Dy.# 472 dated
27-06-2012
Rs. 12000/-vide
Dy#415 dated
20-02-2013
Pack size of
Diora (Getz) Deferred asproduct
underreview /
expertopinion.
(M-257)
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Minutes for 269th
Registration Board Meeting 10
3x10‘s/as per
SRO
12. M/s Lowitt Pharma (Pvt.)
Ltd, 24-
Industrial
Estate,
Hayatabad,
Peshawar.
Priority # 2062
Capsule Atorin 50mg
Each capsule contains
Diacerein … 50 mg
Anti Rheumatics
In house specification
Form 5 with fee
Rs.20,000/-
Dy.#1049 dated
18-12-2012
Pack size30‘s
Rs. 1000/-
Or fixed by
Competent
authority
Artrodar(Highnoo
n)
GMP compliant
section dated
06.7.2015
Deferred asproduct
isunder review
/expert opinion.
(M-257)
13. M/s CSH Pharmaceutical
s– North (Pvt.)
Ltd, 38-A,
IndustrialEstate,
Hayattabad,
Peshawar
Priority # 2032
Capsule DISE 50mg
Each Capsule contains
Diacerein 50mg
Anthraquinone
Derivatives
In-house
specification
Form 5 with fee
Rs.20,000/-
Dy. #1024 R&I
10-12-2012
Pack size 3 x
10‘s Rs. 840
Rs.28/percapsul
e
Dibro (Winbrain) Deferred asproduct
underreview
/expert opinion
(M-257)
14. M/s AGP (Private)
Limited, B-23
SITE Area
Karachi.
Diacerein 50mg
Capsule
Each capsule contains:
Diacerein….. 50mg
(Anti-inflamatory &
antirheumatic
Form-5
Dy. No: 1256
15.10.2012
Rs.20,000/-
Rs.850/30‘s
Not Provided
Rein (S.J.& G
Fazul ellahie)
Deferred as
product is under
review / expert
opinion
(M-257)
15. M/sUnipharma (Pvt) Ltd.4.5km
Manga-Raiwind
RoadLahore.
Priority
No. 1113
Uviarein
Tablet
Each tabletcontains.
Diacerein…….50mg
Form-5
Dy. No: 1525
Rs.8000/-
Dated.
08-06-2011
Rs.12,000/-
Dated.
31-07-2013
Rs.270/1x10‘s
Artrodar byProter
PharmaItlay
(need to
beverified)
Diacerein by
GenomePharma
(need to
beverified)
Deferred
forthesubmission
ofCommitmentasp
er decisionof
theboard
in256thmeetingof
RB
(M-256)
Deferred
astheformulationis
underreview
/expertopinion (M-
257)
16. M/s OBS Pakistan
(Pvt) Ltd,
C14 SITE
Karachi.
2543
Arthoheal 50mg
capsule
Each capsule contains:
Diacerein…..50mg
(Anti-osteoarthritis,
analgesic &anti-
inflammatory
drug)(Mfg. specs)
Form-5
Dy. No: 690
14.05.2012
Rs.8,000/-
Differentialfee
Challanmissing
Rs.953/-30‘s
Not Provided
Rein (S.J.& G
Fazul ellahie)
Deferred
forexpertopinion
asper250thmeeting
ofRB
(M-258)
17. M/s.StandPharma, 20 km,
Ferozepur road,
Lahore Pakistan
471
ACER Capsule
Each capsule contains:-
Diacerein….50mg
interleukin inhibitors
(NA)
Form-5
21-3-2014
Dy.No: 481
Routine20,000/-
Rs. 35.00/per
cap
International
availability not
Provided,
Me too,
Inspection report
dated 7-2-14
showingsatisfacto
ry GMP
Deferred as
formulation is
under review
according to 250th
DRB meeting.
(M-262)
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Minutes for 269th
Registration Board Meeting 11
compliance
18. M/s Martin Dow Ltd, Plot
No.37, sector:
19,Korangi
industrial Area,
Karachi
Nairen Capsule
Capsule
Each capsule contains:
Diacerein……….50 mg
Other drugs acting on
musculo-skeletal system
(M01AX21)
(Manufacturers Specs)
Form5
21-3-2014
Dy.No.271
Routine
Rs.20,000/-
Rs.297/10‗s
Rs.891/30‗s
NEGMA
Diacerein 50 mg
capsule
(ANSM-France)
Diora - Getz
Inspection report
dated18-03-2016
showing
compliance of
GMP as
satisfactory.
Deferred as
formulation is
under review
(M-263)
19. M/s Rotexmedica
Pakistan (Pvt)
Ltd, Islamabad
Myobloc 50mg
Capsules
Each capsule contains:-
Diacerein………. 50mg
(Anti-rheumatics)
Manufacturer‗s Specs
Form 5
08-12-2014
Dy No. 2330
Rs.8000/=
Rs.12,000/=
08-12-2014
30‗s
As Per PRC
NEGMA
Diacerein 50 mg
capsule
(ANSM-France)
Diora - Getz
Last Inspection
report of 29.3.16
recommended
issuance of GMP
Deferred as
formulation is
under review
(M-263)
20. M/s. Wnsfield Pharmaceutical
s, Hattar
Osteowin 50mg
Capsules
Each capsule contains:-
Diacerin…….50mg
(Anti-osteoarthritic)
Form-5
Dy No. 1234
29-10-2010
Rs.8000/
26-10-2010
Rs.12000/-
Dated 26-12-14
NEGMA
Diacerein 50 mg
capsule
(ANSM-France)
Artrodar by
Highnoon
Last inspection
report 22-11-2016
Overall firm is
following cGMP
compliance.
Deferred as
formulation is
under review
(M-264)
21. M/s. Sharooq Pharma(Pvt.)
Ltd, Lahore.
Acer Capsule 50mg
Each capsule contains
Diacerein … 50mg
NSAID‘s
Form 5
31.03.2015
Dy. No. 420
Rs. 8000/-
Rs.12000/=
31.03.2015
30‘s
As per SRO
Not provided.
Artrodar capsule
50 mg by
Highnoon.
Last inspection
report12-05-2016
Firm was further
needed to
improve the
testing methods.
Deferred for
confirmation of
approval of applied
formulation in
referenceregulator
yauthorities
(M-265)
Registration Board deferred the case for further deliberation in 268th
meeting. The
details of clinical recommendations, SmPC and EMA assessment report is also provided for
the consideration of the Board.
Diacerein 50mg capsules are approved and currently in the market in Austria, Spain,
Czech Republic and Slovakia as well.
SmPC of Austria provides following clinical recommendations
To treat symptoms in patients with osteoarthritis of the hip or knee joints; With delayed Effect.
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Minutes for 269th
Registration Board Meeting 12
Diacore therapy is not recommended in patients with rapidly progressive coxarthrosis These patients may be less likely to respond to diacrein.
Posology and method of administration
Therapy should be initiated by a specialist in the treatment of osteoarthritis become.
Dosing
adult
Since some patients may experience soft stools or diarrhea, during the first 2 Up to 4
treatment weeks an initial dose of 50 mg once daily with the evening meal recommended.
Thereafter, the recommended daily dose is 50 mg twice a day.
Children and adolescents under 18 years of age
ARTROLYT 50 mg capsules are not intended for use by children and adolescents
under 18 years of age
There are no studies on efficacy and tolerability of diacerein in children and
adolescents under 18 years.
Older people
Diacerein is not recommended for patients over 65 years, as this patient population for
Complications associated with diarrhea. Studies in elderly patients showed no significant
change in pharmacokinetic Parameters (see section 5.2.). In case of treatment, a change is
recommended Dosage is not required. However, caution is advised. Patients must stop
treatment if diarrhea occurs should.
Patients with renal impairment
In patients with mild to moderate renal impairment,
Usual recommended dose is not necessary. In patients with severe renal insufficiency
(Creatinine clearance less than 30 ml / min), the daily dose is however 50% of the
recommendedDosage (equivalent to 50 mg per day)
Special warnings and precautions for use
diarrhea:
The use of diacre is often accompanied by diarrhea (see section 4.8) Dehydration and
hypokalemia. Patients should be advised to discontinue treatment with diarrhea Diacre and
seek medical advice to discuss treatment alternatives.
In patients receiving diuretics, caution is advised, since dehydration and hypokalemia
may occur. Special caution is also needed in the case of hypokalemia in patients who are Are
treated with herbicidal glycosides (digoxin, digoxin) (see section 4.5). The simultaneous
administration of laxatives is to be avoided
Hepatotoxicity
Elevated liver enzyme levels in serum and acute symptomatic liver damage were
noted Diacer after market launch (see section 4.8). Before initiating a diacore therapy, the
patient should be advised of possible concomitant illnesses and with regard to earlier or
simultaneous liver disease important causes of an active liver disease. When diagnosing a
Liver disease, the use of diacerein is contraindicated (see sections 4.3 and 4.8). Patients are
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Minutes for 269th
Registration Board Meeting 13
monitored for signs of liver damage, and the use of Diacerein should be used with other
medicines that are associated with liver damage Caution. Patients should be advised to drink
alcohol during a diacre therapy. Treatment with diacre should be discontinued if an increase
in liver enzymes is observed or the suspicion of signs or symptoms of liver injury. Patients
should be over the signs and symptoms of hepatotoxicity will be elucidated, that they must
seek their doctor immediately if symptoms which indicate a liver damage, occur. The
metabolites of diacerein can change the urine in dependence of pH brownish to reddish to
color; This discoloration is harmless, but it can be diagnostic tests based on coloring (Streak
tests in the urine eg on glucose). Since the discoloration of urine can mask microhematuria,
should be done at regular intervals the renal function (including urine sediment). This applies
in particular to longerlasting ones Application of ARTROLYT.
EMA Assessment report for diacerein containing medicinal products.
Sr. No Date Decision
1 30-11-2012 The procedure for review started on 30-11-2012 by PRAC on the request of
ANSM France
2 08-11-2013 PRAC recommended suspension of diacerein containing medicinal
products
3 07-03-2014 PRAC reexamines its decision upon the requests of MAH‘s and
recommends that it remains available with restrictions
4 21-03-2014 CMDh endorses recommendations to restrict the use of diacerein-
containing medicines
5 19-09-2014 European Commission final decision; Assessment report for diacerein
containing medicinal products (28-08-2014)
Background information on the procedure.
On 22 November 2012, further to the evaluation of data resulting from
pharmacovigilance activities, France informed the European Medicines Agency, pursuant to
Article 31 of Directive 2001/83/EC, of their consideration that, in view of the safety profile
of diacerein containing medical products (very frequent digestive disorders, skin reactions
sometimes serious, hepatic disorders more often cytolytic with one fatal case and some
serious cases reported) and taking into account evidence from clinical trials and the scientific
literature suggesting that the effectiveness of diacerein in osteoarthritis was weak, the benefit-
risk balance of diacerein containing medicinal products in the symptomatic treatment of
osteoarthritis of the hip and knee might become unfavourable and therefore it was in the
interest of the Union to refer the matter to the PRAC for assessment.
The French competent authority (Agence nationale de sécurité du médicament et des
produits de santé, ANSM) therefore requested the PRAC to give a recommendation on the
balance of benefits and risks of diacerein containing medicinal products in the authorised
indications and to conclude on whether relevant marketing authorisations should be
maintained, varied, suspended or withdrawn.
Diacerein is currently authorised through national procedures in the following EU
Member States: Austria, Czech Republic, France, Greece, Italy, Portugal, Slovakia and Spain.
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Minutes for 269th
Registration Board Meeting 14
Overall discussion and benefit-risk assessment
The PRAC reviewed all the available data on the efficacy and safety of diacerein-
containing medicines in particular data in relation to the risk of hepatotoxicity,
gastrointestinal disorders and cutaneous reactions provided by the MAHs in writing and in
the oral explanations as well as data retrieved in the EudraVigilance database.
The data available in order to ascertain the efficacy of diacerein include some double-
blind clinical trials versus placebo with the accepted primary efficacy criteria for
symptomatic treatment of osteoarthritis. Although some of these studies showed a modest but
statistically significant delayed symptomatic effect they were of limited value from the
clinical point of view and also presented methodological issues.
The results of the study on impact on radiologic signs were not considered sufficient
to conclude on a modifying effect of diacerein and future studies would be needed to improve
the understanding of the clinical relevance of these results. No data were available regarding
a potential effect of diacerein for delaying surgery. Also, the data presented regarding a
potential sparing effect of NSAIDs with diacerein failed to demonstrate such an effect.
Regarding safety, the review found that the most frequently reported reactions with diacerein
were, as expected, gastrointestinal disorders, especially diarrhoeas, which were frequently
severe and leading to complications such as dehydration and disturbances of fluid and
electrolyte balance. Furthermore, cases of hepatic enzymes elevations have been reported and
as well as serious cases, including a fatal hepatic reaction in a patient treated with diacerein.
Having considered the overall submitted data provided by the MAHs in writing and at
the oral explanation, the PRAC concluded that the benefit-risk balance of diacerein
containing products is not favourable in the currently approved indications.
Based on those conclusions, the PRAC recommended the suspension of the marketing
authorisation for diacerein containing medicinal products.
Re-examination procedure
Following the adoption of the PRAC recommendation during the November 2013
PRAC meeting, a re-examination request was received from two of the MAHs involved in
the procedure, TRB Chemedica and Laboratoires Negma on 19 and 23 November 2013,
respectively.
The MAHs considered that there is adequate data supporting the efficacy of diacerein
in the symptomatic treatment of osteoarthritis of the hip and the knee and proposed further
risk minimisation measures to reduce the risk of diarrhoea and potential risk of hepatic
reactions associated with diacerein.
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Minutes for 269th
Registration Board Meeting 15
One of the MAHs also expressed concerns over legal aspects of the referral
procedure. However the PRAC is a scientific committee and that while it operates within the
legal framework, it cannot discuss the specific merits of procedural and legal aspects of
administrative procedures laid down in the legislation. As a result, procedural and legal
considerations are outside the remit of the PRAC, and therefore the re-examination of the
referral procedure under Article 31 of Directive 2001/83/EC only focused on the scientific
grounds for re-examination addressed by the MAH.
Overall conclusion of the re-examination procedure
Based on the totality of the data available on the safety and the efficacy of diacerein,
and considering all the new risk minimisation measures proposed during the re-examination
procedure, the PRAC concluded that the benefit-risk balance of diacerein-containing
medicinal products remained favourable in the symptomatic treatment osteoarthritis, subject
to the agreed changes to the product information and conditions.
Changes to the product information
The PRAC recommended that amendments to sections 4.1, 4.2, 4.3, 4.4, 4.5 and 4.8
of the Summary of Product Characteristics (SmPC) of all diacerein-containing medicinal
products should be introduced. Corresponding changes to the package leaflet should also be
introduced
Conclusion and grounds for the recommendation
Whereas,
The PRAC considered the procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data, for diacerein containing medicinal products;
The PRAC reviewed all the available data on the efficacy and safety of diacerein-containing medicines in particular data in relation to the risk of hepatotoxicity,
gastrointestinal disorders and cutaneous reactions provided by the MAHs in writing
and in the oral explanations;
The PRAC considered the grounds for re-examination provided by the MAHs in writing and in the oral explanations;
The PRAC considered that the available data supporting the use of diacerein have shown a modest but statistically significant effect in the treatment of osteoarthritis of
the knee and hip, with a delayed effect. However, treatment with diacerein is not
recommended in patients with rapidly progressive hip osteoarthritis, as they may have
a weaker response to diacerein.
The PRAC considered that available data from pre-clinical studies, clinical trials, post-marketing spontaneous case reports, and published literature have shown that the
use of diacereincontaining products is associated with safety concerns such as
frequent cases of severe diarrhoea and cases of potentially serious hepatotoxicity; a
risk of cutaneous reactions could not be excluded.
The PRAC considered that several new measures should be implemented to minimise these risks. These included a recommendation to start treatment at half the normal
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Minutes for 269th
Registration Board Meeting 16
daily dose, a contraindication in patients with a history and/or current liver disease
and a clear recommendation for patients to stop treatment as soon as diarrhoea occurs.
Also, diacerein is no longer recommended for patients aged 65 years. In addition,
given the gastrointestinal risk and potential risk of hepatic reactions, the PRAC
considered necessary to restrict prescription to specialists experienced in the treatment
of osteoarthritis. Finally, information on the cutaneous risk in the SmPC was
considered necessary.
The PRAC concluded that the risk of severe diarrhoea associated with the use of diacerein containing medicinal products and the occurrence of potentially severe
hepatic reactions could be mitigated by the above mentioned risk minimisation
measures to be reflected in the SmPC and adequately monitored with yearly PSUR
submissions.
The PRAC, as a consequence, concluded that the benefit-risk balance of the medicinal
products containing diacerein identified in Annex I remains favourable, subject to the
changes to the product information and conditions as provided for in Annex IV.
Conditions to the marketing authorization
Condition to the marketing authorisations National Competent Authorities (NCAs) of
Member State(s) or Reference Member State(s) (RMS) where applicable, shall ensure that the
following conditions are fulfilled by the MAH(s): The marketing authorisation holder shall
submit periodic safety update reports for this product in accordance with the requirements set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of
Directive 2001/83/EC and published on the European medicines web-portal.
Information to be added in SmPC and PIL
Information to patients
Diacerein is a medicine used to treat joint diseases such as osteoarthritis (swelling and
pain in the joints). Following an EU-wide review of diacerein, its use has been restricted in
order to minimise the risks of severe diarrhoea and liver problems.
Patients are advised of the following:
Diacerein should only be used for treating symptoms of osteoarthritis affecting the hip or knee.
If you have diarrhoea while taking diacerein, stop taking your medicine and contact your doctor to discuss which other treatments you can take.
If you are taking diacerein and you are 65 years or above, contact your doctor to discuss your treatment.
You should not take diacerein if you have or have had liver problems. Your doctor will monitor your liver function on a regular basis and advise about the symptoms of
liver problems (such as pruritus (itching) and jaundice). Contact your doctor if you
have symptoms of liver problems.
If you have any questions about your treatment, please contact your doctor or pharmacist
Information to healthcare professionals
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Minutes for 269th
Registration Board Meeting 17
Due to the risks associated with severe diarrhoea: −
o it is advisable to start treatment with half the normal dose (i.e. 50 mg per day) for the first 2 to 4 weeks, after which the recommended dose is 50 mg twice a
day.
o treatment should be stopped if diarrhoea occurs. o diacerein is not recommended in patients aged 65 years or above.
Diacerein must not be used in any patient with liver disease or a history of liver disease. Doctors should be monitoring their patients for early signs of liver problems
and advising them how to recognise early symptoms.
Diacerein should only be used to treat symptoms of osteoarthritis of the hip or knee and it is not recommended for rapidly progressive hip osteoarthritis.
Treatment should only be started by doctors experienced in treating osteoarthritis.
The recommendations are based on a review of available data on the efficacy and safety
of diacerein. Efficacy in the symptomatic treatment of osteoarthritis of the hip or knee was
shown in published studies where diacerein was superior to placebo in relieving pain1-5 . The
first beneficial effects of diacerein in these studies were seen after 2 to 4 weeks of continuous
use. With regard to safety, loose stools or diarrhoea were the most frequently reported
adverse events in clinical studies with diacerein at a dose of 100 mg per day. The proportion
of patients with diarrhoea in clinical trials ranged from 0% to 54.4%. In the majority of cases
diacerein-induced diarrhoea started in the first weeks of treatment. Elevated serum liver
enzymes and cases of symptomatic acute hepatic injury have been reported in the post-
marketing phase with diacerein. In clinical studies, around 0.5% of patients on diacerein had
some kind of liver reaction, with most cases being mild, reversible increases in serum
transaminases. The proportion of patients who develop drug-induced liver injury following
treatment with diacerein is estimated to be 0.03%.
Decision: Registration Board deliberated the matter in detail and decided as
follows:
i. Keeping in view the approval status of Diacerein capsule 50mg byAustrian Agency for Health and Food Safety (reference regulatory
authority as per decision of Registration Board in 249th
meeting), the
Registration Board approved the formulation of Diacerein 50mg capsule
only for the following clinical indication.
Treatment of symptoms of osteoarthritis of the hip or knee joint. ii. The information for prescribers (Summary of Product Characteristics-
SmPC) and patients (Patient Information Leaflet-PIL) including clinical
indications, adverse reactions and contraindications shall be same as per
approval by Austrian Agency for Health and Food Safety, EMA
assessment report and the final decision of European Commission.
iii. Registration holders of Diacerein capsule 50mg shall also follow above decision. In case of non-compliance, legal proceedings shall be started
accordingly.
iv. Registration Board decided to place above decision on DRAP’s website and same shall be communicated to all stake holders.
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Minutes for 269th
Registration Board Meeting 18
v. Registration Board advised PE&R Division to evaluate already deferred cases of formulations containing diacerin as per the checklist approved in
251st meeting.
2. Review of formulation of Ciprofloxacin as HCl 125mg Dry Suspension
Formulations containing ciprofloxacin as HCl 125mg dry suspension were deferred in
various meeting of Registration Board for review by the review committee. The review
committee compiled its final working and presented the case in 250th
RB meeting. The
comments and decision of the meeting is as follows:
Ciprofloxacin as Hcl 125mg Dry Suspension
International
availability
Me too status Remarks
Not available in
reference agencies.
NOVIDAT of M/s
Sami
CIPRIN of M/s
Werrick
HIFLOX of M/s
Hilton
Ciprofloxacin Oral Suspension is available in 250mg/5 ml and
500mg/5 ml strengths.
Adults: : 250 mg twice daily to 750 mg twice daily depending
upon nature and severity of infection.
Peads: ≥1 year (PO): 10-20 mg/kg q12hr; individual dose not to
exceed 750 mg q12hr (UTI).
Decscription:
Ciprofloxacin Oral Suspension is a white to slightly yellowish
suspension with strawberry flavor which may contain yellow-
orange droplets.
It is composed of ciprofloxacin microcapsules and diluent which
are mixed prior to dispensing.
The components of the suspension have the following
compositions:
Microcapsules–ciprofloxacin, povidone, methacrylic acid
copolymer, hypromellose, magnesium stearate, and Polysorbate
20.
Diluent–medium-chain triglycerides, sucrose, lecithin, water,
and strawberry flavor.
Five (5) mL of 5% suspension contains approximately 1.4 g of
sucrose and 5 mL of 10% suspension contains approximately 1.3
g of sucrose.
(Ref: US FDA)
Decision:
i. Rejected as the formulation is not available in reference drug regulatory agencies.
ii. Show cause notice for deregistration of already registered formulations.
Since then many applicants have submitted application for registration of the said
formulation claiming that many generic me-too are available in Pakistan. The case along the
SmPC of innovator is again presented before the Board for deliberation.
Name of the medicinal product
Ciproxin 250 mg/5 mL granules and solvent for oral suspension
Qualitative and quantitative composition
5 mL suspension after reconstitution (1 measuring spoon) contains 250 mg ciprofloxacin.
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Minutes for 269th
Registration Board Meeting 19
2.5 mL suspension after reconstitution (1/2 measuring spoon) contains 125 mg ciprofloxacin.
Excipients: Sucrose
One measuring spoon (5 mL of suspension) contains approx. 1.4 g of sucrose.
Dose in Paediatric population
Indications Daily dose in mg and in mL Total duration of
treatment
Cystic fibrosis 20 mg/kg body weight twice daily with a maximum
of 750 mg per dose, corresponding to a 0.4 mL/kg
body weight twice daily with a maximum of 15mL
per dose
10 to 14 days
Complicated urinary
tract infections and
pyelonephritis
10 mg/kg body weight twice daily to 20 mg/kg body
weight twice daily with a maximum of 750 mg per
dose, corresponding to a 0.2 mL/kg body weight
twice daily to 0.4 mL/kg body weight twice daily
with a maximum of 15mL per dose
10 to 21 days
Inhalation anthrax
postexposure
prophylaxis
and curative treatment
for persons able to
receive treatment by oral
route when clinically
appropriate
Drug administration
should begin as soon
as possible after
suspected or confirmed
exposure
10 mg/kg body weight twice daily to 15 mg/kg body
weight twice daily with a maximum of 500 mg per
dose, corresponding to a 0.2 mL/kg body weight
twice daily to 0.3 mL/kg body weight twice daily
with a maximum of 10 mL per dose
60 days from the
confirmation of
Bacillus
anthracis
exposure
Other severe infections 20 mg/kg body weight twice daily with a maximum
of 750 mg per dose, corresponding to a 0.4 mL/kg
body weight twice daily with a maximum of 15mL
per dose
According to the
type of infections
As per University of Iowa Carver College of Medicine the average weight of pediatric
population with age is as follows:
Approximate Weight Per Age [Weight in kg = (8 + (2 * years)]
Age Average Weight
Newborn 4 kg
6 months 7 kg
1 year 10 kg
2-3 years 12 – 14 kg
4-5 years 16 – 18 kg
6-8 years 20 – 26 kg
8-10 years 26 – 32 kg
10-14 years 32 – 50 kg
14 years > 50 kg
This table is accessed from
http://www.dmconsortium.org/filesimages/clerkship%20resources/peds_pediatric_norms.pdf
on 25th April 2017
The average dose as per SmPC for pediatric population is 10 – 20 mg/kg twice daily.
The required dose can be calculated as
http://www.dmconsortium.org/filesimages/clerkship%20resources/peds_pediatric_norms.pdf
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Minutes for 269th
Registration Board Meeting 20
Age Average Weight Calculated Dose
(10 – 20 mg/kg twice daily)
Newborn 4 kg 40 – 80 mg
6 months 7 kg 70 – 140 mg
1 year 10 kg 100 – 200 mg
2-3 years 12 kg
14 kg
120 – 240 mg
140 – 280 mg
4-5 years 16 kg
18 kg
160 – 320 mg
180 – 360 mg
6-8 years 20 kg
26 kg
200 – 400 mg
260 – 520 mg
8-10 years 26 kg
32 kg
260 – 520 mg
320 – 640 mg
10-14 years 32 kg
50 kg
320 – 640 mg
500 – 1000 mg
14 years > 50 kg > 500 – 1000 mg
Dose for age groups between newborn and 2 years is between 40 mg to 240 mg which
might be difficult to measure in spoon for 250mg/5ml suspension.
Ciprofloxacin is low water soluble drug and has been classified as BCS-IV due to its
low solubility in a research review available at
https://www.ncbi.nlm.nih.gov/pubmed/20602455 (accessed on 25th April 2017).
The innovator product is marketed with a solvent containing following ingredients
Soya lecithin,
Medium chain triglycerides,
Strawberry flavour,
Sucrose,
Purified water.
Special precautions for disposal and other handling
The small brown bottle contains the active substance as granules and the large white
bottle contains the solvent.
a) Open both bottles. Childproof cap: Press down according to instructions on the cap while turning to the left.
b) Pour the content of the brown bottle (granules) completely into the large white bottle with the suspension fluid. Do not pour water into the suspension!
c) Reclose the large white bottle properly according to the instructions on the cap and shake vigorously for about 15 seconds. The correct mixture is now prepared; the
suspension is ready for use
Taking the Ready to Use Suspension
Take the prescribed amount of suspension by using the measuring spoon. Do not
chew the granules present in the suspension, simply swallow them. A drink of water may be
taken afterwards. Reclose the bottle properly after use according to the instructions on the
cap. The ready to use suspension is stable for 14 days when stored in a refrigerator (2 °C -
8°C) or at ambient temperatures below 30°C. After treatment has been completed, it should
not be reused. Shake vigorously each time before use for approximately 15 seconds.
https://www.ncbi.nlm.nih.gov/pubmed/20602455
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Minutes for 269th
Registration Board Meeting 21
The graduated measuring spoon with the markings 1/2 is equivalent to 2.6 mL containing
2.5mL of final suspension and 1/1 is equivalent to 5.2 mL containing 5.0 mL of final
suspension. The graduated measuring spoon must be used for measuring the required
prescribed amount of Ciprofloxacin oral suspension 250 mg/5 mL
Decision: Registration Board decided as follows:
i. Keeping in view the following statement written in Qualitative and quantitative composition “2.5 mL suspension after reconstitution (1/2
measuring spoon) contains 125 mg ciprofloxacin” and domestic conditions
for difficulties in dispensing 250mg/5ml suspension for children under 2
years of age, Registration Board decided to approve the formulation of
ciprofloxacin 125mg/5ml granules and solvent for oral suspension as per
reference product approved by USFDA and MHRA.
ii. Registration Board was apprised that already registered products were either not providing diluent with the ciprofloxacin suspension or the
compositionof diluent was not as per the reference product. Registration
Board advised Pharmaceutical Evaluation Cell to prepare the case along
with details including manufacturing area requirements of the
solvent/diluent and considering the legal requirements for the separate
registration of the solvent for further deliberation in Registration Board.
3. Review of formulation of of Nimesulide Tablets 100mg.
Nimesulide 100mg tablet formulations were deferred for review by the review
committee. The review committee presented the case in 250th
meeting of Registration Board
with following comments/recommendations.
NIMESULIDE 100MG TABLETS
International
availability
Me too status Remarks
Available in EMA with
limited indications i.e.
acute pain and pimary
dysmeanorrhoea.
NIMEROL of M/s
Brayon
NEMSIS of M/s
Genome
NIMS of M/s SAMI
Having considered the overall submitted data provided
by the MAHs in writing and in the oral explanation,
the CHMP (Committee for Medicinal Products for
Human Use) concluded:
That evidence of clinically efficacy of nimesulide containing products for systemic use in the
indications for short-term treatment has been
shown. No unequivocal and clinically meaningful
advantage over other NSAIDs has been
demonstrated and, therefore the Committee
considered the efficacy of nimesulide to be similar
to other NSAIDs available.
That nimesulide overall gastrointestinal toxicity is comparable to other NSAIDs but that nimesulide is
associated with an increased risk for hepatotoxicity.
The combined safety profile in terms of
hepatotoxicity and gastro intestinal toxicity for
nimesulide is shown as worse than some other
alternative NSAIDs such as diclofenac and
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Minutes for 269th
Registration Board Meeting 22
naproxen. Furthermore, the limitations of the
current available data lead to uncertainties on
hepatotoxicity, and concerns remain especially with
prolonged use of nimesulide.
Considering the maximum duration of 15 days of treatment to minimize the risk for hepatotoxicity
and aiming a further minimization of the risks
associated with nimesulide, the Committee
considered that nimesulide use should be restricted
to acute conditions only i.e. treatment of acute pain
and primary dysmenorrhoea.
That in the light of above, considered that there is a risk of chronic use of nimesulide in ―symptomatic
treatment of painful osteoarthritis‖ and concludes
that the risk-benefit balance of nimesulide-
containing medicinal products for systemic use is
no longer favorable in this indication.
CHMP Recommendations:
o Prescribers should no longer prescribe systemic nimesulide for treating painful
osteoarthritis
o Prescribers should review treatment of patients being treated for painful osteoarthritis
with a view to choosing an appropriate
alternative treatment.
o Nimesulide should only be used as a second choice, and only in the treatment of acute pain
or dysmenorrhoea.
o Patient currently receiving systemic nimesulide for painful osteoarthritis should
consult their doctor in order to arrange
alternative treatment.
o Patients who have any questions should speak to their doctor or pharmacist.
The European Commission issued a decision on 20
January 2012.
(Ref: EMA Asessment Report)
Decision
I. Rejected on the grounds that the drug has no clinically meaningful advantage over other NSAIDS and that nimesulide is associated with increased risks of hepatotoxicity compared to
other drugs in the class. Moreover, the combined safety profile in terms of hepatotoxicity and GI
toxicity is shown as worse than some other alternative NSAIDS such as Diclofenac and
naproxen. Hence keeping in view Risk vs benefit ratio, registration application containing
Nimesulide are rejected.
II. Showcause notice shall be issued for de-registration of registered drugs containing Nimesulide.
Nimesulide-containing medicinal products for systemic use are currently marketed in more
than 50 countries world-wide mainly in Europe and South America. In the European Union,
nimesulide is authorised in 17 Member States on prescription only and marketed in 15
Member States (Bulgaria, Czech Republic, Cyprus, France, Greece, Hungary, Italy, Latvia,
Lithuania, Malta, Poland, Portugal, Romania, Slovakia and Slovenia).
Sr.
No
Date Incidents/Decision
1. January 1998 cases of hepatic adverse reactions, ranging from asymptomatic increases in liver enzymes to hepatic failure that required liver transplant, have
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Minutes for 269th
Registration Board Meeting 23
been reported in Finland
2. 13thMarch 2002 Finnish National Agency for Medicines had received altogether 109 Adverse Drug Reaction reports concerning nimesulide, of these 66 were
hepatic reactions, including serious reactions (e.g. hepatitis,hepatic
failure, including two cases necessitating liver transplantation)
3. 18thMarch 2002 Based on these serious hepatic reactions and taking into account the relatively non-serious conditions for which nimesulide is indicated for as
well as the existence of numerous alternative treatments, the Marketing
Authorisations of nimesulide containing medicinal products for oral
administration have been suspended in Finland
4. 10thApril 2002 Finland notified the CPMP and EMEA Secretariat of a referral under Article 31 of Directive 2001/83/EC as amended, requesting the CPMP to
give its opinion on the risk-benefit balance of all nimesulide containing
medicinal products, especially in view of the hepatic toxicity.
5. 3rdMay 2002 Spain circulated a Rapid Alert about the suspension of the marketing of nimesulide containing medicinal products in their territory
6. 25thJune 2003 Written explanations, supplementary informations and oral explanations by MAH‘s were provided till 25 June 2003
7. 24thJuly 2003 Upon consideration of all available data, the CPMP adopted an opinion
8. 21stOctober 2003 European Commission returned the Opinion back to the CPMP for further consideration of its recommendation as regards to the 200 mg
tablets
9. 17thDecember 2003 CPMP adopted a revised opinion which recommended the maintenance of the Marketing Authorisations for nimesulide containing medicinal
products as amended and/or the granting of Marketing Authorisations in
accordance with the Summaries of Product Characteristics approved
10. 26thApril 2004 On the basis of the CPMP Opinion, the European Commission issued a Decision ―The CPMP considered that the risk-benefit profile of
nimesulide containing products for systemic and topical use is favourable
and that marketing authorisations, except for the 200mg tablets, should
be maintained/granted with the restrictions‖
11. 15thMay 2007 Following new safety information regarding cases of fulminant hepatic failure associated with nimesulide, Irish medicines board suspended the
national marketing authorisations for all systemic medicinal products
containing nimesulide available in Ireland and triggered an article 107
procedure to suspend the marketing authorisation for systemic
nimesulide-containing medicines, mainly because of liver problems
12. September 2007 CHMP concluded that the available data did not support a suspension of all marketing authorisations in Europe. However, it recommended that
some restrictions should be placed on the way these medicines are
prescribed, including limiting the pack size to 30 doses, and that the
information provided to doctors and patients be amended to limit the risk
of liver injury
13. 08thFebruary 2008 The CHMP opinion adopted in September 2007 was transmitted to the European Commission so that it could issue a final decision. This process
involves a consultation step with the Standing Committee for Medicinal
Products for Human Use, a body of representatives from Member States.
The Standing Committee could not reached an agreement, and, on 8
February 2008, the European Commission therefore asked the CHMP to
further consider its opinion, taking new data on the risk of liver problems
into account, in particularly new data supplied by Ireland, and looking at
ways of minimizing the risk associated with nimesulide
14. 16thOctober 2009 The European Commission issued a decision based on the CHMP recommendations:
Based on the additional information reviewed, the CHMP has not
changed its conclusions from September 2007, namely that the benefits
of systemic formulations of nimesulide still outweigh their risks,
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Minutes for 269th
Registration Board Meeting 24
provided that the use of these medicines is restricted to ensure that the
risk of patients developing liver problems is kept to a minimum.
The CHMP noted that the only additional measures taken by Member
States were changes to the prescription status or reimbursement levels for
nimesulide-containing medicines. This suggested that the measures
recommended in September 2007, including the changes to the
prescribing information, were appropriate to reduce the risk of liver
problems associated with nimesulide.
However, the CHMP further concluded that the benefits and risks of
nimesulide should be assessed in a wider context. This review should
look at all of the potential risks of the medicine, especially the risk of
side effects affecting the stomach and the gut, which were outside the
scope of the original Article 107 procedure. This should be carried out in
a separate ‗Article 31‘ referral procedure. This type of referral is used
when it is of ‗Community interest‘ (for the benefit of all Member States)
to have a common view on the benefit-risk balance of a medicine.
Because of the severity of the side effects, the European Commission
recommended that further measures be taken to ensure that the risk of
these side effects is lowered. The European Commission noted that, in
some Members States, nimesulide was restricted to second-line
treatment. The restriction was therefore added into the prescribing
information for nimesulide-containig medicines. The Commission also
made it clear that the companies that market nimesulide-containing
medicines should inform doctors about the medicines‘ risks.
15. 19thJanuary 2010 European Commission asked the CHMP to carry out a full assessment of the benefit-risk balance of nimesulide and to issue an opinion on whether
the marketing authorizations for systemic medicine containing
nimesulide should be maintained, varied, suspended or withdrawn across
the European Union.
16. 20thJanuary 2012 The European Commission issued a decision based on the recommendations of CHMP
Overall conclusion:
Having considered the overall submitted data provided by the MAHs in writing and in the
oral explanation, the CHMP concluded:
That evidence of the clinically efficacy of nimesulide-containing products for systemic use in the indications for short-term treatment has been shown. No
unequivocal and clinically meaningful advantage over other NSAIDs has been
demonstrated and, therefore the Committee considered the efficacy of nimesulide to
be similar to other NSAIDs available.
That nimesulide overall gastrointestinal toxicity is comparable to other NSAIDs but that nimesulide is associated with an increased risk for hepatotoxicity. The combined
safety profile in terms of hepatotoxicity and gastro intestinal toxicity for nimesulide is
shown as worse than some other alternative NSAIDs such as diclofenac and
naproxen. Furthermore, the limitations of the current available data lead to
uncertainties on hepatotoxicity, and concerns remain especially with prolonged use of
nimesulide.
Considering the maximum duration of 15 days of treatment to minimise the risk for hepatotoxicity and aiming a further minimisation of the risks associated with
nimesulide, the Committee considered that nimesulide use should be restricted to
acute conditions only i.e. treatment of acute pain and primary dysmenorrhoea.
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Minutes for 269th
Registration Board Meeting 25
That in light of the above, considered that there is a risk of chronic use of nimesulide in ―symptomatic treatment of painful osteoarthritis‖ and concludes that the risk-
benefit balance of nimesulide-containing medicinal products for systemic use is no
longer favourable in this indication.
Therefore, the CHMP recommended the variation to the terms of the marketing
authorisations for the medicinal products referred to in Annex I of the Opinion, for which
amendments to the relevant sections of the summary of product characteristics and package
leaflet are set out in Annex III to the opinion. The conditions affecting the marketing
authorisations are set out in Annex IV of the Opinion
Annex I: List of the names, pharmaceutical forms, strengths of the medicinal products, routes
of administration, marketing authorisation holders in the member states (Accessed at)
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_3
1/WC500125570.pdf
Annex II: Scientific conclusions and grounds for the amendments of the Summary of
Product Characteristics and Package Leaflet presented by the EMA (Accessed at)
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_3
1/WC500125571.pdf
Annex III: Amendments of the Summary of Product Characteristics and Package Leaflet
(Accessed at)
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_3
1/WC500125572.pdf
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500125570.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500125570.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500125571.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500125571.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500125572.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500125572.pdf
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Minutes for 269th
Registration Board Meeting 26
The screenshot of SmPC is accessed on 26
th April 2017.
Annex IV: Condition of the marketing authorizations
Conditions of the Marketing Authorisations
National Competent Authorities, coordinated by the Reference Member State where
applicable, shall ensure that the following conditions are fulfilled by the Marketing
Authorization Holders:
Communication Plan
The MAHs should inform healthcare professionals on the outcome of this review on
nimesulide via a ―Direct Healthcare Professional Communication‖ (DHPC) as agreed by the
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Minutes for 269th
Registration Board Meeting 27
CHMP. The harmonized date for release of the letter is of 15 working days following the
European Commission decision.
All the data provided above have been accessed from the following links on 26th
April 2017.
1st Referral starting 2003:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/
human_referral_000152.jsp&mid=WC0b01ac05805c516f
2nd
Referral starting 2007:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/
human_referral_000115.jsp&mid=WC0b01ac05805c516f
3rd
Referral starting 2011:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/
human_referral_000275.jsp&mid=WC0b01ac05805c516f
The case is presented before the Board for deliberation.
Decision: Registration Board deliberated the case and decided as follows:
i. Keeping in view the approval status of Nimesulide 100mg tablet in EMA, the Registration Board approved the formulation of Nimesulide Tablets 100mg with
a pack size of 15 tablets as per recommendations of EMA only for the following
clinical indications as a second line choice.
Treatment of acute pain
Primary dysmenorrhea
ii. The information for prescribers (Summary of Product Characteristics-SmPC) and patients (Patient Information Leaflet-PIL) including clinical indications,
adverse reactions and contraindications shall be same as per approval by
European Medicine Agency (EMA) assessment report and the final decision of
European Commission.
iii. Registration Board noticed that some of the marketing authorization / registration holders are promoting and the prescribers are subsequently
prescribing nimesulide for clinical indications which are not approved by EMA
assessment report. These indications also include post-operative dental pain,
post-surgical pain, painful extraarticular disorders and tendinitis for even more
than 15 days. Registration Board deliberated those registration holders of
Nimesulide 100mg tablet shall also follow above decision. In case of non-
compliance, legal proceedings shall be started accordingly.
iv. Registration Board decided to place above decision on DRAP’s website and same shall be communicated to all stake holders.
v. Registration Board advised PE&R Division to evaluate already deferred cases of formulations containing nimesulide as per the checklist approved in 251
st
meeting.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/human_referral_000152.jsp&mid=WC0b01ac05805c516fhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/human_referral_000152.jsp&mid=WC0b01ac05805c516fhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/human_referral_000115.jsp&mid=WC0b01ac05805c516fhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/human_referral_000115.jsp&mid=WC0b01ac05805c516fhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/human_referral_000275.jsp&mid=WC0b01ac05805c516fhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Nimesulide/human_referral_000275.jsp&mid=WC0b01ac05805c516f
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Minutes for 269th
Registration Board Meeting 28
Case No.02: Registration of imported products.
a. Import Cases for priority consideration
Registration Board in 257th
meeting decided that drugs for treatment of cancer, viral
diseases, thalassemia, immunosuppressants, vaccine and sera, new molecules/formulations,
blood factors and bags will be given priority consideration.
Following applications fall in the defined category of priority consideration.
1. Name and address of Applicant M/s Muller & Phipps Pakistan Pvt. Ltd. Uzma Court, Main Clifton rod Karachi
Name and address of manufacturer Fresenius Kabi Austria GmbH, Hafnertrabe 36, 8055
graz, Austria.
Name and address of Marketing
authorization holder
Fresenius Kabi Deutschland GmbH, D-61346 Bad
Homburg v. d. H. / Germany.
Exporting country Germany
Brand Name+Dosage Form + Strength ZOLEDRONIC ACID FRESENIUS KABI 4mg/5ml
Concentrate for solution for IV infusion
Composition Each 5ml contains:
Zoledronic acid…. 4mg
Pharmacological Group (Bishosphonate)
Finished product Specification In House
Shelf life 3 years
Type of Form Form 5-A
Diary No. & Date of R& I Dy. No. 1313 Dated 22/10/2014
Fee including differential fee Rs. 100,000/- Dated 22/10/2014
Pack size 1‘s (5ml vial)
Demanded Price 17859/- per vial
International Availability Pms-Zoledronic Acid By Pharmascience Inc, Health
Canada
Me-too status Zoledronic acid by Scotmann Pharma
Detail of certificates attached 1. Original legalized CoPP (certificate No. ROHQ7)
issued by Regierungsprasidium Darmstadt Luisenplatz
2 D-64278 Darmstadt, Germany on 23/01/2017 is
attached which confirms the free sale of the product in
exporting country.
2.GMP certificate of manufacturer.
Remarks of the Evaluator. The firm has claimed In House manufacturing
specifications while following documents have not been
provided as per decision of Registration Board taken by
it in its 267th meeting;
1. Product and formulation development data 2. Manufacturing method development and process validation
3. Analytical method development and validation (accuracy, precision, specificity, linearity, ruggedness
and robustness) against analytical method and
innovator‘s product
4. Comparative pharmaceutical equivalence against innovator‘s product including comparative
dissolution profiling and preferably bio-equivalence
5. Stability study data of the product for accelerated and real time period against innovator‘s
product as a reference
Decision of 269th
meeting:Approved as per Import Policy for Finished Drugs with Innovator’s
specifications.
https://health-products.canada.ca/dpd-bdpp/search-fast-recherche-rapide.do?code=3550&lang=en
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Minutes for 269th
Registration Board Meeting 29
2. Name and address of Applicant M/s RG Pharmaceutica Pvt. Ltd. Suite No. 703 Progressive square PECHS Block 6 Shahrah-e-faisal
Karachi 75400, Pakistan
Name and address of manufacturer M/s Laboratorios Rubio SA. Industra 29, Comte De Sert
08755 Castellpisbal Barcelona Spain
Name and address of Marketing
authorization holder
M/s Laboratorios Rubio SA. Industra 29, Comte De Sert
08755 Castellpisbal Barcelona Spain
Exporting country Spain
Brand Name+Dosage Form + Strength RESINCALCIO powder for oral Suspension
Composition Each sachet of 15gm powder contains:
Calcium polystyrene sulphonate...............14.96 gm
Pharmacological Group Drug for treatment of hyperkalemia and
hyperphosphatemia
Finished product Specification B.P.
Shelf life 5 years
Type of Form Form 5-A
Diary No. & Date of R& I Dy. No. 07 Dated 04/12/2015
Fee including differential fee Rs. 1,00,000/- Dated 04/12/2015
Pack size 15g per Sachet ( Pack of 26 Sachet of 15g)
Demanded Price 250/- per sachet
International Availability Calcium resonium by Sanofi MHRA
Me-too status Not provided by the firm and couldn‘t be confirmed as
well.
Detail of certificates attached Original Legalized CoPP (certificate No. 2015/04083)
issued by Agencia Espanola Del Meidcaomento Y
Productos Sanitarios, Spain on 17th November, 2015
confirms the good level of GMP compliance. The
product is in the market of country of origin for free sale
as per CoPP.
Remarks of the Evaluator. CoPP is expired on 15th November, 2016.
Decision of 269th
meeting:Approved as per Import Policy for Finished Drugs. As CoPP was valid at
time of submission of application, thus the Board advised to provide legalized and valid CoPP
and authorized Chairman, Registration Board for approval to issue registration letter.
3. Name and address of Applicant M/s Zenith International Tahir Plaza, A/20, Block 7 & 8, K.C.H.S.U, Karachi,
Pakistan
Name and address of manufacturer M/s Sichuan Nigale Biotechnology Co., Ltd
No. 28 Kuixing Road, Dongxi Town Jianyang, Sichuan
Province, China
Name and address of Marketing
authorization holder
M/s High Hope Int‘l Group Jiangsu Medicines &
Healtjh Products Imp. & Exp. Corp. Ltd., Nanjing
210001, China
Exporting country China
Brand Name+Dosage Form + Strength PERFECT Brand Blood Bags
CPDA-1, with transfusion set, Single, 500ml
(70 ml Anticoagulant solution)
Composition Each 100ml CPDA-1 contains:
Citric acid (monohydrate) USP.......... 0.327g
Sodium Citrate (dehydrate) USP........ 2.63g
Monobasic Sodium Phosphate (monohudrate)
USP.......0.222g
Dextrose (monohydrate) USP .............3.19g
Adenine USP .............0.0275g
Water for injection to 100ml
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Minutes for 269th
Registration Board Meeting 30
Pharmacological Group ------
Finished product Specification USP
Shelf life 3 years
Type of Form Form 5-A
Diary No. & Date of R& I Dy. No. 2189 Dated 11/11/2016
Fee including differential fee Fee Rs.50,000/- Dated 11/11/2016
Pack size 1‘s in sterile PE bag and 5‘s in aluminium foil
Demanded Price Not proposed
International Availability TGA Australia
Me-too status HOFFMANN HUMAN HEALTH PAKISTAN LTD.,
LAHORE
Detail of certificates attached 1. Legalized copy of Certificate of exportation valid up
to October 2017, confirms the registration and sale of
product in China.
2. Valid copy of ISO 13485 certificate is attached.
3. Valid Copy of EC certificate (full quality assurance
system)
Remarks of the Evaluator. Differential fee of Rs.50,000/- should be submitted as
the product is me too.
Decision of 269th
meeting:Deferred for further deliberation for status of blood bags, whether
considered as a drug or medical device.
4. Name and address of Applicant M/s Zenith International Tahir Plaza, A/20, Block 7 & 8, K.C.H.S.U, Karachi,
Pakistan
Name and address of manufacturer M/s Sichuan Nigale Biotechnology Co., Ltd
No. 28 Kuixing Road, Dongxi Town Jianyang, Sichuan
Province, China
Name and address of Marketing
authorization holder
M/s High Hope Int‘l Group Jiangsu Medicines &
Healtjh Products Imp. & Exp. Corp. Ltd., Nanjing
210001, China
Exporting country China
Brand Name+Dosage Form + Strength PERFECT Brand Blood Bags
CPDA-1, with transfusion set, Double, 500ml
(70 ml Anticoagulant solution)
Composition Each 100ml CPDA-1 contains:
Citric acid (monohydrate) USP.......... 0.327g
Sodium Citrate (dehydrate) USP........ 2.63g
Monobasic Sodium Phosphate (monohudrate)
USP.......0.222g
Dextrose (monohydrate) USP .............3.19g
Adenine USP .............0.0275g
Water for injection to 100ml
Pharmacological Group ------
Finished product Specification USP
Shelf life 3 years
Type of Form Form 5-A
Diary No. & Date of R& I Dy. No. 2188 Dated 11/11/2016
Fee including differential fee Fee Rs.50,000/- Dated 11/11/2016
Pack size 1‘s in sterile PE bag and 5‘s in aluminium foil
Demanded Price Not proposed
International Availability TGA Australia
Me-too status HOFFMANN HUMAN HEALTH PAKISTAN LTD.,
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Minutes for 269th
Registration Board Meeting 31
LAHORE
Detail of certificates attached 1. Legalized copy of Certificate of exportation valid up
to October 2017, confirms the registration and sale of
product in China.
2. Valid copy of ISO 13485 certificate is attached.
3. Valid copy of EC certificate (full quality assurance
system)
Remarks of the Evaluator. Differential fee 50,000/- should be submitted as the
product is me too.
Decision of 269th
meeting:Deferred for further deliberation for status of blood bags, whether
considered as a drug or medical device.
5. Name and address of Applicant M/s Zenith International Tahir Plaza, A/20, Block 7 & 8, K.C.H.S.U, Karachi,
Pakistan
Name and address of manufacturer M/s Sichuan Nigale Biotechnology Co., Ltd
No. 28 Kuixing Road, Dongxi Town Jianyang, Sichuan
Province, China
Name and address of Marketing
authorization holder
M/s High Hope Int‘l Group Jiangsu Medicines &
Healtjh Products Imp. & Exp. Corp. Ltd., Nanjing
210001, China
Exporting country China
Brand Name+Dosage Form + Strength PERFECT Brand Blood Bags
CPDA-1, with transfusion set, Double, 250ml
(35 ml Anticoagulant solution)
Composition Each 100ml CPDA-1 contains:
Citric acid (monohydrate) USP.......... 0.327g
Sodium Citrate (dehydrate) USP........ 2.63g
Monobasic Sodium Phosphate (monohudrate)
USP.......0.222g
Dextrose (monohydrate) USP .............3.19g
Adenine USP .............0.0275g
Water for injection to 100ml
Pharmacological Group ------
Finished product Specification USP
Shelf life 3 years
Type of Form Form 5-A
Diary No. & Date of R& I Dy. No. 2187 Dated 11/11/2016
Fee including differential fee Fee Rs.50,000/- Dated 11/11/2016
Pack size 1‘s in sterile PE bag and 5‘s in aluminium foil
Demanded Price Not proposed
International Availability TGA Australia
Me-too status HOFFMANN HUMAN HEALTH PAKISTAN LTD.,
LAHORE
Detail of certificates attached 1. Legalized copy of Certificate of exportation valid up
to October 2017, confirms the registration and sale of
product in China.
2. Valid copy of ISO 13485 certificate is attached
3. Valid Copy of EC certificate (full quality assurance
system
Remarks of the Evaluator. Differential fee 50,000/- should be submitted as the
product is me too.
Decision of 269th
meeting:Deferred for further deliberation for status of blood bags, whether
considered as a drug or medical device.
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Minutes for 269th
Registration Board Meeting 32
b. Import cases of List-II
1 Name and address of Applicant M/s Medi Mark Pharmaceutical, Liaqat Chowk
Sahiwal Pakistan.
Name and address of manufacturer M/s Furen Pharmaceutical Group Co., Ltd., Xuanwu
Economic Developing Area Luyi Country Henan China
Name and address of Marketing
authorization holder
M/s Furen Pharmaceutical Group Co., Ltd., Xuanwu
Economic Developing Area Luyi Country Henan China
Exporting country China
Brand Name+Dosage Form + Strength INJ. SOLUCORT-M 100mg IV/IM
(powder for solution)
Composition Each vial Contains:
Hydrocortisone Sodium Succinate eq. toHydrocortisone
............. 100mg
Pharmacological Group Adrenal Cortical Hormone
Finished product Specification USP
Shelf life 3 years
Type of Form Form 5-A
Diary No. & Date of R& I Dy. No. 1289 Dated 23/10/2014
Fee including differential fee Rs. 100,000/0- Dated 23/10/2014
Pack size 1‘s (2ml Vial)
Demanded Price Not proposed
International Availability Hydrocortisone sodium succinate injection by Teva
Canada Limited,Health Canada
Me-too status Solu cortef by Pfizer Laboratories LTD.
Detail of certificates attached Original legalized CoPP (certificate No. 14-07-014)
issued by Zhoukou Food and Drug Administration which
was valid up to July, 2016 confirms the free sale of the
product in exporting country. The facilities and
operations conform to GMP as recommended by WHO.
Remarks of the Evaluator. CoPP is expired. The firm has committed to submit the
same with valid date.
The firm has claimed for both IV and IM route.
Decision of 269th
meeting:Approved as per Import Policy for Finished Drugs. As CoPP was valid at
time of submission of application, thus the Board advised to provide legalized and valid CoPP and
authorized Chairman, Registration Board for approval to issue registration letter.
2 Name and address of Applicant M/s Medi Mark Pharmaceutical, Liaqat Chowk
Sahiwal Pakistan.
Name and address of manufacturer M/s Furen Pharmaceutical Grou