Minutes for 269th Meeting Registration Board held on 27 ... Minutes for 269th Registration Board...

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

Minutes for 269th


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&LT 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.

Minutes for 269th


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.

Minutes for 269th


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

Minutes for 269th


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;

Minutes for 269th


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

Minutes for 269th


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


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


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

Minutes for 269th


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


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,

Minutes for 269th


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


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)

Minutes for 269th


3x10‘s/as per

SRO

12. M/s Lowitt Pharma (Pvt.)

Ltd, 24-

Industrial

Estate,

Hayatabad,

Peshawar.

Priority # 2062

Capsule Atorin 50mg


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


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


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


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)

Minutes for 269th


compliance

18. M/s Martin Dow Ltd, Plot

No.37, sector:

19,Korangi

industrial Area,

Karachi

Nairen Capsule

Capsule


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


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


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


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.

Minutes for 269th


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

Minutes for 269th


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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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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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

Minutes for 269th


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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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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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


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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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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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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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


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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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

Minutes for 269th


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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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.

Minutes for 269th


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)


1/WC500125571.pdf

Annex III: Amendments of the Summary of Product Characteristics and Package Leaflet

(Accessed at)


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

Minutes for 269th


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

Minutes for 269th


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:



3rd

Referral starting 2011:



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

Minutes for 269th


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

Minutes for 269th


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



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



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



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

Minutes for 269th


Pharmacological Group ------

Finished product Specification USP

Shelf life 3 years



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.


Pakistan



Province, China





210001, China



CPDA-1, with transfusion set, Double, 500ml






USP.......0.222g


Adenine USP .............0.0275g




Shelf life 3 years








Minutes for 269th


LAHORE



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




Pakistan



Province, China





210001, China



CPDA-1, with transfusion set, Double, 250ml






USP.......0.222g


Adenine USP .............0.0275g




Shelf life 3 years








LAHORE



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



Minutes for 269th


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



M/s Furen Pharmaceutical Group Co., Ltd., Xuanwu

Economic Developing Area Luyi Country Henan 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


Shelf life 3 years



Fee including differential fee Rs. 100,000/0- Dated 23/10/2014

Pack size 1‘s (2ml Vial)


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

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