Suspension of Drug Registration: Combination of Paracetamol, Thioridazine and Caffeine

Drug Safety Alert

Update from Registration Board of Drugs

Date:15th of June 2022.
Target Audience:• Provincial Drugs Control Units and Provincial Pharmacovigilance Centres;
• Manufacturers of irrational drugs combination (Paracetamol, Thioridazine and Caffeine);
• Healthcare Professionals; and
• Patients, consumers or caregivers.
Problem or Issue:The Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of foregoing discussions, benefit-risk analysis and public health impact suspended all drug registrations of the combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) under Section 7 (11) (b, c & d) read with Section 42 of the Drugs Act, 1976 in the larger public interest, with immediate effect as this combination is neither approved by any Reference Regulatory Authorities nor safety and efficacy data is available with the registration holders. These formulations will stay suspended for a period of one (01) year; or till the time its safety and efficacy is well established through indigenous clinical trials in accordance with the Bio Study Rules, 2017; or if it is approved by the Reference Regulatory Authorities, whichever is earlier. Likewise, Registration holders were directed to suspend the manufacturing and import of these drug products immediately and to withdraw available stocks from the market in the larger public interest.
Background:The Registration Board in its 263rd meeting held on 28th and 30th November, 2016 had decided that “the combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) is not available in any of the reference regulatory authorities as approved by the Board i.e. FDA, TGA, EMA, PMDA, MHRA, Health Canada, Germany, France, Switzerland, Sweden, Norway, Denmark, Austria and Netherland. Since it is reported vide WHO newsletter no.1, 2005 about the voluntary withdrawal of Thioridazine worldwide by the brand leader Novartis, hence all irrational combinations containing Thioridazine, which are also not existent worldwide be also withdrawn throughout the country. Show cause notice will be served by the concerned Registration section after confirming international availability”

In 293rd meeting held on 6th-8th January, 2020, the board was informed that show-cause notices were served to registration holders. Later on, M/s. Wilson Pharmaceutical, Islamabad filed a case in the Court of Senior Civil Judge (West) Islamabad. The Court vide their order dated 01-11-2018 rejected plaint under order VII rule 11 of CPC.

Meanwhile, Provincial Drug Inspector, Nowshera on account of safety and efficacy concerns and the decision made in 263rd meeting of the Drug Registration Board seized the said drug combination product from multiple sales outlets at district Nowshera and then served a show-cause notice to M/s. Wilson, Islamabad. The General Manager of M/s. Wilson Pharmaceuticals Islamabad replied to him that the registration of Diagesic-P Tablet (Reg.No.015654) is still intact and renewed regularly from the DRAP and no proceeding regarding the cancellation/de-registration of Diagesic-P Tablet is initiated by DRAP. He had, therefore, requested for the final decision by DRAP in the case to further proceed in the matter.

Registration Board in its 293rd meeting held on 6-8th of January, 2020 deliberated on the matter in detail and decided to give an opportunity of personal hearing as per Drug Act, 1976 and Rules framed there under to both registration holders. In their reference Shifa international hospital also seconded the decision of the 263rd meeting that “in the best interest of patient safety it is requested that company is to be directed by DRAP to remove this medicine Thioridazine from its combination product Diagesic-P. as its brand Melliril has been voluntarily recalled by Novartis due to serious cardiac side effects and later many other countries suspended its usage/ registration or imposed restrictions for use.”

Accordingly, in 313th meeting of the Registration Board it was discussed “that as show-cause notices have already been issued to M/s Wilson Pharmaceuticals, Islamabad and M/s Cirin Pharmaceuticals (New Title: ICI Pakistan Ltd.), Hattar, therefore, Registration Board decided that management of abovementioned firms shall be given the opportunity of personal hearing in the forthcoming meeting of the Board under section 42 of the Drugs Act, 1976.”

Personal hearing before the Registration Board in its 317th meeting was granted on 17th May, 2022 at 10:00 A.M, wherein the board in light of the discussion of personal hearing, risk-benefit analysis and public health impact of the combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) decided to suspend all drug registrations of the combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) under Section 7 (11) (b, c & d) read with Section 42 of the Drugs Act, 1976 in the larger public interest, with immediate effect as this combination is neither approved by any Reference Regulatory Authorities nor safety and efficacy data is available with any registration holder for a period of 1 year or earlier subject some conditions.
Therapeutic Goods Affected:Combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg)
Brand Names:
Diagesic P of Wilson‘s Pharmaceutical Islamabad; and
Pregesic of Cirin Pharmaceutical Hattar (Now ICI Pakistan).

Drug Combination (Paracetamol 500mg, Thioridazine 3mg & Caffeine 70mg) was prescribed by physicians as an analgesic and sold by pharmacies and medical stores.
Advice for healthcare professionals:Healthcare professionals are informed that the Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, benefit-risk analysis and public health impact suspended all drug registrations of the combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) under Section 7 (11) (b, c & d) read with Section 42 of the Drugs Act, 1976 in the larger public interest, with immediate effect as this combination is neither approved by any Reference Regulatory Authorities nor safety and efficacy data is available with the registration holders. Healthcare professionals may stop prescribing to patients the Drug Combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg). Healthcare professionals may prescribe other treatment options available in the market as analgesics to the patients.
Advice for patients:Patients and consumers are informed that the Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, benefit-risk analysis and public health impact suspended all drug registrations of the combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) under Section 7 (11) (b, c & d) read with Section 42 of the Drugs Act, 1976, therefore, patients who are using Drug Combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) may consult/ speak with their healthcare professionals for other treatment options available in the market.
Guidelines for reporting Adverse Drug Reactions (ADRs):Both healthcare professionals and patients are requested to report any adverse events they have experienced during their past treatment with Drug Combination (Paracetamol 500mg, Thioridazine 3mg and Caffeine 70mg) to the National Pharmacovigilance Centre, Drug Regulatory Authority of Pakistan through DRAP Med Vigilance E-reporting system or at npc@dra.gov.pk.

Similarly, adverse events can also be reported through Med Safety Mobile Application that is available for download from the App store (For iOS devices) and Google Play (For Android devices).
References:Partial Minutes of 317th Meeting of Registration Board.

Suspension of Drug Registration: Famotidine Liquid Suspension in the Strengths of 10mg/5mL and 40mg/mL

Drug Safety Alert

Update from Registration Board of Drugs

Date:15th of June 2022.
Target Audience:• Provincial Drugs Control Units and Provincial Pharmacovigilance Centres.
• Manufacturer/registration holders of Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension;
• Healthcare Professionals; and
• Patients, consumers or caregivers.
Problem or Issue:The Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, benefit-risk analysis and public health impact suspended all drug registrations of Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension under Section 7(11)(d) read with Section 42 of the Drugs Act, 1976 in the larger public interest, with immediate effect as these products were neither approved by any Reference Regulatory Authorities nor efficacy data is available with any registration holder. These products will stay suspended for a period of one (01) year; or till the time its efficacy is well established through indigenous clinical trials in accordance with the Bio Study Rules, 2017; or if it is approved by the Reference Regulatory Authorities, whichever is earlier. Likewise, Registration holders were directed to suspend the manufacturing and import of these drug products immediately and to withdraw available stocks from the market in the larger public interest. The decision applies to all registration holders of Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension except those who have obtained interim relief from the Hon’ble Lahore High Court, Lahore or who have registration of Famotidine 40mg/5ml Dry Suspension.
Background:
The Registration Board in its 250th meeting held on 10th July, 2015 had decided that Famotidine 10mg/5ml Suspension is not registered in any reference regulatory agencies and the internationally available formulation is a dry powder for suspension in the strength of 40 mg/ 5 ml and asked applicants to revise their formulation as per innovator (new registration application With complete fee) within six months if the manufacturing facility is approved by Central Licensing Board.

However, DRAP’s Authority in its 70th meeting held on 05th Sep 2019 decided that “For formulations containing “drugs” which were previously registered by the Registration Board and have proof of availability and prescription of last 10 years but are not available in the Reference Regulatory Authorities shall continue to be considered/ registered as drugs until and unless withdrawn on Safety, Efficacy and Quality reasons”.

Accordingly, Registration Board in its 296th meeting held 8th-10th Sep, 2020 decided that “since all such formulations which are not approved by the Reference Regulatory Authorities; the safety and efficacy profile cannot be established in the absence of a well-established system for reporting of adverse events, so a reference shall be forwarded to DRAP’s Authority with the request to review the decision taken in its 70th meeting held on 05-09-2019. In this regard, PE&R Division shall prepare a comprehensive document/agenda for consideration of Authority”. It was also decided that “For all those formulations which are registered/ applied in strengths, different from those approved by reference regulatory authorities, the registration holders/ applicants shall standardize their formulations (by submitting registration application with requisite fee, provided that the firm did not have same registration) in line with those approved by reference regulatory authorities. Meanwhile, the policy of reliance on reference regulatory authorities was approved by the Authority in its 73rd meeting held on 06-11-2019. Subsequently, the registration board in its 313th meetings, dated 16-18th Nov, 2021 decided to issue show-cause notices to registration holders/ manufacturers under Section 7 (11)(d) of the Drug Act, 1976 and opportunity of personal hearings. The decision of the Registration Board was endorsed by Authority in its 128th meeting of Authority held on 14th Dec 2021 and decided that “Drug formulations/strengths which were previously registered by the Registration Board but are not available in any Reference Regulatory Authorities, shall be reviewed and disposed-off keeping in view of safety and efficacy evidence/data in the Reference Regulatory Authorities”.

In line with the decision taken by the Board in its 313th meeting, show-cause/personal hearing notices were issued to registration holders for hearing before the Registration Board on 1st February, 2022 at 2:30 pm. However, due to prevailing cases of COVID-19, personal hearings were postponed. Many of registration holders of Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension challenged the Show Cause Notices issued for cancellation of their drugs stating violation of the decision taken in the 70th Meeting of the DRAP Authority held on the 05-09-2019. However, the decision taken in the 70th Meeting of the DRAP Authority has been reviewed in the 128th Meeting held on 14-12-2021, whereby the Registration Board was allowed to review and dispose of the registration of drugs keeping in view their safety and efficacy. The Registration Board in its 315th meeting held on 1st Feb 2022 noted the information and advised to provide the opportunity of a personal hearing in the next meeting of the Registration Board.

Lastly, the Registration Board in its 317 meetings held on 16-17th May, 2022 gave an opportunity of a personal hearing and after reviewing the discussion of personal hearing, risk-benefit analysis and public health impact suspended all drug registrations of Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension under Section 7(11)(d) read with Section 42 of the Drugs Act, 1976 in the larger public interest, with immediate effect, for 1 year or earlier subject to some conditions, as Famotidine Suspensions in strength/ dosage form other than 40mg/5ml Powder for Oral Suspension are neither approved by any Reference Regulatory Authorities nor efficacy data is available with any registration holder.
Therapeutic Goods Affected:Famotidine 10mg/5ml & 40mg/5ml Liquid Suspension (not Famotidine 40mg/5ml Dry Suspension)
Famotidine is used in gastric and duodenal ulcers, Zollinger-Ellison Syndrom, Gastro-Eesophgeal disease, heart burns, and indigestion. Whereas, in children, it is used for peptic ulcers and gastro oesophagal disease.
Advice for healthcare professionals:Healthcare professionals are informed that the Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, benefit-risk analysis and public health impact suspended all drug registrations of Famotidine 10mg/5ml and 40mg/5ml Liquid Suspensions under Section 7(11)(d) read with Section 42 of the Drugs Act, 1976 in the larger public interest, with immediate effect as these products were neither approved by any Reference Regulatory Authorities nor efficacy data is available with any registration holder. Healthcare professionals may stop prescribing Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension to patients. Famotidine 40mg/5ml Dry Suspension or other treatment options available in the market may be prescribed.
Advice for patients:Patients and consumers are informed that the Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, benefit-risk analysis and public health impact suspended all drug registrations of Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension under Section 7(11)(d) read with Section 42 of the Drugs Act, 1976, therefore, patients who are using the above-mentioned Famotidine suspensions may consult/speak with their healthcare professionals to shift/change their treatment to Famotidine 40mg/5ml Dry Suspension or other treatment options available in the market.
Guidelines for reporting Adverse Drug Reactions (ADRs):Both healthcare professionals and patients are requested to report any adverse events they have experienced with their previous treatment with Famotidine 10mg/5ml and 40mg/5ml Liquid Suspension or even with Famotidine 40mg/5ml Dry Suspension to the National Pharmacovigilance Centre, Drug Regulatory Authority of Pakistan through DRAP Med Vigilance E-reporting system or at npc@dra.gov.pk.

Similarly, adverse events can also be reported through Med Safety Mobile Application that is available for download from the App store (For iOS devices) and Google Play (For Android devices).
References:Partial Minutes of 317th Meeting of Registration Board.

Suspension of Drug Registration: Tablets of Diclofenac Potassium in Strengths of 75mg and 100mg

Drug Safety Alert

Update from Registration Board of Drugs

Date:15th of June 2022.
Target Audience:• Provincial Drugs Control Units and Provincial Pharmacovigilance Centres.
• Manufacturers and Importers of Diclofenac Potassium 75mg and 100mg;
• Healthcare Professionals; and
• Patients, consumers or caregivers.
Problem or Issue:The Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, risk-benefit analysis and public health impact, suspend all drug registrations of Diclofenac Potassium 75mg and 100mg under Section 7 (11) (d) read with Section 42 of the Drugs Act, 1976 due to the reason that these formulations are neither approved by any Reference Regulatory Authority nor any safety and efficacy data regarding these products is available with any registration holder. These formulations will stay suspended for a period of one (01) year; or if safety and efficacy is well established through indigenous clinical trials in accordance with the Bio Study Rules, 2017; or if it is approved by the Reference Regulatory Authorities, whichever is earlier. Likewise, Registration holders were directed to suspend the manufacturing and import of these drug products immediately and to withdraw available stocks from the market in the larger public interest. The decision applies to all registration holders of Diclofenac Potassium 75mg and 100mg except those who have obtained interim relief from the Hon’ble Lahore High Court, Lahore.
Background:The Registration Board in its 258th meeting held on 25th and 26th April, 2016 had decided that Diclofenac Potassium is not registered in any reference country in doses more than 50mg, thus decided to issue show-cause notices to manufacturers of Diclofenac Potassium (75 and 100mg) for de-registration of these products. Subsequently, the registration board in its 288th meeting, dated 14-15th Feb 2019, decided that all registration holders of Diclofenac Potassium 75mg & 100mg shall be called for personal hearings. However, DRAP’s Authority in its 70th meeting heldon 05th Sep 2019 decided that “For formulations containing “drugs” which were previously registered by the Registration Board and have proof of availability and prescription of last 10 years but are not available in the Reference Regulatory Authorities shall continue to be considered/ registered as drugs until and unless withdrawn on Safety, Efficacy and Quality reasons”.

Accordingly, Registration Board in its 296th meeting held on 8-10th Sep, 2020 decided that “Since, all such formulations which are not approved by the Reference Regulatory Authorities; the safety and efficacy profile cannot be established in the absence of a well-established system for reporting of adverse events, so a reference shall be forwarded to DRAP’s Authority with the request to review the decision taken in its 70th meeting held on 05-09-2019. In this regard, PE&R Division shall prepare a comprehensive document/agenda for consideration of Authority, keeping in view the practices adopted by RRA for all such formulations.”

Meanwhile, the policy of reliance on reference regulatory authorities was approved by the Authority in its 73rd meeting held on 06-11-2019. Subsequently, the registration board in its 313th meetings, dated 16-18th Nov, 2021 decided to issue show causes to registration holders/ manufacturers under Section 7 (11)(d) of the Drug Act, 1976 and opportunity of personal hearings. The decision of the Registration Board was endorsed by Authority in its 128th meeting of Authority held on 14th Dec 2021 and decided that “Drug formulations/strengths which were previously registered by the Registration Board but are not available in any Reference Regulatory Authorities, shall be reviewed and disposed-off keeping in view of safety and efficacy evidence/data in the Reference Regulatory Authorities.”

Many of registration holders of Diclofenac Potassium 75mg and 100mg challenged the Show Cause Notices issued for cancellation of their drugs stating violation of the decision taken in 70th Meeting of the DRAP Authority held on the 05-09-2019. However, the decision taken in the 70th Meeting of the DRAP Authority has been reviewed in the 128th Meeting held on 14-12-2021, whereby the Registration Board was allowed to review and dispose of the registration of drugs keeping in view their safety and efficacy. The Registration Board in its 315th meeting held on 1st Feb 2022 noted the information and advised to provide the opportunity of a personal hearing in the next meeting of the Registration Board.

Meanwhile, the Pharmaceutical Evaluation and Registration Division of the DRAP reviewed all the available facts and finding along with the product monograph of diclofenac potassium in stringent regulatory authorities which depicts that the daily dose of diclofenac potassium is from 75- to 200mg in divided doses, whereas the maximum strength of available diclofenac potassium tablet is 50mg. The Division also prepared two questions that were communicated for guidance to various RRA’s including USFDA, Health Canada, MHRA UK, Sweden, TGA Australia and BNF.

Lastly, the registration board in its meeting 317th meeting dated 16th to 17th May, 2022 after giving personal hearings to registration holders of diclofenac potassium 75-100mg, discussion during the meeting, risk-benefit analysis and public health impact of the Diclofenac Potassium 75mg and 100mg, decided to suspend drug registrations of Diclofenac Potassium 75mg and 100mg under Section 7 (11) (d) read with Section 42 of the Drugs Act, 1976 in the larger public interest for 1 year or earlier subject to some conditions.
Therapeutic Goods Affected:Diclofenac Potassium 75MG and 100MG (Not 50mg or below)

Diclofenac potassium is used in divided doses for treatment of pain or primary dysmenorrhea; relief of osteoarthritis, relief of rheumatoid arthritis etc. It is approved by various reference regulatory authorities in 12.5mg, 25mg and 50mg tablet strengths. A daily dose of diclofenac potassium is from 75-200mg in divided doses, whereas the maximum strength of available diclofenac potassium tablet is 50mg. However, in Pakistan, as per the PER Division, it was also approved in the strength of 75 and 100mg.
Advice for healthcare professionals:Healthcare professionals are informed that the Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, risk-benefit analysis and public health impact suspended all drug registrations of Diclofenac Potassium 75mg and 100mg under Section 7 (11) (d) read with Section 42 of the Drugs Act, 1976 due to the reason that these formulations are neither approved by any Reference Regulatory Authority nor any safety and efficacy data regarding these products is available. Healthcare professionals may stop prescribing diclofenac potassium having a strength of 75mg and 100mg to patients. Diclofenac Potassium in the strength of 50mg may be prescribed to the patient instead of Diclofenac Potassium of 75mg and 100mg.
Advice for patients:Patients and consumers are informed that the Registration Board of Drug Regulatory Authority of Pakistan (DRAP) in its 317th meeting held on 16-17th of May 2022 in light of discussions, risk-benefit analysis and public health impact suspended all drug registrations of Diclofenac Potassium 75mg and 100mg, therefore, those patients who are using diclofenac potassium in the aforementioned strengths may consult/ speak with their healthcare professionals to shift/change their treatment to standard strength of 50mg of diclofenac potassium or other treatment options available in the market.
Guidelines for reporting Adverse Drug Reactions (ADRs):Both healthcare professionals and patients are requested to report any adverse events they have experienced with Diclofenac Potassium (75mg, 100mg or even 50mg & below) to the National Pharmacovigilance Centre, Drug Regulatory Authority of Pakistan through DRAP Med Vigilance E-reporting system or at npc@dra.gov.pk
Similarly, adverse events can also be reported through Med Safety Mobile Application that is available for download from the App store (For iOS devices) and Google Play (For Android devices).
References:Partial Minutes of 317th Meeting of Registration Board.