Drug Safety Update: Risk of Infusion-Related Hypersensitivity Reactions with Remdesivir

Asad Ullah Safety Alerts, Safety Communication, Safety Info November 18, 2022November 29, 2022

Drug Safety Alert

Update from Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of Pakistan

Date:	18_^th of November 2022
Target Audience:	• Manufacturers and importers of Remdesivir; • Healthcare Professionals; and • Patients, consumers or caregivers.
Problem or Issue:	The National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP) received a cluster of three serious (life-threatening) adverse drug reaction reports from a hospital with Inj Remdesivir (100mg/20ml). The events of tachycardia, dyspnoea, chills and pyrexia were noted after the use of Remdesivir through an intravenous drip for COVID-19 Pneumonia, with a time to onset of 0 days. The causality assessment of all three cases was performed by the Causality Assessment Group of the NPC and classified that all three cases have a possible relationship with drug intake. However, at the same time, the NPC also carried out the quality testing of the suspected batch of Remdesivir, which was declared of standard quality with regard to the tests performed by the Central Drugs Laboratory, DRAP, Karachi. The NPC accordingly labelled it as a potential signal of infusion-related hypersensitivity reactions with the injection of Remdesivir. Further assessment was also carried out at NPC-DRAP, where the signal was confirmed from the approved label of the United States Food and Drugs Administration (US-FDA) and Summary of Product Characteristics (SmPC) of Medicine and Health Products Agency (MHRA) of the United Kingdom. There was also significant disproportionality and potential association of Remdesivir with infusion-related hypersensitivity reactions as per the statistical tools available in VigiLyze of the Uppsala Monitoring Centre. The case was discussed in the 1st meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the NPC, DRAP and decides as to update the prescribing information/ safety specification/ label of Remdesivir injection with the inclusion of information related to infusion-related hypersensitivity reactions and its monitoring in the warning and precaution sections. Furthermore, it was also decided that all registration holders should introduce educational training for healthcare professionals on proper preparation, administration and flow rate of Remdesivir, and monitoring of patients.
Therapeutic Goods Affected:	Remdesivir injection Remdesivir is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleotide analog RNA polymerase inhibitor indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients (28 days of age and older and weighing at least 3 kg) with positive results of direct SARS-CoV-2 viral testing, who are: hospitalized, or not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death.
Advice / Directions for for Registration Holder	Registration holders of Remdesivir injection are hereby advised/directed to update the prescribing information/safety specification/ label of Remdesivir with the inclusion of information related to infusion-related hypersensitivity reactions and its monitoring in the warning and precaution sections. Furthermore, registration holders should also introduce educational training for healthcare professionals on proper preparation, administration and flow rate of Remdesivir, and monitoring of patients.
Advice for healthcare professionals:	Healthcare professionals are informed that the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP has recommended updating the prescribing information/ safety specification/ label of Remdesivir injection with the inclusion of information related to infusion-related hypersensitivity reactions and its monitoring in the warning and precaution sections, and is working with registration holders in this regard. Healthcare professionals are also informed that the signs and symptoms of infusion-related hypersensitivity reactions may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering, which have been observed during and following administration of Remdesivir injection which mostly occurred within one hour. Therefore, slower infusion rates with a maximum infusion time of up to 120 minutes should be considered to potentially prevent these signs and symptoms. Furthermore, monitor patients during infusion and observe patients for at least one hour after the infusion is completed for signs and symptoms of hypersensitivity as clinically appropriate. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue the administration of Remdesivir injection and initiate appropriate treatment.
Advice for patients:	Patients are informed that hypersensitivity reactions including infusion-related reactions have been observed during and following the administration of Remdesivir injection. Immediately call your doctor if you experience signs and symptoms such as hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, diaphoresis, and shivering after administration of Remdesivir injection.
Guidelines for reporting Adverse Drug Reactions (ADRs):	Both healthcare professionals and patients are requested to report any suspected adverse drug reaction (ADRs) with Diclofenac Sodium to National Pharmacovigilance Centre, Drug Regulatory Authority of Pakistan through Med Vigilance E-Reporting system available on DRAP website. Similarly, ADRs can also be reported through MedSafety App that is available for download from App store (for iOS devices) and Google Play (for Android devices).
References:	Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee. Approved label of Veklury (Remdesivir) of US-FDA.

21-Safety-Alert-of-Infusion-related-hypersensitivity-reactions-with-Remdesivir Download

Date:	18_^th of November 2022
Target Audience:	• Manufacturers and importers of Clozapine; • Healthcare Professionals; and • Patients, consumers or caregivers.
Background	The Therapeutic Goods Administration (TGA) of Australia on 22nd, April 2022 through a safety advisory informed that Product Information (PI) and Consumer Medicine Information (CMI) for Clozapine have been updated to strengthen warnings about potential severe gastrointestinal side effects, including constipation. It was informed that Clozapine may also affect the bowels by slowing them down and can cause severe constipation, the condition known as clozapine-induced gastrointestinal hypomotility. If untreated, it can lead to serious problems. Consumers who were using clozapine were informed to look out for changes in their bowel function and to contact their health professionals if they develop any of the symptoms. On 14th January 2022, the United States Food and Drug Administration (US-FDA) through Drug Safety Podcast referred to the already issued communication dated 18th of February 2020 where the FDA strengthens the existing warning that untreated constipation caused by schizophrenia medicine clozapine (Clozaril®) can lead to serious bowel problems. It was informed that serious bowel complications can lead to hospitalization or even death if constipation is not diagnosed and treated quickly.
Action in Pakistan	Accordingly, the case of risk of serious bowel complications with Clozapine was discussed in the 1st meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP) which after detailed deliberation and discussion decided to update and strengthen the warning section of Clozapine with gastrointestinal side effects, including constipation and severe bowel problem in light of Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 as a part of reliance mechanism on stringent regulatory authorities.
Therapeutic Goods Affected:	Clozapine Tablets Clozapine is a medicine that has been used for more than 40 years to treat schizophrenia in patients whose symptoms are not controlled with standard treatment
Advice for healthcare professionals:	Healthcare professionals are advised the following: to evaluate bowel function before starting a patient on clozapine and avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility; advise patients frequently of the significant risk of constipation and life-threatening bowel issues and the need to stay hydrated to prevent constipation; advise patients to contact a healthcare professional right away if they have difficulty having a bowel movement or passing stools, do not have a bowel movement at least three times a week or less than their normal frequency.
Advice for patients:	Patients are advised to contact their healthcare professionals if they have symptoms that can be associated with serious bowel problems such as nausea, vomiting or stomach pain. To prevent constipation, they should eat more fruits, vegetables, and grains that are high in fibre; drink plenty of water and other liquids, and get enough exercise.
Guidelines for reporting Adverse Drug Reactions (ADRs):	Both healthcare professionals and patients are requested to report any suspected adverse drug reaction (ADRs) to National Pharmacovigilance Centre, Drug Regulatory Authority of Pakistan through Med Vigilance E-Reporting system available on DRAP website. Similarly, ADRs can also be reported through MedSafety App that is available for download from App store (for iOS devices) and Google Play (for Android devices).
References:	1-Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee. 2-Safety Advisory- constipation: a potentially serious side effect issued by the Therapeutic Goods Administration of Australia. 3-Drug safety podcast of the United States Food and Drug Administration (US-FDA) regarding constipation caused by schizophrenia medicine clozapine.

Date:	21^st of October 2022.
Target Audience:	• Regulatory Field Force • Manufacturers of Glycerin containing formulations to control level of Diethylene glycol and Ethylene glycol • Healthcare Professionals- Physicians, Pharmacists, and Nurses • General Public
Problem or Issue:	Glycerin, Sorbitol & Propylene glycol are widely used in therapeutic goods as solvents. However, recently there has been report in international media related to the adulteration of these materials with highly toxic Diethylene Glycol (DEG) and Ethylene Glycol(EG). These impurities, DEG and EG are poisonous and may lead to severe health injury or death, as recently reported in Gambia, and also being associated with the incident happened in Indonesia due to consumption of syrups containing glycerin. These reports warrant an emergent need of extraordinary measures and vigilant monitoring of these possible contaminants.
Potential Hazards linked to DEG and EG:	Toxic effects can include abdominal pain, diarrhea, inability to pass urine, headache, altered mental state, vomiting and acute kidney injury which may lead to death especially in children
Advice for healthcare professionals:	DRAP requests increased vigilance within the supply chains of institutions/pharmacies/healthcare facilities to detect any substandard / falsified product in the market. Adverse reactions or quality problems experienced with the use of any product shall be reported to the National Pharmacovigilance Centre(NPC), DRAP using Adverse Event Reporting Form or online through this link. Further information of reporting problems to DRAP is available on this link.
Advice for Manufacturer’s and Importers of Products containing Glycerin Solvent:	Perform test/analysis of for presence of any toxic impurity/contaminants specially when used in oral dosage forms such as syrups/suspensions etc. It is legal responsibility of all manufacturers of therapeutic goods to ensure before marketing that all the manufactured therapeutic goods are safe for consumption. Therefore, it is required that all manufacturers using these solvents must perform proper testing to detect DEG and EG contamination
Advice for General Public:	All therapeutic goods must be obtained from the licensed pharmacies, and other authorized retail outlets. The authenticity and condition of products should be carefully checked. Seek advice from your pharmacists or other healthcare professional in case of any doubt.
Guidelines for reporting Adverse Drug Reactions (ADRs):	Both healthcare professionals and patients are requested to report any adverse events they have experienced to 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:

Date:	12^th of October 2022.
Target Audience:	• Healthcare Professionals- Physicians, Pharmacists, and Nurses. • Manufacturers and Importers of Glycerin containing formulations to control level of Diethylene glycol and Ethylene glycol • General Public
Problem or Issue:	World Health Organization (WHO) has issued Medical Product Alert No. N°6/2022 dated 05^th October 2022 which refers to four substandard products, identified in Gambia. These four products are **Promethazine Oral Solution, Kofexmalin Baby Cough Syrup, Makoff Baby Cough Syrup and Magrip N Cold Syrup. Laboratory analysis of samples of each of the four products confirm that they contain unacceptable amounts of diethylene glycol and ethylene glycol as contaminants. DRAP has never authorized sale of any products from Maiden Pharmaceuticals Limited (Haryana, India)** and these four products referred in WHO medical product alert are neither registered nor available on Pakistan market, however these may have been carried for personal use while visiting other countries. Please do not use any of these products as these are substandard products and their use may result in serious injury.
Potential Hazards linked to DEG and EG:	Toxic effects can include abdominal pain, diarrhea, inability to pass urine, headache, altered mental state, vomiting and acute kidney injury which may lead to death especially in children
Advice for healthcare professionals:	DRAP requests increased vigilance within the supply chains of institutions/pharmacies/healthcare facilities to detect any substandard / falsified product in the market. Adverse reactions or quality problems experienced with the use of any product shall be reported to the National Pharmacovigilance Centre(NPC), DRAP using Adverse Event Reporting Form or online through this link. Further information of reporting problems to DRAP is available on this link.
Advice for Manufacturer’s and Importers of Products containing Glycerin Solvent:	Unacceptable amounts of Diethylene glycol (DEG) and Ethylene glycol (EG) as contaminants may lead to severe injury or death. You are therefore advised to strictly follow the pharmacopoeia guidelines for excipients and ensure testing of all those products where diethylene glycol and ethylene glycol can appear as impurity, to ensure specifications limits are being comply for all those products where glycerin is used especially cough syrups and other oral products.
Advice for General Public:	All therapeutic goods must be obtained from the licensed pharmacies, and other authorized retail outlets. The authenticity and condition of products should be carefully checked. Seek advice from your pharmacists or other healthcare professional in case of any doubt.
Guidelines for reporting Adverse Drug Reactions (ADRs):	Both healthcare professionals and patients are requested to report any adverse events they have experienced 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:	Medical Product Alert No. N°6/2022

Date:	15^th 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.

Date:	15^th 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.

Drug Regulatory Authority of Pakistan

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