2023 – Page 11 – Drug Regulatory Authority of Pakistan

The lot release of biological products is a part of the regulation of biological products. It involves the independent assessment of each lot of a licensed biological product before it is released in the market. In addition to manufacturing, the complexity inherent to biological products, proper storage conditions and efficient supply chain management must be ensured to preserve these products’ sensitivity and limited shelf life properties. For the reasons stipulated above, a careful independent review of manufacturing and quality control data on every lot of product as stated is, therefore, necessary before use. Lot release program enables National Regulatory Authority (NRA) to ascertain the safety, quality, and effectiveness of every lot of these products.

This draft guideline is uploaded on the official website of DRAP dated 5th May 2023, for seeking comments and suggestions from stakeholders on the draft document. Stakeholders can submit their comments and suggestions within 15 days of uploading this document using the prescribed format, (further information on comments submission can access at this link. Comments and suggestions can be forwarded via email to ayub.naveed∂dra.gov.pk, copied at director∂nclb.dra.gov.pk, or can be posted at the mailing address, The Director, National Control Laboratory for Biologicals, Drug Regulatory Authority of Pakistan, Prime Minister’s National Health Complex, Park Road, Chak Shehzad, Islamabad.

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Recall Alert: Drug Product; Fluorazine 1mg Tablet (Batch # T-2065) CKD Pharmaceuticals Pak (Pvt) Ltd, Karachi

Asad Ullah Recall Alerts May 3, 2023May 11, 2023

Recall Alert

DRAP Alert No	N^oI/S/04-23-20
Action Date	11^th April 2023
Target Audience	1. Pharmacists and Chemists at Distributions, Pharmacies and Medical Stores 2. Healthcare Professionals- Physicians, Pharmacists, and Nurses at Hospitals, Clinics and Healthcare Providing Institutions 3. General Public
Product(s) Affected	Fluorazine 1mg Tablets Composition: Trifluoperazine HCl Manufactured by: M/s. CKD Pharmaceutical, Karachi Batch No. 2040006
Problem / Issue	Provincial Drug Inspector, Karachi took the sample of Fluorazine 1mg Tablet. Provincial Government Analyst/Director, Drug Testing Laboratory, Karachi has declared the Batch No. T-2065 of the product as of substandard quality.
Action Initiated	-The manufacturing company/registration holder has been directed to immediately recall the defective product batch from the market. -All Pharmacists and chemists working at distributions and Pharmacies should immediately check their stocks and stop supplying this product batch. The remaining stock should be quarantined and returned to the supplier/company. -Distributors and pharmacies are advised to be vigilant and report any suspected batch of the product(s) in the supply chain to the DRAP using the online form, or through phone at +92 51 910 73 17, or by Email at gsms∂dra.gov.pk. -Regulatory field force of all federating units (DRAP, Provincial Health Departments, and States) has also increased the surveillance in the market to ensure the effective recall of defective product(s).
Advice for Healthcare Professionals	-DRAP requests increase vigilance within the supply chains of healthcare institutions and hospital pharmacies to identify and return this product’s defective batch(es) to the importer/company. -Adverse reactions or quality problems experienced with this product may be reported to the National Pharmacovigilance Centre(NPC), DRAP using Adverse Event Reporting Form or online through this link. -Please click here for further information on problem reporting to DRAP.
Advice for Consumers	-Consumers should stop using this product bearing the affected batch number(s). They shall contact their physician or healthcare provider(s) if they have experienced any problem that may be related to taking or using this product. -All drug products must be obtained from authorized licensed pharmacies /outlets. Their authenticity and condition should be carefully checked. If you have any doubts, please seek advice from your pharmacist.

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GCP_Inspectorate_Notifications

Ijaz Mustafa Clinical Trials, Notifications May 3, 2023May 3, 2023

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Recall Alert: Drug Product; Spadix Injection (Batch# 570) by M/s. Tabros Pharma Karachi

Asad Ullah Recall Alerts April 20, 2023April 20, 2023DRAP, Patient Safety, QA & LT, QualityDefects, Recall

Recall Alert

DRAP Alert No	N^oI/S/20-23-21
Action Date	20^th April 2023
Target Audience	1. Pharmacists and Chemists at Distributions, Pharmacies and Medical Stores 2. Healthcare Professionals- Physicians, Pharmacists, and Nurses at Hospitals, Clinics and Healthcare Providing Institutions 3. General Public
Product(s) Affected	Spadix 4mL Injection Composition: Phloroglucinol and Trimethylphloroglucinol Manufactured by: M/s. Tabros Pharma, (Pvt) Ltd., Karachi Batch No. 570
Problem / Issue	A video is circulating on social media regarding presence of a fly/insect in a liquid injection ampoule visible with naked eye, apparently seems to be having adulterated quality. The matter is still under investigation, however as a precautionary measure, to prevent any public health hazard, the alleged drug is being recalled from market.
Risk Statement	Drug Product contains fly/insect is of adulterated quality which may compromise the standard quality of drugs as not being sterile. The sterility is a basic quality attribute of all Injectable drugs. In this case such adulterated drug may initiate but not limited to following reaction in patients/users (i) Anaphylactic shock in patients which may lead to death of patient (ii) Skin rashes, itching, difficulty in breathing (iii) Sub optimal to no therapeutic effect for indicated medical treatment.
Action Initiated	-The manufacturing company / registration holder has been directed to immediately recall the defected batch of product from the market. -All Pharmacists and chemists working at distributions and Pharmacies should immediately check their stocks and stop supplying this batch of product. The remaining stock should be quarantine and return to the supplier / company. -Distributors and pharmacies are advised to be vigilant and report any suspected batch of product(s) in the supply chain to the DRAP using online form, or through phone at +92 51 910 73 17, or Email at gsms∂dra.gov.pk. -Regulatory field force of all federating units (DRAP, Provincial Health Departments and States) has also increased the surveillance in the market to ensure the effective recall of defective product(s).
Advice for Healthcare Professionals	-DRAP requests increase vigilance within the supply chains of healthcare institutions and hospital pharmacies to identify and return the defective batch(es) of this product to the importer / company. -Adverse reactions or quality problems experienced with the use of this product may be reported to the National Pharmacovigilance Centre(NPC), DRAP using Adverse Event Reporting Form or online through this link. -Please click here for further information on problem reporting to DRAP.
Advice for Consumers	-Consumers should stop using this product bearing the affected batch number(s) and shall contact to their physician or healthcare provider(s) if they have had experienced any problem that may be related to taking or using this product. -All drug products must be obtained from the authorized licensed pharmacies /outlets. Their authenticity and condition should be carefully checked. If you have any doubt, please seek advice from your pharmacist.

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Compliance to the Notice Dated 13-03-2023 with Regard to Specifications and Data related Activity in PIRIMS

Umer Farooq Drugs, General April 20, 2023April 24, 2023

DRAP has deployed an online application management system “Pakistan Integrated Regulatory Information Management Systm (PIRIMS)” ‘ for processing of regulatory information related to licensing, registration, and inspections of pharmaceutical and biological drugs.

Transforming manual operation to PIRIMs, DRAP requested marketing authorization holders of pharmaceutical and biological drug products to review and update their finished products Specifications. Accordingly, a notice was uploaded on the website of DRAP on 13m March, 2023, with the direction to all Registration Holders of pharmaceutical and Biological drug products to update finished products Specifications and validated method of testing i.e. Pharmacopoeial or in case of non-availability in any pharmacopeia, Innovator / Manufacturer’s Specification, in the corresponding product profile / details in the PIRMS at http://pirims.dra.gov.pk.

The timeline for submission of requisite information on the PIRIMS has been further extended till 09^th June 2023 on the request of pharmaceutical industry.

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DRAP issued Consolidated Notification for Regulatory Fees

Asad Ullah Advertisements, Alternative Medicines, Clinical Trials, Controlled Substances, Drugs, General, Licensing and Inspections, Medical Devices, Notifications, SROs April 17, 2023April 17, 2023

Drug Regulatory Authority of Pakistan (DRAP) issued a consolidated notification of Regulatory fess for various functions and services. This notification is issued under the section (1) of section 20 of the Drug Regulatory Authority of Pakistan Act, 2012 (XX.I of 2012) read with sub-rule (3) of rule 4 of the Drug Regulatory Authority of Pakistan (Fee and Levy) Rules, 2022, and in supersession of all such previous Notifications. The Drug Regulatory Authority of Pakistan with the approval of the Policy Board has specified these regulatory fees. The Notification is provided as under: –

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Tender Notice for Purchase of Chromatography Columns

Umer Farooq Tenders April 17, 2023April 17, 2023

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“Purchase of Chromatography Columns

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Drug Safety Alert: Potential risk of suicidal ideation/thoughts & self-injury with Finasteride

Asad Ullah Safety Alerts April 14, 2023April 20, 2023DRAP, Patient Safety, Pharmacovigilance, PRAEC

Drug Safety Alert

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

Date:	11^thof April, 2023
Target Audience:	• Manufacturers and importers of Finasteride; • Healthcare Professionals; and • Patients, consumers or caregivers.
Background:	The Health Sciences Authority (HSA) of Singapore in August 2022 reminded healthcare professionals of the potential risk of suicidal ideation with the use of finasteride following results of a recent pharmacovigilance study that suggests younger patients with alopecia may be more vulnerable to the risk of suicide ideation. In the study, disproportionality analysis was used to assess whether suicidality or psychological adverse events (AEs) were more frequently reported for finasteride than would be expected by chance alone by comparing them against similar reports for all other drugs in VigiBase (WHO global database of ICSRs). The study identified 356 reports of suicidality and 2,926 reports of psychological AEs in users of finasteride, reported from 1993 to 2019. Among the reports with data available, the majority (99%) occurred in males, and 71% occurred in individuals aged between 18 and 44 years. Significant disproportionality signals for suicidality (reporting odds ratio [ROR], 1.63; 95% CI, 1.47-1.81) and psychological AEs (ROR, 4.33; 95% CI, 4.17-4.49) were identified in finasteride users. On 19^th of January, 2023, Health Canada through its summary safety review informed that it is working with the manufacturers to update the product safety information in the Canadian product monographs (CPM) for finasteride-containing products to strengthen the warning statements on the risks of suicidal ideation and self-injury, and to include information about patient screening for psychiatric risk factors prior to starting treatment, as well as continuous patient monitoring during and after stopping treatment. The safety review was triggered by the publication of a media article that discussed the potential risk of suicide in patients using Propecia (finasteride) for male pattern hair loss. Health Canada’s review of the available information found a possible link between the use of finasteride and the risks of suicidal ideation and self-injury. At this time, there is not enough information to establish a link for the risk of suicide. However, strengthening of warning statements was warranted. It was informed that Health Canada was monitoring the risk of suicidal ideation with the use of finasteride since 2012 and has completed 2 safety reviews in 2012 and 2015, and the information available at the time was considered too limited to determine whether there was a link between the use of finasteride and suicidal thoughts and behaviours (suicidality). In 2019, following reports of Canadian and international cases of suicide, suicidal ideation and self-injury with the use of finasteride, the agency completed a third safety review that found a possible link between finasteride and the risk of suicidal ideation. The CPMs of finasteride were accordingly updated to include the risk of suicidal ideation. Most recently in 2022, due publication of a media article that discussed the potential risk of suicide in patients using Propecia (finasteride) for male pattern hair loss, Health Canada completed a review of the risk of suicidal ideation and potential risks of suicide and self-injury with the use of finasteride. The purpose of the current review was to consider recent information and determine if additional measures were warranted. A review of the available information found a possible link between the use of finasteride and the risks of suicidal ideation and self-injury. At this time, there is not enough information to establish a link between the use of finasteride and the risk of suicide. Therefore, strengthening of warning statements on the risks of suicidal ideation and self-injury was warranted and Health Canada is working on it. Furthermore, the most recent Vigilyze statistics related to the finasteride and Standard MedDRA Query(SMQ) selected Depression and suicide/self-injury study identified 2,995 reports and 471 reports specifically with suicidal ideation. The larger portion of the reactions in known gender occurred in males (31.9%, and 45.6% in individuals aged between 18 and 44 years respectively, with the broader SMQ and specifically suicidal ideation. Significant disproportionality signals for suicidal ideation (reporting odds ratio [ROR], 10.6) and SMQ (ROR, 4.5) were identified.
Therapeutic Good(s) Affected:	Name: Finasteride. Finasteride is indicated for the treatment of benign prostatic hyperplasia and androgenic alopecia.
Action in Pakistan	Accordingly, the case of the potential risk of suicidal ideation/thoughts & self-injury with finasteride was discussed in the 2^nd 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 decided as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 that registration holders should update prescribing information/safety specification of finasteride containing drugs by strengthening the warning statements on the risks of suicidal ideation and self-injury, and to include information about patient screening for psychiatric risk factors before starting treatment.
Advice for healthcare professionals:	Healthcare professionals are informed that mood alterations including depression and, less frequently, suicidal ideation have been reported in patients treated with finasteride and are hereby advised to consider the potential risk of psychological adverse events when assessing the benefit-risk of finasteride for their patients. Healthcare professionals should also advise their patients to consult their doctors at the earliest when such thoughts are developed.
Advice for patients:	Patients are advised to immediately consult their doctors if they experience mood alterations including depression and less frequently, suicidal ideation or self-injury etc.
Guidelines for reporting Adverse Drug Reactions (ADRs):	Both healthcare professionals and patients are requested to report any suspected Adverse Drug Reaction (ADR) 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:	M inutes of 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee .

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Drug Safety Alert: Risk of complex sleep behaviours with Zolpidem

Asad Ullah Safety Alerts April 13, 2023April 20, 2023

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Drug Safety Alert

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

Date:	11^thof April, 2023
Target Audience:	• Manufacturers and importers of Zolpidem • Healthcare Professionals; and • Patients, consumers or caregivers.
Background:	The Ministry of Health Labour and Welfare (MHLW) and the Pharmaceutical and Medical Device Agency (PMDA) of Japan in July, 2022 have announced that the product information for triazolam, zolpidem, zopiclone and eszopiclone should be revised to include the risk of abnormal behaviour as parasomnia. In addition, the use of triazolam, zolpidem or zopiclone is to be contraindicated in patients who have experienced abnormal behaviour such as parasomnia. Based on the published literature on the pharmacological mechanisms of parasomnia and cases of parasomnia reported in Japan, it was concluded the four drugs can increase the risk of abnormal behaviour as parasomnia, which may lead to serious self/other injuries or accidents. Also, a contraindication is considered necessary for triazolam, zolpidem and zopiclone in patients with a history of drug-induced parasomnia due to the risk of recurrence. Regarding eszopiclone, careful administration is still required but it is not a contraindication at this time, as there have been no reports of parasomnia in Japan for this drug. Previously, the United States Food and Drug Administration (US-FDA) in April 2019 announced that rare but serious injuries have occurred with some medicines used to treat insomnia such as eszopiclone (Lunesta®), zaleplon (Sonata®) and zolpidem (Ambien®.). The injuries are a result of sleep behaviours which include: sleepwalking, sleep driving and engaging in other activities while not fully awake. These complex sleep behaviours have also resulted in deaths. Serious injuries and death from complex sleep behaviours have occurred in patients with and without a history of such behaviours, even at the lowest recommended doses, and the behaviours can occur after just one dose. These behaviours can occur after taking these medicines with or without alcohol or other central nervous system depressants that may be sedating such as tranquillizers, opioids, and anti-anxiety medicines. As a result, FDA required information about this risk to be added to the Boxed Warning, the FDA’s prominent warning and also to the contraindication (strongest warning) to avoid use in patients who have previously experienced an episode of complex sleep behaviour with eszopiclone, zaleplon, and zolpidem.
Therapeutic Good(s) Affected:	Name: Zolpidem. Zolpidem tartrate is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
Action in Pakistan	Accordingly, the case of the risk of complex sleep behaviours with Zolpidem was discussed in the 2^nd 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 decided as per Rule 10 (1) (h) (ii), (iv) and (vi) of Pharmacovigilance Rules, 2022 that registration holders should update the prescribing information/safety specification of zolpidem-containing drugs by including information related to complex sleep behaviour in the warning and precaution sections, information related to contraindications in patients who have experienced complex sleep behaviours after taking these drugs in the past, and to create a boxed warning as per the format of Reference Regulatory Authority (RRA).
Advice for healthcare professionals:	Healthcare professionals are requested to ask patients and their families or other caregivers at the time of prescribing or dispensing of zolpidem tartrate as to whether the patients have experienced abnormal behaviour as a symptom of parasomnia after they used these drugs in the past. Examples of abnormal behaviour as a symptom of parasomnia include: walking around indoors or outdoors; driving a car; making or eating a meal; making a phone call; behaving violently or calling out, etc. Most of the abnormal behaviours occur after the use of the drug without being fully awake, and those behaviours are not remembered the next day. Healthcare professionals are also advised to not prescribe zolpidem to patients who have previously experienced complex sleep behaviours after taking this medicine. Also, healthcare professionals should advise all patients that although rare, those behaviours have led to serious injuries or death and that if patients experience an episode of complex sleep behaviour, they should discontinue taking the medicines.
Advice for patients:	Patients should stop taking Zolpidem and contact their healthcare professionals right away if they experience a complex sleep behaviour where a patient is engaged in activities while he/she is not fully awake or if the patient do not remember activities they have done while taking the medicine.
Guidelines for reporting Adverse Drug Reactions (ADRs):	Both healthcare professionals and patients are requested to report any suspected Adverse Drug Reaction (ADR) 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:	M inutes of 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee .

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