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Month: November 2022

Rapid Alert: Drug Product; Falsified Tablin 300mg Capsule identified in the market

Asad Ullah News & Updates, Product Recalls, Recall Alerts, Regulatory Updates

Rapid Alert

Suspected Falsified Product

DRAP Alert NoNoI/S/10-22-36
Action Date24th November 2022
Target Audience1. Regulatory Field Force
2. Pharmacists and Chemists at Distribution, Pharmacies and Medical Stores
3. Healthcare Professionals- Physicians, Pharmacists, and Nurses at hospitals, Clinics and Healthcare Institutions
4. General Public
Problem StatementDuring the market surveillance activities in different areas of District Sheikhupura Punjab, Regulatory Field Force has identified the suspected sample for product and sent for analysis to laboratory. The Provincial Drugs Testing Laboratory, has declared the samples as “spurious”. The stated manufacturers on the label has informed that they have not manufactured this batch number of product.
Product detail is as under:-

Therapeutic Good Affected:-

SrProduct NameCompositionBatch #Manufactured by (as stated on label)
1TABLIN 300mg Capsule
Pregabalin 300mgBatch No. 699M/s Theramed Pharmaceuticals (Pvt) Ltd, Lahore.
Action InitiatedThe Regulatory Field Force has been directed to increase the market surveillance and confiscate this batch of the product. All Pharmacists and chemists working at distributions and Pharmacies should immediately check the stock and stop supplying this product. The remaining stock should be quarantine immediately, and supplier(s) information should be provided to the Regulatory field force (DRAP, Provincial Health Departments and States) in order to ensure the removal of suspected products.
Advice for Healthcare Professionals-DRAP requests increased vigilance within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by these batches of above-mentioned product.

-Adverse reactions or quality problems experienced with the use of this product shall 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 and shall contact to their physician or healthcare provider if they have experienced any problems that may be related to taking or using this drug product, and report the incident to Drug Regulatory Authority of Pakistan / National Pharmacovigilance Centre.

-All therapeutic goods must be obtained from the licensed pharmacies, and other authorized / licensed retail outlets. The authenticity and condition of products should be carefully checked. Seek advice from your pharmacists or other healthcare professionals in case of any doubt.
Suspected-Falsified-Product-in-market-Tablin-300mg-CapsuleDownload

Recall Alert: Drug Product; Ponstan Forte 500mg Tablets (Batch # 2050533) by M/s Pfizer Pakistan Ltd, Karachi.

Asad Ullah Recall Alerts, Regulatory Updates

Recall Alert

DRAP Alert NoNoI/S/10-22-35
Action Date30th November 2022
Target Audience1. 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 Ponstan Forte 500mg Tablets,
Active Ingredient(s): Mefenamic Acid
Company: M/s. Pfizer Pakistan Ltd, Karachi
Batch No. 2050533
Manufacturing Date: 09-2020
Expiry Date: 08-2025
Problem / Issue The Drug Testing Laboratory, Baluchistan has analyzed the sample of batch No. 2050533 of Ponstan Forte 500mg Tablets manufactured by M/s. Pfizer Pakistan Ltd Karachi, Pakistan and declared it as “Substandard” based on the analysis.
Action Initiated-The company is directed to immediately recall the defected batch of product from the market.

-All Pharmacists and chemists working at distributions and Pharmacies are required to immediately return the stock of above-mentioned batch of product to the supplier / importer / 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.
    Recall-of-Ponstan-Forte-TabDownload

    Recall Alert: Drug Product; Diamicron 80mg Tablets (Batch#1740) by M/s. Servier Research & Pharmaceuticals Pakistan (Pvt) Ltd Lahore.

    Asad Ullah Recall Alerts, Regulatory Updates

    Recall Alert

    DRAP Alert NoNoII/S/10-22-33
    Action Date23rd November 2022
    Target Audience1. 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 Diamicron 80mg Tablets,
    Active Ingredient(s): Gliclazide
    Company: M/s. Servier Research & Pharmaceuticals Pakistan (Pvt) Ltd Lahore.
    Batch No. 1740
    Manufacturing Date: 04-2022
    Expiry Date: 04-2025
    Problem / Issue Central Drug Laboratory, Karachi has analyzed the samples of Diamicron 80mg Tablets manufactured by M/s Servier Research & Pharmaceuticals Pakistan (Pvt) Ltd Lahore and declared the batch No. 1740 as “substandard” based on the analysis report.
    Action Initiated-The company is directed to immediately recall the defected batch of product from the market.

    -All Pharmacists and chemists working at distributions and Pharmacies are required to immediately return the stock of above-mentioned batch of product to the supplier / importer / 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.
      Diamicron-80mg-Recall-AlertDownload

      Drug Safety Alert: Risk of Kidney Injury and Death due to Hydroxyethyl-Starch Solutions for Infusion.

      Asad Ullah Pharmacovigilance, Regulatory Updates, Safety Alerts

      Drug Safety Alert

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

      Date:29th of November, 2022
      Target Audience:• Manufacturers and importers of hydroxyethyl-starch solutions for infusion.
      • Healthcare Professionals; and
      • Patients, consumers or caregivers.
      Background:The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicine Agency (EMA) on 11th February, 2022 recommended that the market authorization of hydroxyethyl-starch (HES) solutions for infusion should be suspended across the European Union. These solutions for infusion products are indicated as an addition to other treatments for plasma volume replacement following acute (sudden) blood loss.
      The safety of these solutions for infusion was reviewed in 2013, and a number of restrictions and measures to minimise the risk of kidney injury and death in certain patients (those critically ill, with burn injuries or with sepsis, a bacterial infection in the blood) were put in place at that time.

      Likewise, as a result of a third review conducted in 2018, the use of HES solutions for infusion was further restricted to only accredited hospitals, and healthcare professionals prescribing or administering the medicines had to be trained in their appropriate use. In addition, further warnings were introduced to remind healthcare professionals that these medicines must not be used in patients with sepsis or kidney impairment or in other vulnerable patients such as the critically ill in order to ensure these solutions for infusion were not used in patients who were at increased risk of harm. Market authorization holders of HES solutions for infusion were also requested to conduct a drug utilization study to check that the restrictions were adhered to in clinical practice.

      The PRAC of the EMA accordingly reviewed the results of the study, which show that HES solutions for infusion are still being used outside the recommendations included in the product information and concluded that the further restrictions introduced in 2018 have not sufficiently ensured that the medicines are used safely and that HES solutions were continually used in certain groups of patients in whom serious harm has been demonstrated. In view of the serious risks that certain patient populations were still exposed to, the PRAC recommended the suspension of the marketing authorizations for HES solutions for infusion in the European Union. Accordingly, the European Commission on 24th May, 2022 issued a legal decision confirming the suspension of the market authorization of HES solution for infusion.
      Therapeutic Good(s) Affected:Name: Hydroxyethyl-Starch solutions for infusion.

      These solutions for infusion products are indicated as an addition to other treatments for plasma volume replacement following acute (sudden) blood loss.
      Action in PakistanAccordingly, the case of the risk of kidney injury and death due to hydroxyethyl-starch solutions for infusion 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). The PRAEC-DRAP after detailed deliberation and discussion and as per Rule 10 (1) (h) (v) of Pharmacovigilance Rules, 2022 (reliance mechanism) decided to recommend to the Registration Board of the DRAP to suspend the registration of Hydroxyethyl-Starch (HES) solutions in Pakistan subject to the availability of alternative treatment options.
      Advice for healthcare professionals:Healthcare professionals are informed that the National Pharmacovigilance Centre, DRAP is working with the Registration Board and manufacturers/importers of hydroxyethyl-starch solutions for infusion to suspend the registration of these solutions in Pakistan. Therefore, healthcare professionals are reminded that there are alternative solutions for infusion available in the Pakistani market for the treatment of plasma volume replacement following acute (sudden) blood loss and the same must be considered as the treatment in these conditions.
      Advice for patients:Patients are informed that the National Pharmacovigilance Centre, DRAP is working with the Registration Board and manufacturers/importers of hydroxyethyl-starch solutions for infusion to suspend the registration of these solutions in Pakistan. Therefore, talk with your doctor before initiation of treatment with those solutions as alternative treatment options are available in the market.
      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:Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
      European Medicine Agency update regarding hydroxyethyl-starch solutions for infusion recommended for suspension from the market.
        29_Safety_Alert_of_Risk_of_Kidney_Injury_and_Death_due_Hydroxyethyl-Starch_Solutions_for_Infusion.Download

        Drug Safety Alert: Increased Risk of Cardiovascular Events with Co-administration and Interaction Between Hydroxychloroquine or Chloroquine, and Macrolide Antibiotics

        Asad Ullah Safety Alerts

        Drug Safety Alert

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

        Date:29th of November, 2022
        Target Audience:• Manufacturers and importers of hydroxychloroquine or chloroquine, and systemic macrolide antibiotics;
        • Healthcare professionals; and
        • Patients, consumers or caregivers.
        Background:The MHRA on 15th February, 2022 announced that the product information for hydroxychloroquine, chloroquine and macrolide antibiotics (azithromycin, erythromycin or clarithromycin) will be revised to include the increased risk of cardiovascular events and cardiovascular mortality if hydroxychloroquine or chloroquine is taken with a macrolide-antibiotic. A review was conducted by the Pharmacovigilance Expert Advisory Group of the Commission on Human Medicines following the results of a retrospective observational study which shows that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events (including angina or chest pain and heart failure) and cardiovascular mortality.

        It was recommended in the review that the product information for hydroxychloroquine and systemic azithromycin medicines should be amended to include new warnings and advice on these risks. Owing to the similar safety profiles, the risks with concurrent use of hydroxychloroquine and azithromycin were considered to apply to the concurrent use of hydroxychloroquine and other systemic macrolide antibiotics (clarithromycin or erythromycin) and to the use of chloroquine with systemic macrolide antibiotics. Therefore, the review recommended that similar warnings should also be added to the product information for chloroquine and for systemic clarithromycin or erythromycin. However, these warnings were not being introduced for topical macrolide products (which are indicated for conjunctivitis or acne).

        The MHRA also reminded the healthcare professionals that the product information for hydroxychloroquine and chloroquine already contains warnings about cases of cardiomyopathy resulting in cardiac failure, in some cases with fatal outcomes. It was also informed that evidence suggests both hydroxychloroquine and chloroquine can prolong the QT interval, especially in overdose or when used in combination with other medicines with the potential to induce cardiac arrhythmias. Likewise, warnings are also in place across the product information for azithromycin, clarithromycin, and erythromycin to use caution in patients with a history of QT interval prolongation or in patients receiving a medicine known to cause QT prolongation. Although the mechanism of the observed effects was not examined in detail by the study, it was proposed that events could have been caused by cumulative effects of hydroxychloroquine and azithromycin on the QT interval, potentiating arrhythmias and cardiac death, or through other additive cardiotoxic effects more generally.
        Therapeutic Good(s) Affected:Name of Drugs: (i)Hydroxychloroquine,
        (ii) Chloroquine; and
        (iii) Systemic macrolide antibiotics (not topical).

        Hydroxychloroquine is indicated for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and dermatological conditions aggravated by sunlight. Chloroquine is indicated for malaria prophylaxis or treatment and other indications. Macrolide antibiotics such as erythromycin, clarithromycin and azithromycin are used to manage and treat various bacterial infections like pneumonia, sinusitis, pharyngitis and tonsillitis etc.
        Action in PakistanAccordingly, the case of risk of cardiovascular events with co-administration and interaction between hydroxychloroquine or chloroquine, and macrolide antibiotics 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). The PRAEC-DRAP after discussion decided as per Rule 10 (1) (h) (iv) and (vi) of Pharmacovigilance Rules, 2022 (reliance mechanism) to update prescribing information (warning and interaction sections) of hydroxychloroquine, chloroquine and macrolide antibiotics (azithromycin, erythromycin or clarithromycin excluding topical macrolides) about the potential interaction of increased risk of cardiovascular events and cardiovascular mortality if hydroxychloroquine or chloroquine is taken with a macrolide-antibiotic.
        Advice for healthcare professionals:Healthcare professionals are informed that an observational study has shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events (including angina or chest pain and heart failure) and cardiovascular mortality. Therefore, carefully consider the benefits and risks before prescribing systemic azithromycin or other systemic macrolide antibiotics (erythromycin or clarithromycin) to patients being treated with hydroxychloroquine or chloroquine. If there is a clinical need to prescribe systemic macrolide antibiotics with hydroxychloroquine or chloroquine, use caution in patients with risk factors for cardiac events.
        Advice for patients:Patients are informed that some antibiotics (known as macrolides) taken by mouth or given as an injection at the same as hydroxychloroquine or chloroquine have been associated with an increased risk of side effects that affect the heart. Seek urgent medical help if you have any signs of problems with your heart (for example, palpitation, fainting, chest pain, or unexplained breathlessness).
        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:Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
        MHRA update regarding Hydroxychloroquine, chloroquine: increased risk of cardiovascular events when used with macrolide antibiotics; reminder of psychiatric reactions.
          28_Safety_Alert_of_Interaction_Between_Hydroxychloroquine_or_Chloroquine_and_Macrolide_Antibiotics_FDownload

          Drug Safety Alert: Risk of Major Congenital Malformations with Pregabalin

          Asad Ullah Regulatory Updates, Safety Alerts

          Drug Safety Alert

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

          Date:29th of November, 2022
          Target Audience:• Manufacturers and importers of Pregabalin;
          • Healthcare Professionals; and
          • Patients, consumers or caregivers.
          Background:The Medicine and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom on 19th April, 2022 announced that the product information for pregabalin will be updated to include information from a new study which has suggested pregabalin may slightly increase the risk of major congenital malformations if used in pregnancy. The MHRA reviewed the results of a Nordic observational study that consisted of 2,700 pregnancies exposed to pregabalin in the first trimester, alongside a recent European review which had the same conclusions. The study showed a higher prevalence of major congenital malformations in the babies (live or stillborn) exposed to pregabalin in the first trimester of pregnancy compared with those not exposed to pregabalin or any other antiepileptic drug.
          The review concluded that pregabalin’s use during the first trimester of pregnancy may cause a slight increase in the risk of major congenital malformations in the unborn child. Furthermore, the Health Products Regulatory Authority (HPRA) of Ireland back in February 2022 also recommended that product information of Pregabalin along with other anti-epileptic drugs be updated based on the evidence of risks associated with in-utero exposure to these drugs. The product information of pregabalin continues to advise that effective contraception should be used during treatment and that use in pregnancy should be avoided unless it is necessary.
          Therapeutic Good(s) Affected:Name of Drug: Pregabalin

          Pregabalin is indicated for the treatment of peripheral and central neuropathic pain in adults, as adjunctive therapy in adults with partial seizures with or without secondary generalization, and for generalized anxiety disorder in adults.
          Action in PakistanAccordingly, the case of the risk of major congenital malformations with Pregabalin 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). The PRAEC after detailed deliberation and discussion decided as per Rule 10 (1) (h) (iv) and (vi) of Pharmacovigilance Rules, 2022 (reliance mechanism) to update prescribing information of Pregabalin to include information from a new study that pregabalin may slightly increase the risk of major congenital malformations if used in pregnancy and include advise on effective contraception during treatment in pregnancy.
          Advice for healthcare professionals:A new study has demonstrated that pregabalin may slightly increase the risk of major congenital malformations if used in first trimester of pregnancy. Therefore, healthcare professionals should provide counselling to the patients on potential risks to an unborn baby with pregabalin and also on the need to use effective contraception during the treatment. Healthcare professionals are also advised to continue to avoid the use of pregabalin during pregnancy unless clearly necessary and only if the benefit to the patient clearly outweigh the potential risk to the fetus. In case where the benefit outweighs the risk, and it is clearly necessary that pregabalin has to used during the pregnancy, then the lowest effective dose should be used.
          Advice for patients:Patients are advised to talk to their doctors before initiation of treatment with Pregabalin and discuss the benefit-risk of the medicine, particularly related to their case. Patients are also advised to talk with their healthcare professionals and use an appropriate contraception method during the treatment with Pregabalin to avoid pregnancy.
          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:Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
          Pregabalin (Lyrica): findings of safety study on risks during pregnancy of MHRA.
            27_Safety_Alert_of_Risk_of_Major_Congenital_Malformations_with_Pregabalin.Download

            Rapid Alert: Drug Product; Falsified Xanax 0.5mg Tablets identified in the market

            Asad Ullah News & Updates, Recall Alerts, Regulatory Updates

            Rapid Alert

            Suspected Falsified Product

            DRAP Alert NoNoI/S/11-22-37
            Action Date28th November 2022
            Target Audience1. Regulatory Field Force
            2. Pharmacists and Chemists at Distribution, Pharmacies and Medical Stores
            3. Healthcare Professionals- Physicians, Pharmacists, and Nurses at hospitals, Clinics and Healthcare Institutions
            4. General Public
            Problem StatementDuring the market surveillance activities in different areas of Ferozewala District Sheikhupura Punjab, Regulatory Field Force has identified the suspected sample of Xanax 0.5mg Tablets and sent for analysis. The Provincial Drugs Testing Laboratory, has declared the samples as “spurious” based on the analysis report. Details of the falsified product is as under: –

            Therapeutic Good(s) Affected:-

            SrProduct NameCompositionBatch #Manufactured by (as stated on label)
            1Xanax 0.5mg TabletAlprazolam 0.5mgFM7597M/s Pfizer Pakistan Ltd,
            B-2, S.I.T.E, Karachi.
            Action InitiatedThe Regulatory Field Force has been directed to increase the market surveillance and confiscate this batch of the product. All Pharmacists and chemists working at distributions and Pharmacies should immediately check the stock and stop supplying this product. The remaining stock should be quarantine immediately, and supplier(s) information should be provided to the Regulatory field force (DRAP, Provincial Health Departments and States) in order to ensure the removal of this falsified product.
            Advice for Healthcare Professionals-DRAP requests increased vigilance within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by this defective batch of above-mentioned product(s).

            -Adverse reactions or quality problems experienced with the use of this product shall 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 reporting problems to DRAP.
            Advice for Consumers-Consumers should stop using this product and shall contact to their physician or healthcare provider if they have experienced any problems that may be related to taking or using this drug product, and report the incident to Drug Regulatory Authority of Pakistan / National Pharmacovigilance Centre.

            -All therapeutic goods must be obtained only from the licensed pharmacies, and other authorized / licensed retail outlets. The authenticity and condition of products should be carefully checked. Seek advice from your pharmacists or other healthcare professionals in case of any doubt.
            Suspected-Falsified-Product-xanax-0.5mg-TabDownload

            DRAP finalized guidelines on Post Registration Variations of Pharmaceutical and Biological Drug Products

            Asad Ullah Drugs, General, Regulatory Updates

            DRAP has finalized its guidelines on procedure and data requirement for post registration variation of pharmaceutical and biological drug products. This document will assist manufacturers and importers to incorporate variations in their product to account administrative changes, technical and scientific progress, or to improve or introduce additional safeguards.

            These Guidelines will assist both Regulators and Industry on the regulation of variation / changes to the original registrations / Market Authorization of products in terms of procedures and criteria for the appropriate categorization, reporting of changes and subsequent approval as required. Data requirements are listed out to evaluate the impact of the proposed / intended change on the quality, safety and efficacy of the locally manufactured / imported finished pharmaceutical and biological drug products intended for human and veterinary use.

            Registration holders of Pharmaceutical / Biological drug products for human and veterinary use are responsible for the safety, efficacy and quality of a finished pharmaceutical / biological drug product that is placed on the market throughout its approved life cycle. These guidelines are intended to provide supportive information for submission of post registration variation application by the registrations / marketing authorization holders of the finished drug products to implement a change. These guidelines will:-

            1. Facilitate the interpretation of the relevant regulations and decisions of Registration Board regarding post registration variations of registered drug products.
            2. Assist applicants to determine type of variation applies in each case with the classification entailing prior approval or intimation to DRAP.
            3. Provide guidance as per applicable SOPs on the conditions and other data requirements to support variance application.

            The draft guidelines on data requirements for post registration variation were prepared three years ago and was available on the DRAP’ s website. Stakeholders have submitted their comments on the draft document and accordingly guidelines have been finalized after careful consideration of stakeholder’s comments.

            Post Registration Variation GuidelinesDownload

            For more information on Regulatory Guidelines published by DRAP, please navigate to Publications tabs on our website.

            Drug Safety Alert: Risk of Reduced Vitamin B12 Level with Metformin and Metformin-Containing Medicines

            Asad Ullah Safety Alerts, Safety Communication, Safety Info

            Drug Safety Alert

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

            Date:23rd of November, 2022
            Target Audience:• Manufacturers and importers of metformin and metformin-containing medicines;
            • Healthcare Professionals; and
            • Patients, consumers or caregivers.
            Background:The Medicine and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom on 20th June, 2022 through a drug safety update informed that decreased vitamin B12 levels, or vitamin B12 deficiency, is now considered a common side effect in patients on metformin treatment, especially in those receiving a higher dose or longer treatment duration and in those with existing risk factors. It was informed that the known adverse drug reaction of vitamin B12 deficiency was recently reviewed for the brand leader Glucophage (Metformin) within Europe with input from the MHRA. After this review, the MHRA agreed that the product information for patients and healthcare professionals for medicines containing metformin should be updated to state that vitamin B12 deficiency is a common adverse drug reaction, and may affect up to 1 in 10 people who take it. The product information for other medicines containing metformin will also be updated including fixed-dose combination products containing metformin.
            The product information has also been updated to note that the risk of this adverse reaction occurring increases with increasing metformin dose and treatment duration and in patients with risk factors known to cause vitamin B12 deficiency such as:

            i. baseline vitamin B12 levels at the lower end of the normal range;
            ii. conditions associated with reduced vitamin B12 absorption (such as elderly people and those with gastrointestinal disorders such as total or partial gastrectomy, Crohn’s disease and other bowel inflammatory disorders, or autoimmune conditions);
            iii. diets with reduced sources of vitamin B12 (such as strict vegan and some vegetarian diets);
            iv. concomitant medications that are known to impair vitamin B12 absorption (including proton pump inhibitors or colchicine); and
            v. genetic predisposition to vitamin B12 deficiency, such as intrinsic factor receptor deficiency (Imerslund-Gräsbeck syndrome) and transcobalamin II deficiency.
            Therapeutic Good(s) Affected:Metformin and metformin-containing medicines
            Metformin is a medicine authorized to treat type 2 diabetes mellitus and to help prevent type 2 diabetes in patients at high risk of developing it.
            Action in PakistanAccordingly, the case of the risk of reduced vitamin B12 level with metformin and metformin-containing medicines 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). The PRAEC after discussion decided as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 (reliance mechanism) to update prescribing information of Metformin and other medicines containing Metformin to state that vitamin B12 deficiency is an adverse drug reaction with Metformin use and the risk of this adverse reaction occurrence increases with increasing metformin dose and treatment duration and in patients with risk factors known to cause vitamin B12 deficiency.
            Advice for healthcare professionals:Healthcare professionals are informed that metformin can commonly reduce vitamin B12 levels in patients, which may lead to vitamin B12 deficiency. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and in patients with risk factors for vitamin B12 deficiency. Healthcare professionals are advised to test vitamin B12 serum levels if deficiency is suspected and also consider periodic vitamin B12 monitoring in patients with risk factors of vitamin B12 deficiency.
            Advice for patients:Patients who have low vitamin B12 levels or elderly patients and those with gastrointestinal disorders such as total or partial gastrectomy, Crohn’s disease and other bowel inflammatory disorders, or autoimmune conditions or those patients who have a genetic predisposition to vitamin B12 deficiency are advised to talk to their healthcare professionals during the treatment with metformin and metformin containing medicines.
            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:Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
            MHRA update on Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk.
              26_Safety_Alert_of_Risk_of_reduced_vitamin_B12_level_with_Metformin_and_metformin-containing_medicinesDownload

              Drug Safety Alert: Risk of Severe Cutaneous Adverse Reactions (SCARs) with Atezolizumab

              Asad Ullah Safety Alerts, Safety Communication, Safety Info

              Drug Safety Alert

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

              Date:23rd of November, 2022
              Target Audience:• Manufacturers and importers of Atezolizumab;
              • Healthcare Professionals; and
              • Patients, consumers or caregivers.
              Background:The National Pharmaceutical Regulatory Agency (NPRA) of Malaysia in April, 2021 announced that the product information for Atezolizumab (Tecentriq®) has been updated to include the risk of severe cutaneous adverse reactions (SCAR). Based on analysis from the company’s global safety data of 99 cases of SCARs identified globally, of which 36 cases were confirmed by histopathology or specialist diagnosis.

              Similarly, the Medicines and Healthcare Products Regulatory Agency (MHRA) in June, 2021 also announced that the product information for Atezolizumab (Tecentriq®) has been updated to include information about the risk of severe cutaneous adverse reactions (SCARs), which includes Stevens-Johnsons syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). SCARs were previously known to be potentially associated with the use of Atezolizumab. A review of safety data for Atezolizumab and the risk of SCARs was recently completed in Europe. Based on this review SCARs are an identified risk for Atezolizumab. Also, other products used for cancers in the same class as atezolizumab, including cemiplimab, ipilimumab, nivolumab and pembrolizumab list SCARs as possible adverse effects in the Summary of Product Characteristics (SmPC). In addition, Direct Healthcare Professional Communication (DHPC) were also issued by the manufacturers in New Zealand and European Medicine Agency back in November, 2020.

              SCARs are a heterogeneous group of delayed hypersensitivity reactions. These events mainly consist of acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) and can be potentially life-threatening, and lead to severe, potentially chronic sequelae.
              Therapeutic Good(s) Affected:Atezolizumab

              Atezolizumab is an immunostimulatory drug indicated to treat non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, urothelial carcinoma and triple-negative breast cancer.
              Action in PakistanAccordingly, the case of risk of severe cutaneous adverse reactions (SCARs) with Atezolizumab
              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). The PRAEC after deliberation decided as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 (reliance mechanism) to update prescribing information of Atezolizumab (Tecentriq®) to include the risk of severe cutaneous adverse reactions (SCAR) including Stevens-Johnsons Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). Furthermore, it was decided that registration holders should issue direct healthcare professional communication in this regard.
              Advice for healthcare professionals:Healthcare professionals are informed that severe cutaneous adverse reactions (SCARs), including cases of Steven-Johnsons Syndrome(SJS) and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with immune-stimulatory anti-cancer drugs including Atezolizumab. Advise patients to seek urgent medical assistance if severe skin reactions occur. Also, monitor patients for signs and symptoms of severe skin reactions and exclude other causes. If a SCAR is suspected, treatment should be withheld and patients should be referred to a specialist for diagnosis and treatment. If SJS or TEN is confirmed or in case of any grade 4 SCAR, permanently discontinue treatment with immune stimulatory drugs.
              Advice for patients:Patients are advised to be vigilant for the signs of severe skin reactions with the use of Atezolizumab and to seek urgent medical advice if they occur.
              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:Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
              MHRA update on Atezolizumab (Tecentriq▼) and other immune-stimulatory anti-cancer drugs: risk of severe cutaneous adverse reactions (SCARs).
                25_Safety_Alert_of_Risk_of_severe_cutaneous_adverse_reactions_SCARs_with_AtezolizumabDownload