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Year: 2022

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

      Stakeholder Comments are invited on the Draft Therapeutic Goods (Federal Inspectors, Laboratories and Federal Government Analysts) Rules, 2022

      Asad Ullah Licensing and Inspections, News & Updates, Notifications, Regulatory Updates

      Drug Regulatory Authority of Pakistan Act, 2012 provides the legal mandate to inspect and enforce GXPs through out the supply chain of therapeutic Goods. Inspection of establishments is an essential regulatory function, to monitor the regulatory compliance to ensure that operations at these establishments are carried out in accordance with approved standards, conditions, guidelines and legislations. The scope of the Inspections applies to different Good Practices (GXPs) including Good Manufacturing Practices (GMPs), Good Distribution Practices(GDPs) and Good Clinical Practices (GCPs), etc.

      DRAP Act 2012, under its Schedule-V provides the legal provisions for appointment, powers and procedures for working of Inspectors. These draft rules are intended to replace the existing Drugs (Federal Inspectors, Federal Drug Laboratory and Federal Government Analyst) Rules, 1976 and are aimed at converting Inspection activities to be based on a risk management approach, capable of revealing weaknesses and deficiencies in the production, quality control, storage or distribution of therapeutic goods, as well as to devise a uniform procedures for taking regulatory actions and handling of products with suspected quality defects or identified as substandard and falsified.

      These draft Therapeutic Goods (Federal Inspectors, Laboratories and Federal Government Analysts) Rules, 2022 were uploaded on the official website of DRAP dated 24th November, 2022, seeking comments and suggestions from stakeholders on the draft rules. Stakeholders can submit their comments and suggestions within 14 days of uploading this draft using prescribed format, (further information on comments submission is available on this link). Comments and suggestions can be forwarded via email to aamar.latif∂dra.gov.pk , copying at ajmal.shoail∂dra.gov.pk , or can be posted at mailing address, Additional Director, Division of Legal Affairs, Drug Regulatory Authority of Pakistan, 1st floor, TF Complex, 7th Mauve Area, G-9/4, Islamabad.

      Draft-Therapeutic-Goods-Federal-Inspectors-Laboratories-and-Federal-Government-Analysts-Rules-2022Download

      Drug Safety Update: Risk of Hypothyroidism in Babies and Young Children with Iodinated Contrast Media (ICM) Injections

      Asad Ullah Safety Alerts, Safety Communication, Safety Info

      Drug Safety Alert

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

      Date:19th of November 2022
      Target Audience:• Manufacturers and importers of Iodinated contrast media (ICM) injections such as iohexol, iopromide and iodixanol etc;
      • Healthcare Professionals; and
      • Patients, consumers or caregivers.
      Background:On 30th March, 2022, the United States Food and Drug Administration (US-FDA) through a Drug Safety Communication informed that they have approved a new warning to the prescribing information for the entire class of iodinated contrast media (ICM) injections and monitoring recommendations for children 3 years or younger. The warning describes the risk of an underactive thyroid or a temporary decrease in thyroid hormone levels. These risks and recommendations pertain to ICM given as an injection through an artery or vein. Newborns, particularly those born premature, and children in their first 3 years with underlying conditions such as heart issues may be at higher risk for problems with the thyroid. It was informed that the agency first alerted the public about cases of underactive thyroid in infants receiving ICM back in 2015 and now six new research studies evaluating this risk have been published. The FDA has concluded based on their review of the published studies that there is compelling evidence of a significant risk for an underactive thyroid or a temporary decrease in thyroid hormone levels in newborns and children through 3 years after exposure to ICM. Back in December 2017, the Medicines and Medical Devices Safety Authority (Medsafe) of New Zealand also requested that data sheets for iodine-containing contrast agents (ICAs) to be updated with information on the risk of hypothyroidism, particularly in neonates and should include advice on thyroid monitoring.
      Therapeutic Goods Affected:Iodinated contrast media (ICM) injections such as iohexol, iopromide and iodixanol etc.

      ICM are drugs containing iodine that are given to patients to enhance the ability to see blood vessels, organs, and tissues on medical images such as X-rays or computed tomography (CT) scans, thus helping healthcare professionals to diagnose potential problems. Examples include iohexol (Omnipaque), iopromide (Ultravist 300, 370) and iodixanol (Visipaque 270, 320) etc. Common side effects associated with ICM include flushing in the face, nausea or vomiting, mild itchiness, and skin rash.
      Action in PakistanAccordingly, the case of the risk of hypothyroidism in babies and young children with iodinated contrast media (ICM) injections 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) of Pharmacovigilance Rules, 2022 (reliance mechanism) to update the warning and precaution section of the prescribing information of the entire class of iodinated contrast media (ICM) that are used for radiological purposes to include risks of an underactive thyroid or a temporary decrease in thyroid hormone levels in children 3 years or younger i.e newborns, particularly those born premature, and children in their first 3 years with underlying conditions such as heart issues etc.
      Advice for healthcare professionals:Healthcare professionals are advised to perform appropriate monitoring of patients from birth through 3 years for the possibility of hypothyroidism or a temporary decrease in thyroid hormone levels following exposure to iodinated contrast media (ICM) injections. Healthcare professionals are also advised to consider evaluating thyroid function within 3 weeks, especially in term and preterm neonates and children with some underlying conditions. If thyroid dysfunction is detected, it should be properly treated and monitored as clinically needed to avoid future cognitive and other developmental disabilities. Increased-risk pediatric patients include those who are newborns or have very low birth weight, prematurity, or the presence of cardiac or other conditions such as those requiring care in neonatal or pediatric intensive care units. Patients with cardiac conditions may be at the greatest risk since they often require high doses of contrast during invasive cardiac procedures. These increased-risk pediatric patients require close monitoring.
      Advice for patients:Parents and caregivers of a child below 3 years and receiving ICM injections should talk with healthcare professionals for additional information. If the child is a newborn, has very low birth weight, was premature, has a heart condition, or was admitted to a neonatal or pediatric intensive care unit, they may be at higher risk of developing underactive thyroid or a temporary decrease in thyroid hormone levels. Babies & young children typically do not show any visible signs of thyroid problems & may need to be monitored by their healthcare professionals after receiving ICM.
      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:Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
      Drug Safety Communication of the United States Food and Drug Administration (US-FDA) regarding Iodinated contrast media (ICM).
        23_Safety_alert_of_risk_hypothyroidism_in_babies_and_young_children_with_Iodinated_contrast_New-1Download

        DRAP invited Comments from Stakeholders on the Draft Therapeutic Goods (Advertisement) Rules, 2022

        Ijaz Mustafa Advertisements, Drugs, Notifications, Publications

        Drug Regulatory Authority of Pakistan Act, 2012 under section 7 (c)(iii) and (x) mandated the DRAP for the regulation of Advertisements, enforcement and monitoring of advertisement rules and ban on false advertisement. Schedule II- B of the DRAP Act, 2012 prohibits the advertisements of any therapeutic goods except in accordance with the prescribed conditions.

        The current changing trend of advertisement and promotional activities by pharmaceutical companies and the requirement of extension of scope from drugs to therapeutic goods has led to the development of these draft rules. These draft rules contain provisions almost similar to the ones given in Rule 31 of the Drugs (Licensing, Registering & Advertising) Rules 1976, included but not limited to; amended Schedule with the list of drugs permissible for advertisement as earlier consulted with stakeholders, Schedule with diseases for which advertisement is prohibited, schedule with the details on advertisement or promotional material keeping in consideration the ethical criteria; Forms for submitting applications of advertisement approval, Formats for granting approval for advertisement and schedule with details on advertisement or promotional material keeping in consideration the ethical criteria.
        These draft Therapeutic Goods (Advertisement) Rules, 2022 were uploaded on the official website of DRAP dated 21st November, 2022, seeking comments and suggestions from stakeholders on the draft rules. Stakeholders can submit their comments and suggestions within 14 days of uploading this draft using prescribed format, (further information on comments submission can be accessed on this link). Comments and suggestions can be forwarded via email to aamar.latif∂dra.gov.pk , copying at aqsa.hashmi∂dra.gov.pk , or can be posted at mailing address, Additional Director, Division of Legal Affairs, Drug Regulatory Authority of Pakistan, 1st floor, TF Complex, 7th Mauve Area, G-9/4, Islamabad.

        Click here to View/Download the draft Therapeutic Goods (Advertisement) Rules, 2022

        Draft-Therapeutic-Goods-Advertisement-Rules-2022Download

        Drug Safety Update; PRAEC issued a Safety Alert on Risk of Sinus Bradycardia with Remdesivir

        Asad Ullah Safety Alerts, Safety Communication, Safety Info

        Drug Safety Alert

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

        Date:21st of November 2022
        Target Audience:• Manufacturers and importers of Remdesivir;
        • Healthcare Professionals; and
        • Patients, consumers or caregivers.
        BackgroundHealth Canada in August, 2021 announced that it will work with the manufacturer of Remdesivir to update the product information to include a warning on the potential risk of sinus bradycardia. Health Canada assessed case reports of sinus bradycardia in patients receiving Remdesivir in their database and in the literature and concluded that a link between the use of Remdesivir and the risk of sinus bradycardia is possible.

        Previously, in June 2021, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicine Agency (EMA) recommended a change to the product information for Remdesivir (Veklury®) to include sinus bradycardia as an adverse drug reaction. The PRAC reviewed available data on rare reported cases of bradycardia in patients treated with Remdesivir as well as data from clinical trials and the scientific literature. The PRAC concluded that a causal relationship between the use of Remdesivir and the event is reasonably possible and recommended the revision of the product information. The majority of the events of sinus bradycardia resolved a few days after the treatment with Remdesivir was discontinued.

        Sinus bradycardia occurs when the heart beats slower than normal. Sinus bradycardia can very rarely cause symptoms, such as dizziness, tiredness, shortness of breath, and chest discomfort.
        Action in PakistanAccordingly, the case of the risk of sinus bradycardia with Remdesivir 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 the prescribing information (warning & adverse drug reactions sections) of Remdesivir to include the potential risk of sinus bradycardia.
        Therapeutic Goods Affected:Remdesivir injection

        Remdesivir is an antiviral medicine that is indicated to treat COVID-19 in adults and adolescents with pneumonia requiring supplemental oxygen. 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 HolderRegistration 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 NPC-DRAP has decided to update the prescribing information (warning & adverse drug reactions sections) of Remdesivir to include the potential risk of sinus bradycardia. Therefore, healthcare professionals should monitor patients receiving Remdesivir for sinus bradycardia and accordingly treat the patients as appropriate.
        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:Minutes of 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
        Minutes of Meeting of PRAC of European Medicines Agency.
          24-Safety-Alert-of-Risk-of-Sinus-Bradycardia-with-RemdesivirDownload

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

          Asad Ullah Safety Alerts, Safety Communication, Safety Info

          Drug Safety Alert

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

          Date:18th 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 HolderRegistration 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-RemdesivirDownload

            Drug Safety Alert: Risk of Serious Bowl complications with clozapine

            Asad Ullah Safety Alerts, Safety Communication, Safety Info

            Drug Safety Alert

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

            Date:18th of November 2022
            Target Audience:• Manufacturers and importers of Clozapine;
            • Healthcare Professionals; and
            • Patients, consumers or caregivers.
            BackgroundThe 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 PakistanAccordingly, 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.
            22-Safety-Alert-of-Risk-of-Serious-Bowel-Complications-with-Clozapine.Download

            Drug Safety Alert: Risk of Anaphylactic Reaction / Anaphylactic Shock with Diclofenac Sodium Injection

            Asad Ullah Safety Alerts, Safety Communication, Safety Info

            Drug Safety Alert

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

            Date:10th of November 2022
            Target Audience:• Manufacturers and importers of Diclofenac Sodium.
            • Healthcare Professionals; and
            • Patients, consumers or caregiver
            Problem or Issue:The National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP) through the Provincial Pharmacovigilance Centre (PPC), Directorate of Drugs Control Punjab received two serious cases of anaphylactic reactions upon STAT dose administration of injection Diclofenac Sodium 75mg/3ml intramuscular (IM). The cases were reported by Clinical Pharmacy and Pharmacovigilance Officers (CPPOs) of two public sector hospitals in the Punjab province. The diclofenac injection was used in these cases for the wound pain in the left leg and backache. One of the patients has a history of asthma. The symptoms noted were pruritus, erythema, sweating, apprehension and fainting due to a sudden drop in blood pressure, severe shortness of breath, wheezy chest, hypoxia and hypotension. The adverse drug reactions were assessed for causality using the WHO Causality Assessment Criteria and were categorized as “Possible” and “Probable” based on plausible time to onset (same day immediately after administration), positive dechallenge (recovered on withdrawing) and unable to explain from other drugs/ disease.

            The case were, therefore, discussed in the 1st meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the NPC, DRAP which decided to update the warning, precaution & contraindication sections of the prescribing information / safety specification / label of Diclofenac Sodium injection about the occurrence of anaphylactic reaction/ anaphylactic shock and its contraindication in a patient with a history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
            Therapeutic Goods Affected:Diclofenac Sodium injection
            Advice for healthcare professionals:Healthcare professionals are informed that Pharmacovigilance Risk Assessment Expert Committee of the DRAP has recommended to update the warning, precaution & contraindication sections of the prescribing information/ safety specification/ label of Diclofenac Sodium injection about the occurrence of anaphylactic reaction/ anaphylactic shock and its contraindication in a patient with a history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Therefore, healthcare professionals should know that are rare chances that anaphylactic reactions may occur with diclofenac sodium injection in patients with the aspirin triad or in patients without prior exposure to diclofenac. Immediately discontinue the diclofenac injection if an anaphylactic reaction occurs. Likewise, Diclofenac is contraindicated in patients with a history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
            Advice for patients:Patients are informed that there are rare chances of the development of anaphylactic reaction/ anaphylactic shock with an injection of diclofenac sodium. Talk to your doctor if you have a history of asthma or urticaria, or if you had previously experienced an anaphylactic reaction/ allergic-type reaction with diclofenac sodium or after taking aspirin or other NSAIDs.
            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.
            20-Safety-Alert-of-Anaphylactic-reaction-with-Diclofenac-Sodium.Download