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Drug Safety Alert: Risk of dental problems with orally dissolved Buprenorphine

Asad Ullah Safety Alerts

Drug Safety Alert

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

Date:10th of April, 2023
Target Audience:• Manufacturers and importers of Buprenorphine medicines;
• Healthcare Professionals; and
• Patients, consumers or caregivers.
Background:The United States Food and Drug Administration (US-FDA) on 12th of January, 2022 through a drug safety communication warned that dental problems have been reported with medicines containing buprenorphine that are dissolved in the mouth. Dental problems, including tooth decay, cavities, oral infections, and loss of teeth have been reported, even in patients with no prior history of dental issues. The buprenorphine medicines that are associated with dental problems are tablets and films that are dissolved under the tongue or placed against the inside of the cheek. There are also buprenorphine products for pain and opioid use disorder (OUD) delivered by other routes such as a skin patch and injection, but FDA has not identified a concern for dental health related to these other forms.
Therapeutic Good(s) Affected:Name: Buprenorphine medicines that are orally dissolved.

Buprenorphine is an opioid used to treat opioid use disorder (misuse of prescribed opioid medications) and pain. The comprehensive approach of buprenorphine combined with counselling and other behavioural therapies is often one of the most effective ways to treat OUD. At proper doses, buprenorphine also decreases the pleasurable effects of other opioids, making misuse of them less appealing.
Action in PakistanAccordingly, the case of risk of dental problems with orally dissolved Buprenorphine was discussed in the 2nd  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
 
 
as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 to update the prescribing information/safety specification of buprenorphine medicines that are dissolved in the mouth by including information related to the risk of dental issues, pre-prescribing assessment of patients and guidelines of taking extra steps after use in the warning and precaution sections.
Advice for healthcare professionals:Healthcare professionals are advised to be aware that the benefits of buprenorphine medicines still clearly outweigh the risks in treating OUD patients and should ask patients about their oral health history before prescribing treatment with the transmucosal/oral buprenorphine medicines. Healthcare professionals should also counsel patients about the potential for dental problems and the importance of taking extra steps after the medicine has completely dissolved, including to gently rinse their teeth and gums with water and then swallow and to wait at least 1 hour before brushing their teeth.
Advice for patients:Patients are advised to continue taking buprenorphine medicine as prescribed and not to stop it suddenly as it could lead to serious consequences including withdrawal symptoms. Patients are also advised to take extra steps to reduce the risk of serious dental problems such as rinsing their mouth with water and waiting at least 1 hour before brushing their teeth after buprenorphine medicines are dissolved to avoid damage to their teeth.
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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
    31-Safety-Alert-Risk-of-dental-problems-orally-dissolved-BuprenorphineDownload
    Minutes of 2nd Meeting of Pharmacovigilance Risk Assessment Expert Committee (PRAEC) held on March 07, 2023

    Drug Safety Alert: Risk of Hypersensitivity Reactions with Pegaspargase (Peg L Asparaginase)

    Asad Ullah Safety Alerts

    Drug Safety Alert

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

    Date:10th of April, 2023
    Target Audience:• Manufacturers and importers of Peg L Asparaginase;
    • Healthcare Professionals; and
    • Patients, consumers or caregivers.
    Background:The National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP) received six cases of hypersensitivity reactions from Indus Hospital Karachi with Pegaspargase (Peg L Asparaginase) with different batches having the same importer i.e. M/S Lab Diagnostic System and same manufacture i.e. Jiangsu Hengrui Medicine Co Ltd, China. The drug was prescribed for Acute Lymphoid Leukemia/ Leukemia with a dose of 2500 IU/m2 in children. The events of hypersensitivity reactions including swelling of lips, nausea, rash, vomiting, swelling of the tongue, itching all over the body, shivering, red eyes and abdominal pain were noted in the six cases after administration of Pegaspargase (Peg L Asparaginase) 3750IU. The time to onset of reactions was one day. The Pegaspargase was withdrawn in all cases except one case where the status is unknown and the patients recovered in all those cases. The causality assessment of all six cases was performed by the Causality Assessment Group of the National Pharmacovigilance Centre (NPC) and classified all six cases to have a possible relationship with drug intake.
     
    Further assessment was carried out at the National Pharmacovigilance Centre (NPC), Drug Regulatory Authority of Pakistan (DRAP), where the signal was confirmed from the approved label of Peg L Asparaginase of United States Food and Drugs Administration (US-FDA) and Summary of Product Characteristics (SmPC) of Medicine and Health Products Agency (MHRA) and from the published research articles of hypersensitivity reactions with the drug. There was also significant disproportionality and potential association of hypersensitivity with Pegaspargase as per statistical tool available in VigiLyze of the Uppsala Monitoring Centre, Sweden.
     
     The case was therefore discussed in the 2nd meeting of the Pharmacovigilance Risk Assessment
    Expert Committee (PRAEC) of the NPC, DRAP which after detailed deliberation, decided to update the prescribing information/ safety specification/ label of Pegaspargase injection with the inclusion of information related to hypersensitivity reactions and its monitoring in the warning and precaution section and information on treatment modification as per the grade of hypersensitivity reactions in dosage and administration sections. Registration holder was also directed to introduce an educational training programme for healthcare professionals on proper preparation, administration and monitoring of Pegaspargase and to ensure that resuscitation equipment are available at the treatment sites.
    Therapeutic Good(s) Affected:Name: Pegaspargase (Peg L Asparaginase)

    Pegaspargase is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of pediatric and adult patients with Acute Lymphoid Leukaemia (ALL) and hypersensitivity to native forms of L-asparaginase.
    Advice for healthcare professionals:Healthcare professionals are informed that hypersensitivity reactions to Pegaspargase, including life-threatening anaphylaxis, can occur during therapy, including in patients with known hypersensitivity to E. coli-derived asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye-swelling, erythema, decreased blood pressure, bronchospasm, dyspnoea, pruritus and rash. Premedicate patients 30-60 minutes before administration of pegaspargase. As a routine precautionary measure, the patient should be monitored for an hour after administration and resuscitation equipment and other appropriate means for the treatment of anaphylaxis such as epinephrine, oxygen, intravenous steroids, etc should be available at the treatment sites. Pegaspargase should be discontinued in patients with serious hypersensitivity reactions. Monitoring of patients and modification of treatment is recommended as per the following schedule: reduce the infusion rate by 50% in case of Grade 1 hypersensitivity reaction; interrupt the infusion, treat the symptoms, when symptoms resolved, resume the infusion and reduce the infusion rate by 50% in case of Grade 2 hypersensitivity reaction; and for Grade 3 to 4 hypersensitivity reactions permanently discontinue the pegaspargase.
    Advice for patients:Patients are informed that hypersensitivity reactions with Pegaspargase injection can occur during chemotherapy of Acute Lymphoid Leukaemia (ALL). Talk to your doctor if you have a history of hypersensitivity with conventional asparaginase formulations.
    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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
      30-Safety-Alert-of-Hypersensitivity-Reactions-with-Pegaspargase-Peg-L-Asparaginase.Download

      Safety Alert: WHO Global Alert on Tetracycline Hydrochloride Ophthalmic Ointment USP 1%

      Asad Ullah Recall Alerts, Regulatory Updates, Safety Alerts

      Safety Alert

      Update from WHO Global Surveillance and Monitoring System

      Date:28th February 2023
      Target Audience:· Healthcare Professionals- Physicians, Pharmacists, and Nurses at hospitals and clinics etc.
      · International travelers/General Public
      · NGO’s/Supply Donations/Humanitarian Medicines
      Problem or IssueWorld Health Organization (WHO) issued Medical Product Alert No. N°2/2023 dated 22nd February 2023 which refers to the batches of Tetracycline Hydrochloride Ophthalmic Ointment USP 1%, manufactured by Galentic Pharma (India) Pvt. Ltd, located at R-673, T.T.C. MIDC Rabale, Thane- Belapur Road, Navi Mumbai – 400701, Maharashtra, India Supplied in various countries under various labels.
      Visual examination of random samples had shown a range of quality issues with the random samples of the product batches e.g. particles ranging in color, size and shape on the nozzle, in the cap and in the ointment inside each tube, black spots and brown splotches on the inner foil layer of the tube, and phase separation.
      DRAP has never authorized sale of any products from Galentic Pharma (India) Pvt. Ltd (Thane Belapur Road, Navi Mumbai, India). These products are neither registered nor available on Pakistan market, however these may have been carried for personal use while visiting other countries.
      The manufacturer has initiated a voluntary recall for several batches. The manufacturer has indicated that other batches may be included in the voluntary recall
      Potential Hazards:There is currently no established evidence of any adverse events from the affected batches of TETRACYCLINE HYDROCHLORIDE OPHTHALMIC OINTMENT USP 1%. Redness and swollen eyes are common reactions to general use of tetracycline eye ointment. There is currently no indication that the above-mentioned quality issues may give rise to adverse events that are not listed in the product labelling. The affected TETRACYCLINE HYDROCHLORIDE OPHTHALMIC OINTMENT USP 1% is supplied in bulk and as a component of various medical kits supplied by some international organizations providing humanitarian assistance.
      Advice for healthcare professionals:DRAP requests increased vigilance within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by this affected batch of product. Adverse reactions or quality problems experienced with the use of any product shall be reported to the National Pharmacovigilance Centre(NPC), DRAP using Adverse Event Reporting Form or online through this link.  Further information of reporting problems to DRAP is available on this link.
      Advice for patients:Consumers should stop using this product bearing the affected batch number(s) 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.
        Safety-Alert-for-TetracyclineDownload

        All therapeutic goods must be obtained from the licensed pharmacies, and other authorized retail outlets. The authenticity and condition of products should be carefully checked. Seek advice from your pharmacists or other healthcare professional in case of any doubt.

        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

              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

                  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

                    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