Drug Safety Alert: Risk of Medication Errors resulting Errors resulting due to inadvertent intrathecal Tranexmic Acid Injection

Drug Safety Alert

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

Date:28th  of April, 2024
Target Audience:·         Manufacturers and importers of tranexamic acid injection;
·         Healthcare Commissions/ Provincial Health Departments; and
·         Healthcare Professionals.
Background:The WHO in its medical product alert on 16th March, 2022 informed healthcare professionals about the risk of administration errors that can potentially occur with tranexamic acid (TXA) injection. There have been reports of TXA being mistaken for obstetric spinal anaesthesia used for caesarean deliveries resulting in inadvertent intrathecal administration.

In TXA administered intrathecally, potent neurotoxin and neurological sequelae are manifested, with refractory seizures and 50% mortality. The profound toxicity of TXA administered intrathecally was described in 1980. A 2019 review identified 21 reported cases of inadvertent intrathecal injection of TXA since 1988, of which 20 were life-threatening and 10 fatal. Sixteen were reported between 2009 and 2018.

The WHO recommends early use of intravenous TXA within 3 hours of birth in addition to standard care for women with clinically diagnosed postpartum haemorrhage (PPH) following vaginal births or caesarean section. TXA should be administered at a fixed dose of 1g in 10 ml (100 mg/ml) IV at 1 ml per minute, with a second dose of 1g IV if bleeding continues after 30 minutes.

The WHO also informed that TXA is frequently stored in proximity to other medicines, including injectable local anaesthetics indicated for spinal analgesia (e.g., for caesarean section). The presentation of some of the local anaesthetics is similar to the TXA presentation (transparent ampoule containing transparent solution), which can erroneously be administered instead of the intended intrathecal anaesthetic resulting in serious undesirable adverse effects. Recently, obstetricians from several countries have reported inadvertent intrathecal TXA administration and related serious neurological injuries.
Therapeutic Good(s) Affected:Tranexamic acid (TXA) is used for the prevention and treatment of haemorrhages due to general or local fibrinolysis in adults and children from one year. Specific indication inter-alia includes gynaecological surgery or disorders of obstetric origin such as postpartum haemorrhage.
Action in PakistanThe case was discussed in the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26th of February, 2024 which decided the case as per Rule 10 (1) (b) and 10 (1)(h) (vi) of Pharmacovigilance Rules, 2022 and recommended National Pharmacovigilance Centre to issue safety alerts/ advisory related to the risk of medication errors due to inadvertent intrathecal tranexamic acid injection.
Advice for healthcare professionals:Healthcare providers, particularly obstetricians and anesthesiologists, are urged to remain vigilant regarding the potential risk of unintended intrathecal administration of Tranexamic acid (TXA), leading to the development of potent neurotoxicity and subsequent neurological complications. It is recommended that healthcare professionals verify the labelling of Tranexamic acid (TXA) injections before administration. Instances have been documented where TXA has been mistaken for obstetric spinal anaesthesia during cesarean deliveries, resulting in inadvertent intrathecal administration. The similarity in presentation between some local anaesthetics and TXA (both typically packaged in transparent ampoules containing clear solutions) can lead to erroneous administration of the wrong medication instead of the intended intrathecal anaesthetic.

Tranexamic acid (TXA) is a lifesaving medicine; however, this potential clinical risk should be considered and addressed by all operating theatre staff. Reviewing of existing operating theatres’ drug handling practices are required in order to decrease this risk, such as storage of TXA away from the anesthetic drug trolley, preferably outside the theatre.
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 the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee.
· WHO statement on risk of medication errors with tranexamic acid injection resulting in inadvertent intrathecal injection.

Drug Safety Alert: Risks associated with the use of Valproic Acid in Women and Girls of Childbearing potential and minor potential risk in male patients.

Drug Safety Alert

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

Date:28th  of April, 2024
Target Audience:·         Manufacturers and importers of valproic acid;
·         Healthcare Professionals; and
·         Patients, Consumers or Caregivers.
Background:The World Health Organization (WHO) in a safety statement dated 2nd of May 2023 alerted stakeholders to the revised guidance on the use of valproic acid (sodium valproate) for the treatment of epilepsy and bipolar disorder in women and girls of childbearing potential. It was informed that valproic acid (sodium valproate) should not be prescribed to women and girls of childbearing potential because of the high risk of birth defects and developmental disorders in children exposed to valproic acid (sodium valproate) in the womb. In women and girls of childbearing potential, lamotrigine or levetiracetam should be offered as first-line monotherapy for both generalized onset seizures and focal onset seizures.

For women and girls of childbearing potential who are currently prescribed valproic acid (sodium valproate), the WHO also stated that advice should be provided on the use of effective contraception, without interruption, during the entire duration of treatment. Information must be provided on risks associated with valproic acid (sodium valproate) use during pregnancy, pregnancy prevention and referral for contraceptive advice if they are not using effective contraception. Individual circumstances should be evaluated in each case when choosing the contraception method and involving the woman in shared decision-making. If a woman is planning to become pregnant, a person trained in the management of epilepsy/bipolar disorder in pregnant women should consider alternative treatment options. Women should be informed to consult their physician as soon as they are planning pregnancy and the need to urgently consult their physician in case of pregnancy. Every effort should be made to switch to appropriate alternative treatment before conception. If switching is not possible, the woman should receive further counselling regarding the risks of valproic acid (sodium valproate) for the unborn child to support her informed decision-making. A specialist should periodically review whether valproic acid (sodium valproate) is the most suitable treatment for the person.
 
The EMA’s safety committee (PRAC) in its meeting held on 8-11 January, 2023 recommended precautionary measures for the treatment of male patients with valproate medicines. These measures are to address a potential increased risk of neurodevelopmental disorders in children born to men treated with valproate during the three months before conception. In reaching its conclusion, the PRAC reviewed data from a retrospective observational study carried out by companies that market valproate as an obligation following a previous review of valproate use during pregnancy. The committee also considered data from other sources, including non-clinical (laboratory) studies and scientific literature, and consulted patients and clinical experts. The PRAC’s latest recommendations come in addition to restrictions and other measures that are already in place to avoid valproate exposure in pregnancy because exposed babies are at high risk of malformations and developmental problems. These measures were endorsed following a referral of valproate and related substances in 2018. The measures at that time included a ban on the use of such medicines for migraine or bipolar disorder during pregnancy, and a ban on treating epilepsy during pregnancy unless there is no other effective treatment available.

PRAC also discussed a direct healthcare professional communication (DHPC) for valproate medicines which will be forwarded to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh). When adopted, the DHPC will be disseminated to healthcare professionals by the marketing authorization holders. The DHPC will inform healthcare professionals about the potential risk of neurodevelopmental disorders in children of fathers treated with valproate in the three months prior to conception. It is recommended that valproate treatment in male patients is started and supervised by a specialist in the management of epilepsy, bipolar disorder or migraine. Valproate treatment of male patients should be reviewed regularly to consider whether it remains the most suitable treatment, particularly when the patient is planning to conceive a child.

On 22nd January, 2024, the United Kingdom, medicine and Health Product Regulatory Agency (MHRA) through a drug safety update informed that new safety and educational materials had been introduced for men, women and healthcare professionals to reduce the harm from valproate, including the significant risk of serious harm to the baby if taken during pregnancy and the risk of impaired fertility in males. Healthcare professionals were advised to review the new measures and materials and integrate them into their clinical practice when referring patients and when prescribing or dispensing valproate. Healthcare professionals were advised that valproate must not be started in new patients (male or female) younger than 55 years unless two specialists independently consider and document that there is no other effective or tolerated treatment, or there are compelling reasons that the reproductive risks do not apply. For the majority of patients, other effective treatment options are available. At their next annual specialist review, women of childbearing potential and girls receiving valproate should be reviewed using the revised valproate Annual Risk Acknowledgement Form. A second specialist signature will be needed if the patient is to continue on valproate, however subsequent annual reviews will only require one specialist general practice and pharmacy teams should continue to prescribe and dispense valproate and if required offer patients a referral to a specialist to discuss their treatment options.

Valproate has a high teratogenic potential. Exposure to valproate in pregnancy is associated with physical birth defects in 11% of babies and neurodevelopmental disorders in up to 30-40% of children, which may lead to permanent disability. Since 2018, valproate has been contraindicated in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme (PPP) are followed. The purpose of PPP was to ensure all women and girls are fully informed of the risks and the need to avoid exposure to valproate medicines in pregnancy through an annual review and signing a risk acknowledgement form. 

In 2022, the Commission on Human Medicines (CHM) reviewed the latest data on the safety of valproate. The CHM heard from patients and other representatives about how valproate was being used and how the risks were currently managed. The CHM noted that data from the Medicine and Pregnancy Registry showed that pregnancies in England continue to be exposed to valproate. The CHM also considered other known risks of valproate, including the risk of impaired male fertility. The CHM considered pre-clinical data on possible transgenerational risks with prenatal exposure, as well as data from studies in juvenile and adult animals suggesting adverse effects on the testes. There are currently limited data available on many of these risks in humans and further studies are planned. However, the CHM noted many patients receiving valproate have other therapeutic options with fewer potential reproductive harms.

On 28th November 2023, MHRA issued a National Patient Safety Alert to instruct Integrated Care Boards (in England), Health Boards (in Scotland), Health Boards (in Wales), and Health and Social Care Trusts (in Northern Ireland) to prepare for the new risk minimisation measures by 31 January 2024. The new safety and educational materials support these measures. Due to the known significant risk of serious harm to a baby after exposure to valproate in pregnancy, these measures aim to ensure valproate is only used if other treatments are ineffective or not tolerated, and that any use of valproate in women of childbearing potential who cannot be treated with other medicines is in accordance with the Pregnancy Prevention Programme (PPP).
 
The CHM will consider further recent registry data which may suggest an increased risk of neurodevelopmental disorders in children whose fathers took valproate in the 3 months before conception. In the study, around 5 children in 100 born to fathers treated with valproate around conception were diagnosed with a neurodevelopmental disorder. This is compared to 3 in 100 children whose fathers were taking lamotrigine or levetiracetam around conception (two other anti-seizure medicines). As a precaution, male patients on valproate who are planning a family within the next year should speak to a healthcare professional about their treatment options. Moreover, MedSafe, Newzealand on 7th December 2023 informed that the data sheet and the consumer medicines information leaflet of sodium valproate (Epilim) have been recently updated with additional information use in people who can father children.
Therapeutic Good(s) Affected:Valproate (sodium valproate/valproic acid) is authorised for use in epilepsy and bipolar disorder.
Action in PakistanThe case was discussed in the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26th of February, 2024 which decided the case as per Rule 10 (1) (h) (ii) of the Pharmacovigilance Rules, 2022 that registration holders of sodium valproate should update the contraindication not to prescribe sodium valproate-containing medicines in following situations: in pregnancy if there is no other effective or tolerated treatment available and individual benefit-risk assessment is performed and documented for each patient; and in women of childbearing potential aged under 55 years, unless there is no other effective or tolerated treatment available, followed by individual benefit-risk assessment and the patients are made aware of pregnancy prevention programme. Furthermore, also decided as per Rule 10 (1) (h) (vi) of the Pharmacovigilance Rules, 2022 registration holders should initiate an awareness Programme for Pregnancy Prevention (PPP) for sodium valproate-containing medicines. Similarly, as per Rule 10 (1) (h) (iv) of the Pharmacovigilance Rules, 2022, the PRAEC decided that registration holders should also update the warning and precaution section of the prescribing information/ label of sodium valproate-containing medicines by including information about high-risk of birth defects and neuro-developmental disorders in children exposed to valproic acid (sodium valproate) in the womb and about the minor potential risk of neurodevelopmental disorders in children of fathers treated with valproate in the three months before conception and as a precaution advise male patients on valproate who are planning a family within the next year should speak to a healthcare professional about their treatment options.
Advice for healthcare professionals:Healthcare professionals are informed about the high risk of birth defects and neuro-developmental disorders in children exposed to valproic acid (sodium valproate) in the womb and about the minor potential risk of neurodevelopmental disorders in children of fathers treated with valproate in the three months before conception. Therefore, healthcare professionals are advised not to prescribe valproate-containing medicines in pregnant females if there is no other effective or tolerated treatment available and individual benefit-risk assessment is performed and documented for each patient. Likewise, it should also not be prescribed in women of childbearing potential aged under 55 years, unless there is no other effective or tolerated treatment available, followed by individual benefit-risk assessment and the patients are made aware of the pregnancy prevention programme. As a precautionary measure, healthcare professionals should speak to male patients on valproate-containing medicines who are planning a family within the next year about their treatment options.
Advice for patients:Patients are advised to not stop taking valproate or alter their dose without checking with their specialist first; if they stop taking valproate without their specialist’s advice their condition may get worse. Further, it is also informed that valproate is associated with a significant risk of birth defects and neurodevelopmental disorders in children born to women who take valproate during pregnancy and the findings of a new study have suggested that there may be a minor increased risk of neurodevelopmental disorders in children of men who took valproate in the 3 months before conception. Therefore, women and girls of childbearing potential are advised to talk with their doctors if they are planning for pregnancy and otherwise as well. Likewise,  healthcare professionals male patients on valproate-containing medicines who are planning a family within the next year may also talk with their doctors about their treatment options.
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 the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee.
·         WHO-Statement on the risks associated with the use of valproic acid (sodium valproate) in women and girls of childbearing potential.
·         MHRA-UK-Valproate: reminder of current Pregnancy Prevention Programme requirements; information on new safety measures to be introduced in the coming months.
Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 8-11 January 2024 of EMA.

Drug Safety Alert: Risk of Posterior Reversible Encephalopathy Syndrome (PRES) and Reversible Cerebral Vasoconstriction Syndrome (RCVS) with Pseudoephedrine Containing Medicines.

Drug Safety Alert

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

Date:27th  of April, 2024
Target Audience:·         Manufacturers and importers of pseudoephedrine-containing medicines;
·         Healthcare Professionals; and
·         Patients, Consumers or Caregivers.
Background:The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicine Agency (EMA) in its meeting held on 27-30th November 2023 recommended new measures for medicines containing pseudoephedrine to minimize the risks of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) and informed that product information for all pseudoephedrine-containing medicines will be updated to include the risks. The recommendations follow a review of all available evidence, including post-marketing safety data, which concluded that pseudoephedrine is associated with risks of PRES and RCVS. During the review, PRAC sought advice from an expert group of general practitioners, otorhinolaryngologists (specialists in diseases of the ear, nose, throat, head and neck), allergologists (specialists in the treatment of allergies) and a patient representative. PRAC also considered information submitted by a third party representing healthcare professionals. It was recommended that medicines containing pseudoephedrine are not to be used in patients with high blood pressure that is severe or uncontrolled (not being treated or resistant to treatment), or with severe acute (sudden) or chronic (long-term) kidney disease or failure. In addition, as part of its advice on safety-related aspects to other EMA committees, the PRAC discussed a direct healthcare professional communication (DHPC) with important information on pseudoephedrine-containing products which was also forwarded to EMA’s human medicines committee (CHMP).

RES and RCVS are rare conditions that can involve reduced blood supply to the brain, potentially causing serious, life-threatening complications. With prompt diagnosis and treatment, symptoms of PRES and RCVS usually resolve. Healthcare professionals should advise patients to stop using these medicines immediately and seek treatment if they develop symptoms of PRES or RCVS, such as severe headache with a sudden onset, feeling sick, vomiting, confusion, seizures and visual disturbances.

On 25 January 2024, EMA’s Committee for Medicinal Products for Human Use (CHMP) endorsed the measures recommended by the PRAC to minimise the risks of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) for medicines containing pseudoephedrine. CHMP confirmed that medicines containing pseudoephedrine are not to be used in patients with high blood pressure that is severe or uncontrolled (not being treated or resistant to treatment) or in patients with severe acute (sudden) or chronic (long-term) kidney disease or failure. The CHMP opinion has been sent to the European Commission, which will issue a legally binding decision across the EU.
Therapeutic Good(s) Affected:Pseudoephedrine is a stimulant that is often used as a decongestant in people who have a cold or allergies.
Action in PakistanThe case was discussed in the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26th of February, 2024 which decided the case as per Rule 10 (1) (h) (iv) of the Pharmacovigilance Rules, 2022 that registration holders should update the warning and precaution section of the prescribing information/label of pseudoephedrine-containing medicines by including information about the risks of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) along with advise that medicines containing pseudoephedrine are not to be used in patients with high blood pressure that is severe or uncontrolled (not being treated or resistant to treatment), or with severe acute (sudden) or chronic (long-term) kidney disease or failure. Similarly, as per Rules 10 (1) (h) (vi) registration holders were advised to issue direct healthcare professionals communication by highlighting the risk.
 
Advice for healthcare professionals:Healthcare professionals are informed that a review has found that pseudoephedrine-containing medicines are associated with risks of posterior reversible encephalopathy syndrome (PRES) and
reversible cerebral vasoconstriction syndrome (RCVS), a serious condition affecting the cerebral blood vessels. This follows an evaluation of all available data including a few reported cases of these conditions. There were no fatal cases of PRES or RCVS reported internationally, and most of the cases were resolved following discontinuation of the medicine and appropriate treatment. Healthcare professionals are advised that pseudoephedrine-containing medicines must not be used in patients with severe or uncontrolled hypertension or severe acute or chronic kidney disease or renal failure, as these are risk factors for developing PRES or RCVS. Patients should be advised to discontinue treatment and seek immediate medical assistance if they develop symptoms of PRES or RCVS such as sudden, severe headache or thunderclap headache, nausea, vomiting, confusion, seizures and/or visual disturbances. The risks of PRES and RCVS should be considered alongside other risks associated with pseudoephedrine-containing medicines, including cardiovascular or ischaemic events.
Advice for patients:Patients are advised not to take pseudoephedrine-containing medicines if they have high blood pressure that is severe or uncontrolled (not being treated or resistant to treatment) or if they have severe acute (sudden) or chronic (long-term) kidney disease or failure, as these are risk factors for developing PRES or RCVS. Patients are also advised to stop using pseudoephedrine-containing medicines immediately and seek urgent medical assistance if they develop symptoms of PRES or RCVS such as a severe headache with a sudden onset, feeling sick, vomiting, confusion, seizures and changes in vision.
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 the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee.
·         Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 27-30 November 2023.
· Pseudoephedrine-containing medicinal products – referral, EMA.

Drug Safety Alert: Risk of Haemophagocytic Lymphohistiocytosis (HLH) with Sulfamethoxazole and Trimethoprim combination.

Drug Safety Alert

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

Date:27th  of April, 2024
Target Audience:·         Manufacturers and importers of Sulfamethoxazole and Trimethoprim combination;
·         Healthcare Professionals; and
·         Patients, Consumers or Caregivers.
Background:Health Canada in May 2023 announced that the product safety information for combination sulfamethoxazole and trimethoprim-containing products will be updated to include the risk of haemophagocytic lymphohistiocytosis (HLH).  Triggered by a labelling update for these products by the EMA, Health Canada reviewed the available information from the Canadian and international databases, and the scientific literature. Of the ten cases assessed, one case was found to be probably linked to the use of the medicine, eight were found to be possibly linked (including one fatal case) and one (another fatal case) was unlikely to be linked. The review found a possible link between the use of the medicine and the risk of HLH. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of extreme systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis) and is associated with high mortality rates if not recognised early and treated. Healthcare professionals were advised to immediately evaluate patients who develop early manifestations of pathologic immune activation. If HLH is diagnosed, discontinue sulfamethoxazole-trimethoprim treatment.
Previously, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicine Agency in its meeting from 03-06 May 2021 considered the available evidence in EudraVigilance, the literature, and the data submitted by Roche/ Eumedica, Aspen Pharma and Teva regarding the risk of Haemophagocytic lymphohistiocytosis (HLH) with sulfamethoxazole/trimethoprim in combination and agreed that the available information is considered sufficient to support a warning statement in the product information of the drug combination.
Therapeutic Good(s) Affected:Sulfamethoxazole plus Trimethoprim is a prescription antibiotic medicine indicated for the treatment of various bacterial infections, such as urinary tract infections, respiratory tract infections, and gastrointestinal infections.
Action in PakistanThe case was discussed in the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26th of February, 2024 which decided the case as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 to update the warning and precaution section of the prescribing information/label of the drug combination of sulfamethoxazole and trimethoprim by including information about the risk of haemophagocytic lymphohistiocytosis (HLH).
 
Advice for healthcare professionals:Healthcare professionals are informed that cases of HLH have been reported very rarely in patients treated with co-trimoxazole (Sulfamethoxazole+Trimethoprim). HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of excessive systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis). Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If a diagnosis of HLH is established, cotrimoxazole treatment should be discontinued.
Advice for patients:Patients are informed not to stop the medication without the advice of their healthcare professional and to immediately consult their healthcare professional if they experience any symptoms of HLH during treatment with sulfamethoxazole+trimethoprim.
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 the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee.
·         Summary Safety Review – Combination Sulfamethoxazole and Trimethoprim – Assessing the Potential Risk of Hemophagocytic Lymphohistiocytosis. Health Canada.
· EMA-PRAC recommendations on signals adopted on the 3-6th May 2021 meeting.

Drug Safety Alert: Risk of Myasthenia Gravis and Ocular Myasthenia with Statins.

Drug Safety Alert

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

Date:27th  of April, 2024
Target Audience:·         Manufacturers and Importers of statins;
·         Healthcare Professionals; and
·         Patients, Consumers or Caregivers.
Background:The Pharmacovigilance Risk Assessment Committee (PRAC) of EMA in February, 2023 has recommended a change to the product information for statins to include potential risks of myasthenia gravis and ocular myasthenia.  In a few cases, statins have been reported to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia. Treatment with statins should be discontinued in case of aggravation of symptoms. Recurrences when the same or a different statin was (re-) administered have been reported.
 
The MHRA-UK in September 2023 informed the healthcare professional and patient about the European’s review recommendation related to new warnings on the risk of new-onset or aggravation of pre-existing myasthenia gravis with multiple statins. The findings of the European review were considered by the Pharmacovigilance Expert Advisory Committee (PEAG) of the Commission on Human Medicines (CHM), which agreed with the recommendations. It was informed that the product information of all statins is being updated to list myasthenia gravis and ocular myasthenia gravis as adverse drug reactions with a frequency ‘not known’. New warnings will also be added to the Summaries of Product Characteristics and Patient Information Leaflets.
Therapeutic Good(s) Affected:Statins are HMG-CoA reductase inhibitors and include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Statins are an acceptably safe and effective group of medicines that help lower the level of low-density lipoprotein (LDL) cholesterol in the blood. Statins play an important role in the treatment of atherosclerotic cardiovascular disease.
Action in PakistanThe case was discussed in the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26th of February, 2024 which decided the case as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022, that registration holders of statins (HMG-CoA reductase inhibitors) should update the warning and precaution section about the risk of myasthenia gravis and ocular myasthenia gravis and list as adverse drug reactions with a frequency ‘not known’ in the adverse drug reaction section.
 
Advice for healthcare professionals:Healthcare professionals are advised to refer patients presenting with suspected new-onset myasthenia gravis after starting statin therapy to a neurology specialist – it could be necessary to discontinue statin treatment depending on the assessment of the individual benefits and risks. Likewise, healthcare professionals should advise patients with pre-existing myasthenia gravis to be alert to the aggravation of symptoms while taking a statin.
Advice for patients:Patients are informed that many people who take statins do not experience side effects and, where this does happen, these are typically mild – but it is important to read the Patient Information Leaflet that comes with their medicine and talk to a healthcare professional if they are experiencing problems. Patients are also advised not to stop their statin treatment without first discussing this with their doctor. Before taking a statin, inform your doctor if you have a history of myasthenia gravis or ocular myasthenia. Talk to your doctor if you experience weakness in your arms or legs that worsens after periods of activity, double vision or drooping of your eyelids, difficulty swallowing, or shortness of breath. Seek medical help immediately if you develop severe breathing or swallowing problems.
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 the 4th meeting of the Pharmacovigilance Risk Assessment Expert Committee.
·         Statins: very infrequent reports of myasthenia gravis report of MHRA-UK.
· Product Information safety updates – October 2023 of TGA- Australia.

Schedule of Meetings of Clinical Studies Committee (CSC) for the Year 2024

The Clinical Studies Committee (CSC) of Drug Regulatory Authority of Pakistan (DRAP) is mandated under Bio Study Rules 2017 for the regulatory oversight of clinical trials and clinical studies related to therapeutic goods in the country. The CSC reviews and approves clinical study protocols, ensuring they adhere to ethical and scientific standards. It also monitors ongoing clinical trials to assess participant safety and efficacy, makes informed decisions regarding study design, and collaborates with researchers, sponsors, and other stakeholders to ensure quality clinical research and safety of the participants.

The Committee has decided that the CSC meetings will be convened after every 45 days and an annual CSC meeting schedule for 2024 (tentative) has been issued with the aims to enhance transparency, efficiency, and collaboration.

S. No.CSC MeetingProposed Dates
0149th CSC Meeting2nd week of May, 2024
0250th CSC Meeting4th week of June, 2024
0351st CSC Meeting2nd week of August, 2024
0452nd CSC Meeting4th week of September, 2024
0553rd CSC Meeting2nd week of November 2024
0654th CSC Meeting4th week of December, 2024

Change in Manufacturing Unit of M/s Sois Life Sciences to Site at G-77. S.I.T.E. Super Highway, Phase-II, Karachi.

The Enlistment Evaluation Committee (EEC) in 120th meeting has considered the request of M/s Sois Life Sciences for change in manufacturing facility for their products from A-84, SITE, Super Highway, Phase-I, Karachi to their manufacturing site situated at G-77, S.I.T.E, Super Highway, Phase-II, Karachi. The EEC acceded the request of the firm and revoked the Enlistment Certificate No 01304.

Henceforth, all the product of M/s Sios Sois Life Sciences will be manufactured G-77, S.I.T.E, Super Highway, Phase-II, Karachi viz-a-viz Enlistment No. 0090. Therefore, manufacturing of Alternative medicines and health products by M/s Sois Life Sciences at A-84, S.I.T.E, Super Highway, Phase-I is prohibited and punishable offence under Rule 11 of the SRO 412 (I) /2014 read with Schedule II and III of the DRAP Act, 2012. Accordingly Notifications have been issued for strict compliance.