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.

Recall Alert; Drug Products: Mebzole 100mg/5mL Suspension and Bioris 1mg/ml Oral Solution by M/s Biolabs Pvt., Ltd., Islamabad

Recall Alert

DRAP Alert NoNo I/S/04-24-18
Action Date29th April 2024
Target Audience– National Regulatory Field Force.
– Pharmacists and Chemists at Distribution, Pharmacies and Medical Stores
– Healthcare Professionals- Physicians, Pharmacists, and Nurses at hospital and clinics
– General Public
Problem / Issue The Federal Government Analyst, CDL Karachi has declared the following batches of oral liquid preparations manufactured by M/s Biolab Pvt Ltd, Islamabad as of “Sub-standard” quality based on the presence of Ethylene Glycol impurity at an unacceptable level.

Therapeutic Good(s) Affected: –

Product NamesCompositionBatch No Manufactured by
Mebzole 100mg/5mL Suspension
 
Reg No. 046308
MebendazoleBatch No. 22J022(F), 22J022(B)

Mfg. Date: 09-22
Exp. date: 08-24
M/s. Biolabs
(Private.) Limited.,
Islamabad.
Bioris 1mg/ml Oral Solution
 
Reg No. 069917
RisperidoneBatch No. 23B061


Mfg. Date: 02-23
Exp. date: 01-25
M/s. Biolabs
(Private.) Limited.,
Islamabad.
Risk Statement:The presence of Ethylene Glycol (EG) in oral liquid preparations poses serious health risks due to its toxicity as small amounts of EG can be fatal, especially for children. When ingested, both diethylene glycol (DEG) and EG are metabolized into toxic compounds that can adversely affect the central nervous system, heart, and kidneys.
Action InitiatedThe manufacturer has been directed to immediately recall the defective batches of affected products from the market. All pharmacists and chemists working at distributions and pharmacies should immediately check their stocks and stop supplying these batches of products.

Distributors and pharmacies are advised to be vigilant and report any suspected batch of the product(s) in the supply chain to the DRAP using the online form, or through phone at +92 51 910 73 17, or by Email at gsmsdra.gov.pk.

Regulatory field force of all federating units (DRAP, Provincial Health Departments, and States) has also increased the surveillance in the market to ensure the effective recall of defective product(s).
Advice for Healthcare ProfessionalsDRAP requests to enhance vigilance within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by this defective batch of the product.  

-Adverse reactions or quality problems experienced with this product may be reported to the National Pharmacovigilance Centre(NPC), DRAP using the
Adverse Event Reporting Form or online through this link.

-Please click here for further information on problem reporting to DRAP.
Advice for Consumers-Consumers should stop using these product bearing the affected batch number(s). They shall contact their physician or healthcare provider(s) if they have experienced any problem that may be related to using this product.

-All therapeutic products must be obtained from authorized licensed pharmacies /outlets. Their authenticity and condition should be carefully checked. If you have any doubts, please seek advice from your pharmacist.

Recall Alert; 03 Batches of Veterinary Drug Products by M/s Biolabs Pvt., Ltd., Islamabad

Recall Alert

DRAP Alert NoNo I/S/04-24-16
Action Date28th April 2024
Target Audience– National Regulatory Field Force. 
– Points of sale and distributors of veterinary medicine. 
– Veterinary Doctors and professionals. 
– General Public 
Problem / Issue The Federal Government Analyst, CDL Karachi has declared has declared the following 03 batches of veterinary drug products, manufactured by M/s. Biolabs (Private) Limited, Islamabad as “Adulterated” based on the presence of unaccepted level of Ethylene Glycol and Diethylene Glycol impurities.

Therapeutic Good(s) Affected: –

Product NamesCompositionBatch No Remarks 
Clo-Animectin Injection 
 
Reg No.095618
Clorsulon 100mg/ml 
Ivermectin 10mg/ml 
Batch No. 009A24 
 
Mfg. Date: 01-24 
Exp. date: 12-25 
Sample is “Adulterated” due to presence of: 
Ethylene Glycol: 14.36% 
Diethylene Glycol: 2.92% 
Bio-Oxicam 0.75% Injection 

Reg No.088836
Meloxicam 7.5mg/ml Batch No. 083C23 
 
Mfg. Date: 03-23 
Exp. date: 02-25 
Sample is “Adulterated” due to presence of
Ethylene Glycol: 24.19% 
Bio-E-Floxacin 10% Injection 

Reg No.088834
Enrofloxacin 100mg/ml Batch No. 047K22 
 
Mfg. Date: 10-22 
Exp. date: 09-24 
Sample is “Adulterated” due to presence of 
Ethylene Glycol: 12.08% 
Risk Statement:EG (Ethylene Glycol) is a toxic substance that can have serious adverse effects. EG is metabolized into toxic metabolites that can affect the central nervous system, and heart, and can cause kidney damage, which can be fatal. Although, there is no available data on the systemic absorption of injected EG, and no instances of human or animal toxicity from injection of EG have been reported in the literature.
Action InitiatedThe manufacturer has been directed to immediately recall the defected batch of product from the market. All personnel working at distributions and point of sales of veterinary medicine should immediately check their stocks and stop supplying this batch of product. The remaining stock should be quarantined and returned to the supplier/ company. Regulatory field force of all federating units (DRAP and Provincial Health Departments) should also increase surveillance in the market to ensure the effective recall of defective products(s). 

Distributors and pharmacies are advised to be vigilant and report any suspected batch of the product(s) in the supply chain to the DRAP using the online form, or through phone at +92 51 910 73 17, or by Email at gsmsdra.gov.pk.

Regulatory field force of all federating units (DRAP, Provincial Health Departments, and States) has also increased the surveillance in the market to ensure the effective recall of defective product(s).
Advice for Veterinary ProfessionalsDRAP requests to enhance vigilance within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by this defective batch of the product.  

Recall Alert; Drug Products: Artecid 75mg/3mL Injections by M/s Biolabs Pvt., Ltd., Islamabad

Recall Alert

DRAP Alert NoNo I/S/04-24-17
Action Date28th April 2024
Target Audience– National Regulatory Field Force.
– Pharmacists and Chemists at Distribution, Pharmacies and Medical Stores
– Healthcare Professionals- Physicians, Pharmacists, and Nurses at hospital and clinics
– General Public
Problem / Issue The Federal Government Analyst, CDL Karachi has declared the batch number “23E018” of Artecid 75mg/3mL Injection, manufactured by M/s. Biolabs (Private) Limited, Islamabad as “Adulterated” based on the presence of unaccepted level of Ethylene Glycol impurity.

Therapeutic Good(s) Affected: –

Product NamesCompositionBatch No Manufactured by
Artecid 75mg/3mL Injections
 
Reg No.075186
Diclofenac SodiumBatch No.  23E018
 
Mfg Dt: 05-2023
Exp.Dt: 04-2025
M/s. Biolabs
(Private.) Limited.,
Islamabad.
Risk Statement:EG (Ethylene Glycol) is a toxic substance that can have serious adverse effects. EG is metabolized into toxic metabolites that can affect the central nervous system, and heart, and can cause kidney damage, which can be fatal. Although, there is no available data on the systemic absorption of injected EG, and no instances of human or animal toxicity from injection of EG have been reported in the literature.
Action InitiatedThe manufacturer has been directed to immediately recall the defective batch of product from the market. All pharmacists and chemists working at distributions and pharmacies should immediately check their stocks and stop supplying this batch of product. The remaining stock should be quarantined and returned to the supplier/ company. The regulatory field force of all federating units (DRAP and Provincial Health Departments) should also increase surveillance in the market to ensure the effective recall of defective products(s). 

Distributors and pharmacies are advised to be vigilant and report any suspected batch of the product(s) in the supply chain to the DRAP using the online form, or through phone at +92 51 910 73 17, or by Email at gsmsdra.gov.pk.

Regulatory field force of all federating units (DRAP, Provincial Health Departments, and States) has also increased the surveillance in the market to ensure the effective recall of defective product(s).
Advice for Healthcare ProfessionalsDRAP requests to enhance vigilance within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by this defective batch of the product.  

-Adverse reactions or quality problems experienced with this product may be reported to the National Pharmacovigilance Centre(NPC), DRAP using the
Adverse Event Reporting Form or online through this link.

-Please click here for further information on problem reporting to DRAP.
Advice for Consumers-Consumers should stop using this product bearing the affected batch number(s). They shall contact their physician or healthcare provider(s) if they have experienced any problem that may be related to using this product.

-All therapeutic products must be obtained from authorized licensed pharmacies /outlets. Their authenticity and condition should be carefully checked. If you have any doubts, please seek advice from your pharmacist.

Drug Safety Alert: Risk of Neurodevelopmental Disorders in Children during Pregnancy with Topirmate

Drug Safety Alert

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

Date:24th April 2024
Target Audience:·         Manufacturers and importers of Topiramate;
·         Healthcare professionals; and
·         Patients, consumers or caregivers.
Background:The Medsafe of Newzealand in April, 2023 has announced that the product information for topiramate (Topamax®) is updated to include the risk of neurodevelopmental disorders and birth defects in children whose mothers were taking topiramate during pregnancy. The risk of neurodevelopmental disorders was noted in an observational study based on data from five Nordic (Denmark, Finland, Iceland, Norway, and Sweden) pregnancy registries. The registries captured information from over 24,000 children exposed to at least one antiepileptic medicine before birth. Of these children, 471 were exposed to topiramate alone. The authors reported a 2.77-fold increase in the risk of autism spectrum disorder and a 3.47-fold increase in the risk of intellectual disability in children with an epileptic mother taking topiramate during pregnancy compared to those who are not taking any antiepileptic treatment during pregnancy.
The TGA, Australia in its product information safety update of June, 2023 has also announced that the product information for topiramate (Topamax®) is updated to include the risk of foetal neurodevelopment disorder, updated warning about women of childbearing potential, and contraindications in pregnancy and women of childbearing potential for migraine prophylaxis.
The European Medicine Agency (EMA) in July, 2023 started a review to assess new data on a potential risk of neurodevelopmental disorders in children who have been exposed to topiramate during pregnancy. At that time, a study based on data from a Nordic registry that investigated the risk of neurodevelopmental disorders associated with several anti-epileptic drugs, including topiramate was published. The study conclusions suggested a possible increase in the risk of autism spectrum disorders, intellectual disability and child neurodevelopmental disorders with the exposure to topiramate during pregnancy. The PRAC decided at that time that further
 
assessment was warranted to determine the scope and the best regulatory procedure to assess these potential risks.
Accordingly, the Pharmacovigilance Risk Assessment Committee (PRAC) (EMA’s safety committee) in September, 2023 introduced further restrictions i.e. pregnancy prevention programme on the use of topiramate to be put in place. At present, topiramate must not be used to prevent migraine or manage body weight during pregnancy and patients who can become pregnant must use effective birth control when using topiramate. For patients using topiramate for the treatment of epilepsy, the PRAC is now recommending that the medicine should not be used during pregnancy unless there is no other suitable treatment available. The PRAC also recommends additional measures, in the form of a pregnancy prevention programme, to avoid exposure of children to topiramate in the womb. These measures will inform any woman or girl who is able to have children about the risks of taking topiramate during pregnancy and the need to avoid becoming pregnant while taking topiramate. The product information for topiramate-containing medicines will be updated to further highlight the risks and the measures to be taken. A visible warning will also be added to the outer packaging of the medicine. Patients and healthcare professionals will be provided with educational materials regarding the risks of using topiramate during pregnancy, and a patient card will be provided to the patient with each medicine package. The PRAC recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralized Procedures for Human (CMDH), which on 11 October 2023 endorsed new measures recommended by EMA’s safety committee (PRAC). The CMDh has also agreed to additional measures, in the form of a pregnancy prevention programme, to avoid exposure of children to topiramate in the womb.
Therapeutic Good(s) Affected:Topiramate is a medicine used to treat epilepsy in adults and children aged two years and older. It is also indicated in adults for the prevention of migraines. At present, topiramate must not be used to prevent migraine or manage body weight during pregnancy and patients who can become pregnant must use effective birth control when using topiramate.
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 should update the prescribing information of Topiramate to include the risk of foetal neurodevelopment disorder and warning about women of childbearing potential, and also include information about not using the Topiramate in pregnancy for the treatment of epilepsy unless there is no other suitable treatment available. Furthermore, registration holders were also directed as per Rule 10 (1) (h) (ii) of Pharmacovigilance Rules, 2022 to update contraindications in pregnancy and women of childbearing potential for migraine prophylaxis.
Advice for healthcare professionals:Healthcare professionals are advised that topiramate should only be used to treat epilepsy in pregnancy if the potential benefit justifies/outweighs the potential risk to the mother and fetus. Pregnancy testing should be performed before starting treatment, and women of childbearing potential should use a highly effective contraceptive method during treatment. The use of topiramate for migraine prophylaxis is contraindicated in pregnancy. Inform women of childbearing potential about the risks of fetal harm if they become pregnant and refer epileptic women taking topiramate who become or plan to become pregnant for specialist advice.
Advice for patients:Patients are advised not to stop taking topiramate without first talking to their doctor. Topiramate can harm the way an unborn baby grows and develops during pregnancy. Anyone who is able to get pregnant should use effective contraception while taking topiramate. Therefore, those patients are advised to speak with their doctor if they are pregnant or planning to become pregnant whilst taking taking topiramate.
Guidelines for reporting Adverse Drug Reactions (ADRs):Both healthcare professionals and patients are requested to report any suspected Adverse Drug Reaction (ADR) to the 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 4th meeting of Pharmacovigilance Risk Assessment Expert Committee, DRAP.
·         Therapeutic Goods Administration of Australia Safety Updates June 2023.
·         PRAC-EMA recommendation regarding new measures to avoid topiramate exposure in pregnancy.
·  MedSafe Newzealand-Topiramate use in pregnancy: further restrictions for safety.

Drug Safety Alert: Risk of Rare and Serious Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with Levetiracetam and Clobazam

Drug Safety Alert

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

Date:24th April 2024
Target Audience:·         Manufacturers and importers of drug combinations containing Levetiracetam and Clobazam
·         Healthcare professionals; and
·         Patients, consumers or caregivers.
Background:The United States Food and Drug Administration (US-FDA) in November 2023 through a drug safety communication warned that the antiseizure medicines levetiracetam and clobazam can cause a rare but serious reaction that can be life-threatening if not diagnosed and treated quickly. This reaction is called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) which may start as a rash but can quickly progress, resulting in injury to internal organs, the need for hospitalization, and even death. This hypersensitivity reaction to these medicines is serious but rare. DRESS can include fever, rash, swollen lymph nodes, or injury to organs including the liver, kidneys, lungs, heart, or pancreas. The US FDA accordingly decided to add new warnings about DRESS to the prescribing information and the medication guide of levetiracetam and clobazam for patients and caregivers. It was informed that the warnings for both levetiracetam and clobazam medicines would include information that “early symptoms of DRESS such as fever or swollen lymph nodes can be present even when a rash cannot be seen. This is different from other serious skin-related reactions that can happen with these medicines and where a rash is present early on, including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).”
Therapeutic Good(s) Affected:Levetiracetam is an antiseizure medicine indicated for use alone or together with other medicines to control certain types of seizures in adults and children such as partial seizures, myoclonic seizures, or tonic-clonic seizures. 

Clobazam is a benzodiazepine indicated for use in combination with other medicines to control seizures in adults and children 2 years and older who have a specific severe form of epilepsy called Lennox-Gastaut syndrome).
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 as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 that registration holders should include information about rare and serious DRESS reactions in warning and precaution sections of the prescribing information/label of medicines containing levetiracetam and clobazam.
Advice for healthcare professionals:Healthcare professionals are informed that levetiracetam and clobazam have been linked to a rare, potentially life-threatening reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), occurring 2-8 weeks post-treatment. This may lead to severe inflammation and organ damage, requiring prompt medical attention. Prescribers should inform patients, explain DRESS signs, and advise seeking immediate care. DRESS involves cutaneous reactions, eosinophilia, fever, and systemic complications. Early recognition, discontinuation, and supportive care are crucial.
Advice for patients:Patents are informed that levetiracetam and clobazam, prescribed for seizures, can trigger a rare but severe reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). This immune system response may cause widespread inflammation and organ damage, leading to hospitalisation or death if untreated. Patients are advised not to stop the medication abruptly and; to consult their healthcare professionals if necessary. DRESS symptoms, such as fever, rash, and organ-related issues, may occur 2 to 8 weeks after starting treatment. Seek immediate medical attention for concerning symptoms.
Guidelines for reporting Adverse Drug Reactions (ADRs):Both healthcare professionals and patients are requested to report any suspected Adverse Drug Reaction (ADR) to the 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 4th meeting of Pharmacovigilance Risk Assessment Expert Committee, DRAP.
· US-FDA Drug Safety Communication regarding Levetiracetam and Clobazam.

Drug Safety Alert: Risk of Ocular Adverse Events with Miltefosine

Drug Safety Alert

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

Date:24th April 2024
Target Audience:·         Manufacturers and importers of Miltefosine;
·         Healthcare professionals; and
·         Patients, consumers or caregivers.
Background:The World Health Organization (WHO) through its medical product alert dated 12th April 2023 informed healthcare professionals and regulatory authorities about the risk of ocular adverse events in people who have taken miltefosine and provided advice on measures to minimize this risk in patients exposed to miltefosine. Following reports of ocular disorders following miltefosine use originating mostly from South Asia, the WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) recommended the WHO to investigate this issue further. The proposed method was discussed in June 2022 and WHO established an ad-hoc Multidisciplinary Technical Group (MTG) to advise on the causality, the risk characteristics and frequency, risk minimisation measures, risk communication, remaining uncertainties and the need for further studies. The MTG was also supported by the WHO, the German National Regulatory Authority (BfArM) and the Uppsala Monitoring Centre (UMC).

Based on the available data, the MTG considered that a causal relationship between ocular adverse events and exposure to miltefosine is at least a reasonable possibility. The risk of ocular adverse events, such as redness of the eye, inflammation of different eye structures (keratitis, scleritis, uveitis) and visual impairment up to blindness has been observed mostly during the treatment of patients with Post-Kala-Azar Dermal Leishmaniasis (PKDL) in South Asia in both men and women, including in children under 18 years old, and mostly beyond 28 days of treatment. No further risk factors could be identified. When the information was available, most of the cases were resolved after miltefosine was withdrawn, sometimes after a symptomatic treatment was started. However, in some cases, the adverse ocular event led to permanent loss of sight. The frequency of adverse ocular events during treatment with miltefosine could not be estimated based on the available data, and the mechanism of action remains unclear.
 
Previously, the ACSoMP discussed during its meeting on 14th of December 2022 the issue of ocular adverse events with miltefosine and inter-alia advised the inclusion of the proposed warning and list of ocular adverse events in the summary of product characteristics and the patient information leaflet for miltefosine along with the issuance of Direct Healthcare Professional Communication by National regulatory authorities.

Post-Kala-Azar Dermal Leishmaniasis (PKDL) is a sequela which can generally occur 6 months to several years after the apparent cure of VL. Although uncommon, leishmanial ocular manifestations have been reported, and keratitis and uveitis can also occur with the disease. A 12-week treatment course of Miltefosine is used to treat PKDL specific to VL endemic countries in Southeast Asia.
Therapeutic Good(s) Affected:Miltefosine is an oral anti-infective and one of the medicines with established efficacy in the treatment of some forms of leishmaniasis, a parasitic infection spread by the bite of infected female phlebotomine sandflies. Leishmaniasis can take different clinical forms, including cutaneous leishmaniasis, mucocutaneous leishmaniasis, and visceral leishmaniasis (VL).
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 should update the prescribing information/ label of Miltefosine-containing medicines by including information in the warning and precaution section about the risk of ocular adverse events and also list these in adverse drug reaction section. As per Rule 10 (1) (b) of Pharmacovigilance Rules, 2022 recommended the National Pharmacovigilance Centre to issue a safety alert/advisory related to the risk of ocular adverse events with Miltefosine-containing medicines.
Advice for healthcare professionals:The following is advised to healthcare professionals:
•    Before starting the miltefosine treatment the history of eye disorders should be collected and an eye examination should be done as appropriate.
•    In case of current or past history of ocular disorder, the benefits and the risks of treating a patient with miltefosine should be carefully considered, and advice from an ophthalmologist should be sought where feasible.
 •    All patients should be informed before starting the treatment that in case of eye problems during the treatment (e.g. red eyes, increased watering, eye pain, blurred vision) they should discontinue miltefosine and contact their healthcare professional immediately.
•    If ocular complications occur and a connection with miltefosine cannot be excluded, miltefosine should be discontinued immediately and an alternative treatment for leishmaniasis should be initiated if necessary. Since miltefosine has a very long half-life (>6 days), it is possible that ocular changes will not be reversible without treatment even after discontinuation of miltefosine. Therefore, an eye specialist should be consulted in such cases to avoid the possibility of permanent damage.
Advice for patients:Patients are advised to consult their doctors if they experience any sort of reaction/problem in their eyes after the start of the miltefosine and also inform healthcare professionals about any pre-existing eye disease.
Guidelines for reporting Adverse Drug Reactions (ADRs):Both healthcare professionals and patients are requested to report any suspected Adverse Drug Reaction (ADR) to the 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 4th meeting of Pharmacovigilance Risk Assessment Expert Committee, DRAP.
·  WHO Advisory Committee on Safety of Medicinal Products (ACSoMP): Measures to minimize the risk of ocular adverse events with miltefosine.

Rapid Alert: Drug Product; Falsified Risek 40mg Injection identified in the Market

Rapid Alert

DRAP Alert NoNo I/S/03-24-15
Action Date26th March 2024
Target Audience·         Regulatory Field Force.
·         Healthcare Professionals – Physicians, Pharmacists, and Nurses.
·         Procurement Managers at Hospitals, Clinics, Pharmacies and other Healthcare Institutions
·         General Public.
Problem StatementThe Federal Inspector of Drugs Karachi identified suspected samples of Risek 40mg Injection co-packed with Sterile Water for Injection from the market and sent them to the Central Drug Laboratory (CDL), Karachi for testing/analysis. The Federal Government Analyst, CDL has declared the sample as falsified/spurious under section 3(z-b) (ii) of the Drugs Act 1976.  The samples were also declared as substandard for not complying with the assay test.

The product identification details are as under: –

Therapeutic Good Affected:-

ProductCompositionBatch DetailsPurported to be Manufactured by
(as per label)
Risek 40mg injection
 
Reg No. 024170
OmeprazoleBatch No.059PA5

Mfg. Date: 11-22
Exp. Date:  05-25
Getz Pharma Pvt Limited Karachi.
(as per label)

During the investigation when the suspected samples were compared with the original product of Getz Pharma, Karachi, significant variations were revealed in various segments of the samples. Please click for details.

Threat to Public HealthSpurious or falsified pharmaceuticals may contain harmful levels of toxic substances, posing a significant risk of widespread poisoning. These substandard medications have the potential to undermine the efficacy of disease treatment and exacerbate preexisting medical conditions.
Action InitiatedThe Regulatory Field Force has been instructed to increase surveillance activities at health facilities (hospitals), as well as markets, and confiscate any falsified products. All pharmacists and chemists working at distributions and pharmacies should immediately check their stock and stop supplying any suspected products that differ from the original. Such stock should be quarantined immediately, and supplier information should be provided to the Regulatory Field Force (DRAP, provincial and state drug control administrations) to ensure the removal of these products.
Advice for Healthcare Professionals-DRAP requests increased vigilance at hospitals and within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by this product.

-Adverse Drug Reactions (ADR) or quality problems experienced with the use of these products shall be reported to the National Pharmacovigilance Centre (NPC), DRAP using Adverse Event Reporting Form or online through this link.

-Please click here for further information on problem reporting to DRAP.
Advice for ConsumersConsumers should stop using this product and shall contact 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 the Drug Regulatory Authority of Pakistan / National Pharmacovigilance Centre

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