DRAP issued Guidelines for Public Health Programs (PHPs) to promote Pharmacovigilance activities and enhancing collaboration with National Pharmacovigilance Centre, DRAP.

Drug Regulatory Authority of Pakistan (DRAP) aims at providing a holistic system of Pharmacovigilance in the country. Public Health Programs are key stakeholders involved in the reporting, assessment and risk communication of various un-wanted effects arising after the use of drugs, vaccines and other therapeutic goods. Reporting of Adverse Events associated with the use of therapeutic goods exclusively being used by PHPs is essential to a pharmacovigilance system.

The key objectives of pharmacovigilance activities in public health programs are:-

  1. To improve public health and safety in relation to the use of therapeutic goods in PHPs;
  2. To detect problems related to the use of therapeutic goods and associated risk communication in a timely manner
  3. To encourage the safe, rational and more effective use of therapeutic goods.

This guideline will assist the Public Health Programs (PHPs) for enhancement of pharmacovigilance activities, and provide a guidance on communication channels among PHPs and Pharmacovigilance Centres for collaborative working to synergize activities within the National Pharmacovigilance system of Pakistan.

DRAP published the draft of this guidelines on its website on 23rd April, 2022 inviting the comments of stakeholders on the draft. After through consultation and careful consideration, fist edition of the guidelines on the pharmacovigilance activities in the public health programs are finalized. Nevertheless, anyone can still furnish his/her comments on the guidelines using our comments submissions methods for consideration in the future editions of the document.

Please click to view the document, GUIDELINES ON PHARMACOVIGILANCE FOR PUBLIC HEALTH PROGRAMMES

Rapid Alert: Contaminated Lot of Sorbitol Identified in Karachi

Rapid Alert

DRAP Alert NoNo  II/S/04-24-19
Action Date15th May 2024
Target Audience·         Regulatory Field Force.
·         Therapeutic Goods industry
·         Manufactures of Oral liquid preparations
Problem StatementThe Federal Government Analyst, Central Drugs Laboratory Karachi vide test/analysis report No. RM-2-24-000136 dated 22-03-2024 declared the sample of Sorbitol (Batch 09-LM-023) sent to CDL Karachi by M/s. Herbiotics Healthcare Rawalpindi in compliance to letter vide No. 03-41/2023-QC dated 01-12-2023.

Details of CDL test/analysis report are as under:

Product NameManufacturer as per labelBatch No.Test ResultsLimits
Sorbitol  M/s. Master Sweetener, Karachi09-LM-023Ethylene Glycol: 0.6431% Does not complyEthylene Glycol: NMT 0.1%  
Risk Statement:Ethylene Glycol (EG) contaminated raw materials when used in oral liquid preparations can lead to serious health risks. When ingested, EG is converted into toxic metabolites that can affect the central nervous system and heart. Moreover, it can also cause kidney damage which may lead to fatal consequences.
Action Initiated: –The therapeutic goods manufacturer has been instructed to recall any finished products that were manufactured using the same lot of Sorbitol. The Regulatory Field Force has also been instructed to seize all preparations manufactured using the same batch of Sorbitol if found in the market.
Advice for Therapeutic Goods Manufacturers: –Manufacturers of therapeutic goods are required to follow these instructions:
 
1.      Recall Products: If any batch was manufactured using the same lot of Sorbitol that has been identified as contaminated, all finished products from local and export markets should be recalled.
2.      Hold Other Batches: All finished products manufactured from same lot of sorbitol should be kept on hold. These products should be tested for EG/DEG contamination before releasing them into the supply chain.
3.      Screen Raw Materials: Before using them in the manufacturing of oral liquid preparations, all raw materials should be screened for contamination with EG and DEG.
4.      Compliance: Ensure compliance with all directives issued by DRAP to safeguard public health from contaminated products.
5.      Follow Guidelines: Adhere to the pharmacopoeia monograph and WHO guidelines for testing EG/DEG in oral liquid preparations during the analysis of both raw materials and finished products.
Our utmost priority is public safety. DRAP is committed to supporting the industry in maintaining rigorous quality control and testing procedures to prevent any potential harm caused by contaminated products.
Advice for Healthcare Professionals: –DRAP requests healthcare professionals to stay updated with advisories and recalls. Patients should be educated about the risks and symptoms of DEG/EG toxicity. Close monitoring of patients using the affected products is crucial, and any adverse events should be reported to National or Provincial pharmacovigilance centers.
Adverse reactions 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.  Further information on reporting problems to DRAP is available on this link.

Recall Alert: Drug Product; Novarise 50mg/5ml Syrup by Sharooq Pharmaceuticals, Lahore

Recall Alert

DRAP Alert NoNo I/S/05-24-20
Action Date15th May 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 vide test report No. LHR-1-24-000001 dated 03-04-2024 has declared the Novarise Syrup Batch No. 113 as of substandard quality on the basis of presence of Ethylene Glycol impurity at unacceptable level.

Therapeutic Good(s) Affected: –

Product NamesCompositionBatch No Manufactured by
Novarise 50mg/5mL
Syrup
Iron (iii) Hydroxide
Polymaltose complex
Batch No. 113M/s Sharooq
Pharmaceuticals (Pvt.)
Ltd., Lahore
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.

Report on Availability Status and Supply Disruption of Eye Drops

The Drug Regulatory Authority of Pakistan (DRAP) has received information that certain brands of eye drops are short in supply in the market. The DRAP’s committee has conducted a quick survey of the market and found certain alternative brands available in the market. The main reason behind their short supply is the change of ownership globally from Allergan to AbbVie.

In this regard, Physicians are advised to consider prescribing the available alternative brands to their patients in light of the shortage. Patients should be informed about this during their consultations. Similarly, pharmacists should also communicate the availability of alternative brands to patients or caregivers.

Briefly, the availability status of eye drops reported short along with their alternative brands is presented in the table below:

Sr. No.Name of Drug ProductsManufacturer/ importerStatusReason / Stock positionAlternate brand available
 1Combigan Eye drops (Brimonidine and Timolol)  M/s Barrett HodgsonShort supplyGlobal merger/ acquisition (Change of ownership from Allergan to AbbVie)Brytim Eye Drops (Remington)
Imosol eye Drops (Schazoo)
 2Lumigan Eye drops (Bimatoprost)M/s Barrett HodgsonShort supplyGlobal merger/ acquisition (Change of ownership from Allergan to AbbVie)Allure Eye drops (Sante)
 3Alphagan Eye drops (Brimonidine tartrate)M/s Barrett HodgsonShort supplyGlobal merger/ acquisition (Change of ownership from Allergan to AbbVie)Brimodine Eye drops (Sante)
Brimod eye drops (Remington)
 4Cosopt eye drops (Dorzolamide and Timolol)M/s OBS PakistanShort SupplyStock of 30,000 packs is in transit.Co-Dorzol eye drops (Sante)
Co-Dorz eye drops (Ethical)

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.