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

Asad Ullah Safety Alerts

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.
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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.

Asad Ullah Safety Alerts

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

Asad Ullah Safety Alerts

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

Asad Ullah Safety Alerts

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

Asad Ullah Safety Alerts

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

Asad Ullah Safety Alerts

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

Asad Ullah Safety Alerts

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.
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Drug Safety Alert: Risk of Ocular Adverse Events with Miltefosine

Asad Ullah Safety Alerts

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.
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Drug Safety Alert: Risk of Serious Renal and Gastrointestinal Harms with Codeine plus Ibuprofen Drug Combination.

Asad Ullah Safety Alerts

Drug Safety Alert

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

Date:20 October, 2023
Target Audience:·         Manufacturers and importers of drug combinations containing codeine with ibuprofen;
·         Healthcare professionals; and
·         Patients, consumers or caregivers.
Background:The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) in September 2022 recommended a change to the product information for codeine with ibuprofen combination medicines to include a warning of serious harms, including death, particularly when taken for prolonged periods at higher than recommended doses.
The PRAC reviewed several cases of renal, gastrointestinal and metabolic toxicities that have been reported in association with cases of abuse of and dependence on codeine with ibuprofen combinations, some of which have been fatal. The PRAC found that, when taken at higher than recommended doses or for a prolonged period of time, codeine with ibuprofen can cause damage to the kidneys, preventing them from removing acids properly from the blood into the urine (renal tubular acidosis). Kidney malfunction can also cause hypokalaemia, which in turn may cause symptoms such as muscle weakness and light-headedness. Therefore, renal tubular acidosis and hypokalaemia will be added to the product information as new adverse effects. The PRAC noted that medicines containing a combination of codeine and ibuprofen are authorized at the national level and in some countries these medicines are available without medical prescription. The PRAC considered that prescription-only medicine status would be the most effective risk minimization measure to mitigate the harm associated with abuse and dependence of these products.
Therapeutic Good(s) Affected:Codeine with ibuprofen is a combination of opioid (codeine) and anti-inflammatory (ibuprofen), which is used to treat pain. Repeated use of codeine with ibuprofen may lead to dependence and abuse due to the codeine component.
Action in PakistanThe case was discussed in the 3rd meeting of PRAEC, held on the 8th of September, 2023, which decided as per Rule 10(1)(h)(iv) of Pharmacovigilance Rules, 2022 that registration holders of Codeine with Ibuprofen combination should include information about serious harms (renal, gastrointestinal and metabolic toxicities) including death, particularly when taken for prolonged periods at higher than recommended doses in the warning and precaution section, and to add renal tubular acidosis and hypokalemia as adverse drug reactions in the prescribing information/ label of codeine with ibuprofen combination.
 
Advice for healthcare professionals:Healthcare professionals are informed that severe hypokalemia and renal tubular acidosis have been reported due to prolonged use of ibuprofen at higher-than-recommended doses. This risk is
 
increased with the use of codeine/ibuprofen as patients may become dependent on the codeine component. Presenting signs and symptoms included a reduced level of consciousness and generalized weakness. Ibuprofen-induced renal tubular acidosis should be considered in patients with unexplained hypokalemia and metabolic acidosis.
Advice for patients:Medicine containing codeine with ibuprofen should be used for the duration as recommended by doctors as it may lead to dependence, abuse and addiction, which may result in a life-threatening overdose. If you are taking for longer than the recommended time or at higher than recommended doses you are at risk of serious harm. These include serious harm to the stomach/gut and kidneys, as well as very low levels of potassium in your blood. These can be fatal.
If you experience any of the following signs whilst taking these medicines talk to your doctor or
pharmacist as it could be an indication that you are dependent or addicted.
•      You need to take this medicine for longer than advised
•      You need to take more than the recommended dose
•      You are using this medicine for reasons other than medical reasons, for instance, ‘to stay calm’ or to ‘help you sleep’
•      You have made repeated, unsuccessful attempts to quit or control the use of this medicine
•      When you stop taking this medicine you feel unwell, and you feel better once you take this medicine again (‘withdrawal effects’)
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 3rd meeting of Pharmacovigilance Risk Assessment Expert Committee.
·         EMA-Europe: Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 26-29 September 2022.
·    EMA-Europe: New product information wording – Extracts from PRAC recommendations on signals
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Drug Safety Alert: Risk of Respiratory Failure and Sepsis with Terlipressin.

Asad Ullah Safety Alerts

Drug Safety Alert

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

Date:20 October, 2023
Target Audience:·         Manufacturers and importers of terlipressin products
·         Healthcare professionals; and
·         Patients, consumers or caregivers.
Background:The Medicines and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom (UK) in March 2023 announced that the Pharmacovigilance Expert Advisory Group of the UK’s Commission on Human Medicines agreed with the recommendations made as a result of EMA’s review which was triggered by the CONFIRM trial findings that new measures were required to reduce the risk of respiratory failure and sepsis when terlipressin is used in patients with type 1 hepatorenal syndrome. The clinical trial found that in patients with type 1 hepatorenal syndrome, terlipressin may cause serious or fatal respiratory failure at a frequency higher than previously known and that terlipressin increases the risk of sepsis and septic shock.
 
Previously, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) in September 2022 recommended new measures to reduce the risk of respiratory failure and sepsis when using terlipressin in people with type 1 hepatorenal syndrome (HRS-1), which is a serious kidney problem in people with advanced liver disease. The recommendations follow the PRAC’s review of available data, including results from the CONFIRM clinical trial that included patients with HRS-1. Results of the trial suggested that patients who were treated with terlipressin were more likely to experience and die from respiratory disorders within 90 days after the first dose than those who were given a placebo. Although respiratory failure is a known adverse effect of terlipressin, the frequency of respiratory failure seen in the study was higher (11%) than previously reported in the product information. In addition, the study reported sepsis in 7% of patients in the terlipressin arm compared with none in the placebo group. The new measures include adding a warning to avoid terlipressin in patients with advanced acute-on-  
 
chronic liver disease or advanced kidney failure, to the product information along with necessary recommendations to the patient. The PRAC recommendations were sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) which endorsed them and adopted its position on 10 November 2022. Furthermore, the label of Terlipressin  (TERLIVAZ)- US-FDA also contains a Boxed Warning about respiratory failure.
Therapeutic Good(s) Affected:Terlipressin is a synthetic pituitary hormone indicated for the treatment of bleeding from dilated veins in the food pipe leading to the stomach (bleeding oesophageal varices) and for emergency treatment of type 1 hepatorenal syndrome (rapidly progressive renal failure in patients with liver cirrhosis (scarring of the liver) and ascites (fluid accumulation in the abdomen)). The advice is not relevant to the use of terlipressin for bleeding oesophageal varices.
Action in PakistanThe case was discussed in the 3rd meeting of PRAEC, held on the 8th of September, 2023, which
decided as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 registration holders should include information about strict monitoring of respiratory failure and sepsis when using terlipressin in people with type 1 hepatorenal syndrome (HRS-1) in the warning and precaution section. Adding a warning to avoid terlipressin in patients with advanced acute-on-chronic liver disease or advanced kidney failure and information that patients with breathing problems should receive treatment to manage their condition before starting terlipressin-containing medicines in the prescribing information/ label of terlipressin when used in people with type 1 hepatorenal syndrome (HRS-1). Furthermore, registration holders were also advised to create a boxed warning regarding this risk.
Advice for healthcare professionals:Healthcare professionals were advised to consider the individual benefits and risks for patients with type 1 hepatorenal syndrome when initiating terlipressin treatment, especially for those with severe renal or hepatic impairment and monitor all patients closely during terlipressin treatment. The advice is not relevant to the use of terlipressin for bleeding oesophageal varices. Patients with breathing problems should receive treatment to manage their condition before starting terlipressin. During and after treatment, patients should be monitored for signs and symptoms of respiratory failure and infection. In addition, healthcare professionals can consider giving terlipressin-containing medicines as a continuous infusion (drip) into the vein as an alternative to giving it by bolus injection (full dose injected in one go) as this may reduce the risk of severe side effects.
Advice for patients:Patients are informed that a higher than previously known risk of respiratory failure (severe breathing difficulty that may be life-threatening) has been reported when using terlipressin-containing medicines for the treatment of type 1 hepatorenal syndrome (HRS-1) (kidney problems in people with advanced liver disease). In addition, a new risk of sepsis (when bacteria and their toxins circulate in the blood leading to organ damage) has also been identified when terlipressin is used for treating this disease. Patients who have any questions or concerns should speak to their healthcare professionals.
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 3rd meeting of Pharmacovigilance Risk Assessment Expert Committee.
·         MHRA-UK: Terlipressin: new recommendations to reduce risks of respiratory failure and septic shock in patients with type 1 hepatorenal syndrome.
·         EMA-Europe: New recommendations for terlipressin-containing medicines in the treatment of hepatorenal syndrome
EMA-Europe: Terlipressin-containing medicinal products indicated in the treatment of hepatorenal syndrome
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