Safety Communication – Page 2 – Drug Regulatory Authority of Pakistan

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

Asad Ullah Safety Alerts May 7, 2024May 22, 2024

Drug Safety Alert

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

Date:	27^th 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 27-30^th 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 Pakistan	The case was discussed in the 4^th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26^th 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 4^th 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 May 7, 2024May 22, 2024

Drug Safety Alert

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

Date:	27^th 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 Pakistan	The case was discussed in the 4^th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26^th 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 4^th 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 3-6^th May 2021 meeting.

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

Asad Ullah Safety Alerts May 7, 2024May 22, 2024

Drug Safety Alert

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

Date:	27^th 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 Pakistan	The case was discussed in the 4^th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26^th 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 4^th 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 April 25, 2024April 26, 2024

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 Pakistan	The case was discussed in the 4^th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26^th 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 4^th 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 April 24, 2024April 26, 2024

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 Pakistan	The case was discussed in the 4^th meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the DRAP held on 26^th 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 4^th 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 April 24, 2024April 26, 2024

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 12^th 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 Pakistan	The 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 4^th 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 October 26, 2023October 26, 2023

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 Pakistan	The case was discussed in the 3^rd meeting of PRAEC, held on the 8^th 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 October 26, 2023October 26, 2023

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 Pakistan	The case was discussed in the 3^rd meeting of PRAEC, held on the 8^th 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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Drug Safety Alert: Risk of Tendon Disorders with Third-Generation Aromatase inhibitors

Asad Ullah Safety Alerts October 26, 2023October 26, 2023

Drug Safety Alert

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

Date:	20 October, 2023
Target Audience:	· Manufacturers and importers of third-generation aromatase inhibitors (anastrozole, exemestane and letrozole); · Healthcare professionals; and · Patients, consumers or caregivers.
Background:	Health Canada in January, 2023 announced that the product safety information for third-generation aromatase inhibitors (anastrozole, exemestane and letrozole) will be updated to include the risk of tendon disorders. The review was triggered by an update including the risks of tendonitis and tendon rupture by the EMA to letrozole product safety information. It was informed that Health Canada is working with the manufacturers of third-generation aromatase inhibitors to update the Candian Product Monographs to include these risks. Tendon disorders include tendon inflammation (tendonitis), inflammation of the tendon sheath (tenosynovitis) and tendon tears (tendon rupture). Health Canada reviewed reports of events of tendonitis and tenosynovitis and their potential relation to tendon rupture in five randomized controlled trials (RCTs). The agency also reviewed 25 case reports (2 domestic and 23 international) of tendon rupture (10 cases) and tendonitis (15 cases), where a link between the risk of tendon rupture and tendonitis with the use of a third-generation aromatase inhibitor could not be ruled out. However, these case reports included other medications and/or conditions that could have contributed to the reported adverse events. The review concluded that there is likely a link between the use of third-generation aromatase inhibitors and the risks of tendonitis and tenosynovitis. Also, a link with tendon rupture could not be ruled out.
Therapeutic Good(s) Affected:	Third-generation aromatase inhibitors (anastrozole, exemestane and letrozole) are prescription drugs authorized for the treatment of breast cancer in women who have reached menopause (post-menopausal breast cancer).
Action in Pakistan	The case was discussed in the 3^rd meeting of PRAEC, held on the 8^th of September, 2023, which decided as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 that registration holders of third-generation aromatase inhibitors (anastrozole, exemestane and letrozole) should update their prescribing information by including information about tendon disorders (tendonitis, tendon rupture and tenosynovitis etc.) in the warning and precaution section and list these in adverse drugs reaction section.
Advice for healthcare professionals:	The use of third-generation aromatase inhibitors was found to be associated with tendonitis and tenosynovitis as reported in randomized controlled trials. Tendon rupture was found to be a potential risk. Tendonitis and tenosynovitis were estimated to be of uncommon occurrence, and tendon rupture was of rare occurrence. Treating physicians should monitor patients for these adverse drug reactions.
Advice for patients:	Patients are advised to promptly notify their healthcare professional if they experience symptoms such as pain, swelling and difficulty moving their joints while they are on treatment with third-generation aromatase inhibitors (anastrozole, exemestane and letrozole).
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. ·Health Canada: Summary Safety Review – Third Generation Aromatase Inhibitors (anastrozole, exemestane, letrozole) – ·Assessing the Potential Risk of Tendon Disorders.

Drug Safety Alert: Risk of Seizures with Cephalosporins

Asad Ullah Safety Alerts October 26, 2023October 27, 2023

Drug Safety Alert

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

Date:	20 October, 2023
Target Audience:	· Manufacturers and importers of Fluorouracil and Capecitabine; · Healthcare professionals; and · Patients, consumers or caregivers.
Background:	Health Canada in January, 2023 announced that the product safety information for cephalosporins will be updated to include the risk of seizures in all the cephalosporins. As the risk of seizures was already included for some cephalosporins, this update was applied to cephalosporins that did not include the risk. The review was triggered by a US Food and Drug Administration update to the product safety information for cefazolin to include the risk of seizures. Accordingly, Health Canada reviewed the available information from searches of the Canada Vigilance database, international databases, as well as medical and scientific literature. Health Canada reviewed 84 cases (7 domestic and 77 international) of seizures in patients taking cephalosporins. Of the 84 cases, 13 cases (all international) were found to be probably linked to the use of cephalosporins, and 62 cases (4 domestic and 58 international) were found to be possibly linked. Three cases (all international) were unlikely to be linked to the use of cephalosporins. Six cases (3 domestic and 3 international) could not be assessed. The review concluded that there may be a link between the use of cephalosporins and the risk of seizures and therefore the agency informed that it would work with manufacturers to update the Canadian Product Monographs for the cephalosporins that did not already include the risk. The New Zealand Medicines and Medical Devices Safety Authority (Medsafe) in its publication dated 2nd March, 2023 informed that the risk of neurotoxicity with cephalosporins was discussed at the December 2022 Medicines Adverse Reaction Committee (MARC) meeting wherein the committee recommended that all cephalosporin data sheets should include consistent messaging on the risk of neurotoxicity. Cephalosporin-induced neurotoxicity may present in a range of conditions which are mainly characterized by encephalopathy, myoclonus and/or seizures. Seizures associated with cephalosporins may present as either convulsive or non-convulsive. Symptoms of neurotoxicity have been reported to develop within several days after starting treatment and to resolve following discontinuation. In patients with renal impairment, accumulation can occur, especially when doses are not adjusted appropriately, potentially leading to toxic effects. Additional risk factors for cephalosporin-induced neurotoxicity include older age groups, underlying central nervous system (CNS) disorders and high doses of cephalosporins administered by intravenous injection.
Therapeutic Good(s) Affected:	Cephalosporins are a group of prescription antibiotic medicines (cephalexin, cefazolin, cefadroxil, cefuroxime, cefprozil, cefotaxime, ceftazidime, ceftriaxone, cefixime and cefepime) and are indicated for the treatment of a wide range of bacterial infections including urinary and respiratory tract infections.
Action in Pakistan	The case was discussed in the 3^rd meeting of PRAEC, held on the 8^th of September, 2023, which decided as per Rule 10(1)(h)(iv) of the Pharmacovigilance Rules, 2022 that the registration holders of all cephalosporins should include information on the risk of seizures/ neurotoxicity in the warning and precaution section and also list in adverse drug reaction section in the prescribing information/label of all cephalosporins.
Advice for healthcare professionals:	Seizures may occur with the administration of Cefazolin for Injection, particularly in patients with renal impairment when the dosage is not reduced appropriately. Additional risk factors for cephalosporin-induced neurotoxicity include older age groups, underlying central nervous system (CNS) disorders and high doses of cephalosporins administered by intravenous injection. Discontinue the cephalosporin antibiotic if seizures occur or make the appropriate dosage adjustments in patients with renal impairment. Anticonvulsant therapy should be continued in patients with known Seizure disorders.
Advice for patients:	Patients are advised to take their antibiotic for the recommended duration and indication and promptly notify their healthcare professional about any signs of seizures/ neurotoxicity they experience.
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. · Health Canada: Summary Safety Review – Cephalosporins – Assessing the Potential Risk of Seizures. · Medsafe-New Zealand: Risk Of Neurotoxicity With Cephalosporins.

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