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Drug Safety Alert: Risk of Ocular Adverse Events with Miltefosine

Asad Ullah Health Professional Alerts, 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 When the information was available, most of the cases were resolved after miltefosine was withdrawn, sometimes after a symptomatic treatment was started.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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Stakeholder Nominations are invited to a Webinar on GMP for Blood Establishment

Asad Ullah Events

World Health Organization (WHO) has developed a Guidance on Good Manufacturing Practice (GMP) for Blood Establishment to ensure the safety and quality of blood products with the aim to strengthen the technical capacity of National Regulatory Authorities (NRAs) for implementing the appropriate control of blood products. This GMP webinar will explain GMP principles and concepts comprehensively.

Drug Regulatory Authority of Pakistan (DRAP) invites healthcare professionals and stakeholders working in the blood establishments to attend/participate in the World Health Organization (WHO) webinar on “Good Manufacturing Practice (GMP) for Blood Establishment from 7 to 10 May 2024.

     

Decisions of 65th Meeting of Medical Device Board (Deficiency letter for Medical Devices Applications)

Asad Ullah Medical Devices Board, Meeting Minutes

The Medical Device Board (MDB) of the Drug Regulatory Authority of Pakistan in 65th meeting has deferred the following applications of registration/enlistment of medical devices due to various deficiencies/shortcomings in the applications dossiers. These applicants are requested to furnish the requisite information/documentation as directed by the Medical Device Board. The detail is provided in the below attachment.

Defered-Letter-of-65th-Meeting-of-MDBDownload

Combating Substandard and Falsified Products : Public Alert Reporting

Asad Ullah Press Releases

Islamabad, 4th April, 2024 —  The Drug Regulatory Authority of Pakistan (DRAP) is aiming for effective communication and public awareness on combating Substandard and Falsified (SF) products to protect public health; hence the frequency of public alerts is likely to increase, and media communication of key messages represents an important mediator of the behaviour of individuals in response to public health countermeasures. Since culpability is commonly used as a tool to influence public behaviour, it is important to keep the public informed while avoiding panic due to misinformation/disinformation,

In a recent event, DRAP issued an alert No I/S/03-24-15 regarding the presence of falsified Risek 40mg injections in the market. This alert was intended to caution healthcare providers and the public about the presence of counterfeit products in the market and to procure the product from authorized sources only. Unfortunately, some misinterpretations of the alert have led to widespread misinformation.

DRAP is committed to ensuring the safety and well-being of the public and calls for responsible reporting. We are working diligently to remove the falsified products from the market and to hold those responsible, accountable.

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

Asad Ullah Recall Alerts
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Rapid Alert

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

The product identification details are as under: –

Therapeutic Good Affected:-

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

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

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

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

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

-Please click here for further information on problem reporting to DRAP.
Advice for ConsumersConsumers should stop using this product and shall contact their physician or healthcare provider if they have experienced any problems that may be related to taking or using this drug product and report the incident to the Drug Regulatory Authority of Pakistan / National Pharmacovigilance Centre

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

DRAP Releases 2nd Edition of Guidelines for Good Clinical Practice (GCP) Inspections

Mughees Mudassir Uncategorized

The Drug Regulatory Authority of Pakistan (DRAP) is pleased to announce the release of the second edition of the “GUIDELINES FOR CONDUCT AND REPORTING OF GOOD CLINICAL PRACTICE INSPECTIONS“.

These guidelines provide a comprehensive framework for all stakeholders involved in clinical research related to therapeutic goods in Pakistan.

Key Features of the Updated Guidelines:

  • Enhanced Clarity: This second edition streamlines the guidance, making it easier for sponsors, investigators, research institutions, and laboratories to understand the procedures for GCP inspections.
  • Broader Applicability: The guidelines now explicitly cover Contract Research Organizations (CROs), BA/BE Study Centers, and Bio-Analytical Laboratories involved in clinical trials.
  • Improved Transparency: The revised document clearly outlines the roles and responsibilities of both clinical research participants and DRAP inspectors during the inspection process.
  • Risk based GCP Inspections

Benefits of Following these Guidelines:

  • Ensuring Patient Safety: Adherence to GCP principles is critical for safeguarding the well-being of participants in clinical trials.
  • Promoting Research Quality: Clear communication of inspection procedures fosters a transparent and high-quality research environment.
  • Facilitating Regulatory Compliance: Understanding inspection protocols allows research entities to prepare effectively and demonstrate compliance with DRAP regulations.

We encourage all parties involved in conducting clinical research in Pakistan to download and familiarize themselves with these updated guidelines.

Download the “GUIDELINES FOR CONDUCT AND REPORTING OF GOOD CLINICAL PRACTICE INSPECTIONS”

Recall Alert: Drug Product; Barpon 100mg/5mL Suspension (Batch # 202) by M/s. JASM Pharmaceutical, KPK

Asad Ullah Recall Alerts

Recall Alert

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DRAP Alert NoNo II/S/03-24-13
Action Date13th March 2024
Target Audience·         National Regulatory Field Force.
·         Pharmacists and Chemists at Distribution, Pharmacies and Medical Stores
·         Healthcare Professionals- Physicians, Pharmacists, and Nurses at hospital and clinics etc.
Problem / Issue Federal Government Analyst, CDL Karachi vide test report No. KQ-11-23-000155 dated 12-12-2023 has declared the subject mentioned product namely Barpon 100mg/5mL (Batch No. 202) as of substandard quality.

Therapeutic Good(s) Affected: –

Product NamesCompositionBatch No Manufacturer
Barpon 100mg/5mL Suspension
 
Reg No.114785		IbuprofenBatch No.  202
 
Mfg Dt: 07-2023
Exp.Dt: 06-2025		M/s. JASM Pharmaceutical
(Pvt.) Ltd., Risalpur.
Risk Statement:Barpon Infusion contains Ibuprofen, a medicine used to treat mild to moderate pain and fever (high temperature). Administration of substandard products may lead to complications, as well as an increased risk of failure of therapy. The age-profile of patients is important and young patients especially are at risk.
Action Initiated-The manufacturer has been directed to immediately recall the defective batch of above mentioned product from the market. All pharmacists and chemists working at distributions and pharmacies are hereby advised to immediately check their stocks and stop supplying this batch of product. The remaining stock should be quarantined and returned to the supplier/ company. The regulatory field force of DRAP and Provincial Health Departments are also informed regarding the matter and are directed to increase surveillance in the market to ensure the effective recall of defective products(s).

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

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

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

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

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

    Rapid Alert: Contaminated Propylene Glycol Identified and Confiscated

    Asad Ullah Recall Alerts
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    Rapid Alert

    DRAP Alert NoNo  II/S/03-24-14
    Action Date8th March 2024
    Target Audience1.Therapeutic Goods industry
    2. Manufactures of Oral liquid preparations
    Problem StatementFederal Government Analyst, Central Drugs Laboratory Karachi vide test/analysis vide No. RM-2-24-000179 and No. RM-2-24-000180 dated 01-03-2024 declared the sample of Propylene Glycol (Raw material) sent to CDL Karachi by Federal Inspector of Drugs Islamabad-I as of substandard quality due to contamination of DEG and EG. ( Click for details)

    Two samples were collected from separate containers which were labelled as Propylene Glycol, Batch# C815L44R41 and Batch# C815L44R52, purportedly manufactured by Dow Chemical Pacific (Singapore) Private Limited. However, upon further investigation, it seems that none of the samples were actually manufactured by Dow Chemicals and the labels were false.

    It is important to note that on January 11, 2024, a rapid alert was also issued for contaminated Propylene Glycol with batch number C815N3OR41, which was labelled as being manufactured by Dow Chemicals, Thailand. However, Dow Chemicals, Thailand has clarified to DRAP that it was not their original product and was falsified by some miscreants. The company also analyzed the retained samples of the original product and shared an analysis report, which showed that it was in compliance with the required specifications.
    Risk Statement:Diethylene glycol (DEG) and Ethylene Glycol (EG) contamination in Propylene Glycol (PG) can lead to serious health risks when used in oral liquid preparations. Upon ingestion, these chemicals (EG and DEG) are converted into toxic metabolites which can affect the central nervous system and heart. Moreover, it can also cause kidney damage which may lead to fatal consequences.
    Action Initiated: –The Regulatory Field Force has taken possession of contaminated raw materials and commenced an investigation to trace the supply chain of these containers. Manufacturers of therapeutic goods have been prohibited from using propylene glycol without testing for the presence of EG/DEG levels. These materials should only be obtained from authorized suppliers of original manufacturers with thorough verification of the integrity of the supply chain and originality of the product. The Regulatory Field Force has also been directed to ensure compliance and seize any such raw materials or products found to be contaminated in the market.
    Advice for Therapeutic Goods ManufacturersManufacturers of therapeutic goods are required to follow these instructions:
     
    1.      Recall Products: If any batch of finished product has been manufactured using the same batch of the propylene glycol that has been identified as contaminated, the retained sample should be immediately analysed and these finished products should be recalled from local and export markets if found contaminated.


    2       Screen Raw Materials: Before using them in the manufacturing of oral liquid preparations, all raw materials should be screened for contamination with EG and DEG.

    3.     Analyze Finished Products: Before their release into the market, all finished products should be analyzed for EG/DEG contamination.

    4.    Compliance: Ensure compliance with all directives issued by DRAP to safeguard public health from contaminated products.

    5.     Follow Guidelines: Adhere to the pharmacopeial monograph and WHO guidelines for testing EG/DEG in oral liquid preparations during the analysis of both raw materials and finished products.

    Our utmost priority is public safety. DRAP is committed to supporting the industry in maintaining rigorous quality control and testing procedures to prevent any potential harm caused by contaminated products.
    Advice for Healthcare ProfessionalsDRAP requests healthcare professionals to stay updated with advisories and recalls. Patients should be educated about the risks and symptoms of EG toxicity. Close monitoring of patients using the affected products is crucial, and any adverse events should be reported to National or Provincial pharmacovigilance centres.

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

    -Please click here for further information on problem reporting to DRAP.
    Advice for ConsumersConsumers should stay informed about the latest advisories and recalls from DRAP. If they have experienced any problem or unusual symptoms after using oral liquid preparations, seek medical attention immediately and report the incident to the Drug Regulatory Authority of Pakistan / National Pharmacovigilance Centre.

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

    Rapid Alert: Substandard Propylene Glycol (Batch # G01821UG) claimed to be manufactured by SK Picoglobal Korea.

    Asad Ullah Recall Alerts
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    Rapid Alert

    DRAP Alert NoNo  I/S/03-24-12
    Action Date8th March 2024
    Target Audience1. Regulatory Field Force.
    2. Therapeutic Goods industry
    3. Manufactures of Oral liquid preparations
    4. Healthcare professionals
    Problem StatementMs. MKB Pharmaceuticals (Pvt) Ltd., Peshawar sent the sample of Propylene Glycol (PG) to Central Drugs Laboratory Karachi for test/analysis that was used as a solvent in the manufacturing of oral liquid preparations. The batch was claimed to be manufactured by SK picoglobal Co. Ltd. Korea. Analysis of the sample by the Central Drug Laboratory, Karachi detected unacceptable level of Ethylene Glycol.

    The product identification details are as under: –

    Therapeutic Good Affected:-

    ProductBatch NoMfg DateExp. DatePurported to be Manufactured by
    (as per label)    		Remarks
    Propylene Glycol
    (Raw Material)    		G01821UG12-08-202311-08-2025SK Picoglobal Co. Ltd. Korea.The sample is declared substandard
    for unacceptable levels of Ethylene Glycol (0.4671%).
    Risk StatementPropylene Glycol (PG) contaminated with Ethylene Glycol (EG) when used in oral liquid preparations, can lead to serious health risks due to EG’s toxicity. When ingested, EG is metabolized into toxic metabolites that can affect the central nervous system, and heart, and can cause kidney damage, which can be fatal.
    Action InitiatedThe manufacturer has been instructed to recall finished products that were manufactured using the contaminated lot of propylene glycol. The Regulatory Field Force has also been instructed to seize all oral preparations that were made using the same batch of propylene glycol if found in the market. DRAP has directed the therapeutic goods industry to hold finished products manufactured from any other lot of propylene glycol of Ms. SK picoglobal Co. Ltd. Korea and ensure testing of finished products for EG/DEG contamination before releasing them into the supply chain.
    Advice for Therapeutic Goods ManufacturersManufacturers of therapeutic goods are required to follow these instructions:
     
    1.      Recall Products: If any batch was manufactured using the same lot (YF01200730) of propylene glycol that has been identified as contaminated, all finished products from local and export markets should be recalled.

    2.      Hold Other Batches: All finished products manufactured from any other lot of propylene glycol of SK picoglobal Co. Ltd. Korea should be held. These products should be tested for EG/DEG contamination before releasing them into the supply chain.

    3.      Screen Raw Materials: Before using them in the manufacturing of oral liquid preparations, all raw materials should be screened for contamination with EG and DEG.

    4.      Analyze Finished Products: Before their release into the market, all finished products should be analyzed for EG/DEG contamination.

    5.      Compliance: Ensure compliance with all directives issued by DRAP to safeguard public health from contaminated products.

    6.      Follow Guidelines: Adhere to the pharmacopeial monograph and WHO guidelines for testing EG/DEG in oral liquid preparations during the analysis of both raw materials and finished products.

    Our utmost priority is public safety. DRAP is committed to supporting the industry in maintaining rigorous quality control and testing procedures to prevent any potential harm caused by contaminated products.
    Advice for Healthcare ProfessionalsDRAP requests healthcare professionals to stay updated with advisories and recalls. Patients should be educated about the risks and symptoms of EG toxicity. Close monitoring of patients using the affected products is crucial, and any adverse events should be reported to National or Provincial pharmacovigilance centres.

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

    -Please click here for further information on problem reporting to DRAP.
    Advice for ConsumersConsumers should stay informed about the latest advisories and recalls from DRAP. If they have experienced any problem or unusual symptoms after using oral liquid preparations, seek medical attention immediately and report the incident to the Drug Regulatory Authority of Pakistan / National Pharmacovigilance Centre.

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