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Drug Safety Alert: Risk of Kidney Damage with Oral Anticoagulants

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 Fluorouracil and Capecitabine;
·         Healthcare professionals; and
·         Patients, consumers or caregivers.
Background:The Therapeutic Goods Administration (TGA) of Australia in June 2023 announced that a warning about serious kidney damage has been added to the prescribing information for all oral anticoagulants given through the oral route. Anticoagulant-related nephropathy (ARN) is a rare but serious adverse event resulting from profuse glomerular bleeding and has the potential to cause irreversible kidney damage and death.  The TGA investigated the safety signal based on reports of ARN in patients taking oral anticoagulants, mainly from overseas and sought a piece of advice from the Advisory Committee on Medicines (ACM). The committee noted that this adverse event is now well documented in the medical literature with warfarin and there is growing evidence for other oral anticoagulants. The ACM supported a class-wide warning being added to the Product Information for all oral anticoagulants. The ACM does not consider a warning for parenteral anticoagulants to be needed at this stage. This is because they are mainly used in hospitals and for a shorter duration.
Therapeutic Good(s) Affected:Oral anticoagulants are widely used to prevent and treat thromboembolic conditions and include apixaban, rivaroxaban and warfarin etc. Anticoagulants, sometimes called blood thinners, reduce the blood’s natural ability to clot. This alert does not apply to parenteral anticoagulants.
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 the Pharmacovigilance Rules, 2022 that registration holders should include information about Anticoagulant-related nephropathy (ARN) and its monitoring and evaluation in the warning and precaution section and to list ARN as an adverse drug reaction of unknown frequency in the prescribing information/label for oral anticoagulants.
Advice for healthcare professionals:Healthcare professionals are informed that early detection and intervention of ARN is critical to reducing permanent kidney damage and death. Although anticoagulant-related nephropathy is rare, it is likely underdiagnosed as kidney biopsy is required for a definitive diagnosis but is rarely performed in people taking anticoagulants, and patients who develop ARN have comorbidities that may explain their acute kidney injury presentation. Therefore, healthcare professionals are advised that while treating patients who are taking oral anticoagulants, talk to them about the risk of anticoagulant-related nephropathy. Close monitoring, including renal testing, is recommended for those with excessive anticoagulation (or supratherapeutic INR for those on warfarin) and hematuria.
Advice for patients:If you are taking an oral anticoagulant and have any questions or concerns about your treatment, speak to your doctor. Do not stop taking these medicines without discussing it with your doctor first. Contact your doctor immediately if you experience any of the following signs and symptoms: high blood pressure; decreased amount of urine; blood in urine; and swelling in legs, ankles, and around the eyes, which may indicate your kidneys aren’t working properly.
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.
·         TGA: Oral Anticoagulants Can Cause Serious Kidney Damage in Rare circumstances.
· TGA:  Risk Of Kidney Damage with Oral Anticoagulants.
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Drug Safety Alert:Risk of Potentially Life-threatening Toxicity with Fluorouracil and Capecitabine in Di-hydropyrimidine Dehydrogenase (DPD) Deficient Patients.

Asad Ullah Safety Alerts

Drug Safety Alert

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

Date:26 October, 2023
Target Audience:·         Manufacturers and importers of Fluorouracil and Capecitabine;
·         Healthcare professionals; and
·         Patients, consumers or caregivers.
Background:The Therapeutic Goods Administration (TGA) of Australia in Sep-2022 and the Medicine and Health Product Agency (MHRA) in October, 2020 issued updates regarding the use of fluorouracil, capecitabine and flucytosine. These updates included a new warning about the potential for severe and life-threatening toxicity in patients with a partial di-hydropyrimidine dehydrogenase (DPD) deficiency. Previously, these medications were contraindicated for patients with known complete DPD deficiency. Reports of adverse events suggested a link between DPD deficiency and toxicities, although DPD deficiency testing was often not performed in affected patients. Healthcare professionals were advised to consider DPD deficiency testing before initiating therapy and to reduce the starting dose if partial DPD deficiency is detected. Similar recommendations were made by the MHRA, referencing a European safety review, which emphasized the importance of DPD deficiency testing prior to treatment initiation. Testing is not required for topical fluorouracil formulations due to minimal systemic absorption. The PRAC of the EMA in March 2020 also recommended pre-treatment testing for DPD deficiency before administering fluorouracil via injection or infusion. Lack of DPD enzyme can lead to the accumulation of fluorouracil in the blood, resulting in severe and life-threatening adverse reactions. Patients with complete DPD deficiency should not be given these medications, and a reduced starting dose is recommended for patients with partial DPD deficiency.
Therapeutic Good(s) Affected:Fluorouracil and Capecitabine

Fluorouracil is indicated alone or in combination with other medicines to treat various cancers such as malignant tumours, particularly of the breast, colon or rectum. Also, it is applied to the skin for actinic keratosis and dermal warts. The recommendations are related to system fluorouracil not topical.

Capecitabine is indicated for the treatment of certain types of colon, colorectal, oesophagogastric and breast cancer.
Action in PakistanThe case was discussed in the 2nd meeting of PRAEC-DRAP wherein it was decided to Co-opt experts in Oncology as per Rule 9 (5) of the Pharmacovigilance Rules, 2022 to assess the case of testing of DPD deficiency in patients before initiation of treatment with Fluorouracil and Capecitabine and submit their reports in the next meeting of PRAEC. Two expert members of oncology were selected from the leading hospitals in Pakistan.
 
Accordingly, the PRAEC in its 3rd meeting held on the 8th of September, 2023 decided as per Rule 10(1)(h)(ii) of the Pharmacovigilance Rules, 2022 and in light of comments of co-opted experts to update contraindications in patients with known complete absence of di-hydro pyrimidine dehydrogenase (DPD) activity. Likewise, the PRAEC as per Rule 10(1)(h)(iv) of the Pharmacovigilance Rules, 2022 decided to update the warning and precaution section of prescribing information by including information about the importance of testing for DPD deficiency before initiation of the treatment with Fluorouracil and Capecitabine. Include information about the reduced starting dose in partial DPD deficiency, followed by enhanced monitoring for toxicities.
Advice for healthcare professionals:Healthcare professionals are informed that patients with complete or partial DPD deficiency are at increased risk of severe and fatal toxicity during treatment with medicines containing 5-fluorouracil (intravenous) and capecitabin. Therefore, healthcare professionals are advised not to treat patients with known complete DPD deficiency with these medicines. Likewise, in patients with partial DPD deficiency, a reduced starting dose should be considered.  All patients need to be monitored for toxicity particularly during the first cycle of treatment or after a dose increase.
Advice for patients:Patients should inform healthcare professionals if he/she or their family members have a history of complete or partial DPD deficiency. Patients should also promptly notify healthcare professionals about fluoropyrimidines-related toxicity, including for example stomatitis, diarrhoea, mucosal inflammation, neutropenia, and neurotoxicity.
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.
·         Fluorouracil and capecitabine – DPD deficiency of TGA website.
·         5-Fluorouracil (intravenous), capecitabine, tegafur: MHR-UK recommended DPD testing before initiation to identify patients at increased risk of severe and fatal toxicity.
·         PRAC-EMA recommendation.
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Drug Safety Alert: Potential risk of suicidal ideation/thoughts & self-injury with Finasteride

Asad Ullah Safety Alerts , , ,

Drug Safety Alert

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

Date:11th of April, 2023
Target Audience:• Manufacturers and importers of Finasteride;
• Healthcare Professionals; and
• Patients, consumers or caregivers.
Background:The Health Sciences Authority (HSA) of Singapore in August 2022 reminded healthcare professionals of the potential risk of suicidal ideation with the use of finasteride following results of a recent pharmacovigilance study that suggests younger patients with alopecia may be more vulnerable to the risk of suicide ideation. In the study, disproportionality analysis was used to assess whether suicidality or psychological adverse events (AEs) were more frequently reported for finasteride than would be expected by chance alone by comparing them against similar reports for all other drugs in VigiBase (WHO global database of ICSRs). The study identified 356 reports of suicidality and 2,926 reports of psychological AEs in users of finasteride, reported from 1993 to 2019. Among the reports with data available, the majority (99%) occurred in males, and 71% occurred in individuals aged between 18 and 44 years. Significant disproportionality signals for suicidality (reporting odds ratio [ROR], 1.63; 95% CI, 1.47-1.81) and psychological AEs (ROR, 4.33; 95% CI, 4.17-4.49) were identified in finasteride users.
 
On 19th of January, 2023, Health Canada through its summary safety review informed that it is
 
working with the manufacturers to update the product safety information in the Canadian product monographs (CPM) for finasteride-containing products to strengthen the warning statements on the risks of suicidal ideation and self-injury, and to include information about patient screening for psychiatric risk factors prior to starting treatment, as well as continuous patient monitoring during and after stopping treatment. The safety review was triggered by the publication of a media article that discussed the potential risk of suicide in patients using Propecia (finasteride) for male pattern hair loss. Health Canada’s review of the available information found a possible link between the use of finasteride and the risks of suicidal ideation and self-injury. At this time, there is not enough information to establish a link for the risk of suicide. However, strengthening of warning statements was warranted.
It was informed that Health Canada was monitoring the risk of suicidal ideation with the use of finasteride since 2012 and has completed 2 safety reviews in 2012 and 2015, and the information available at the time was considered too limited to determine whether there was a link between the use of finasteride and suicidal thoughts and behaviours (suicidality). In 2019, following reports of Canadian and international cases of suicide, suicidal ideation and self-injury with the use of finasteride, the agency completed a third safety review that found a possible link between finasteride and the risk of suicidal ideation. The CPMs of finasteride were accordingly updated to include the risk of suicidal ideation.
Most recently in 2022, due publication of a media article that discussed the potential risk of suicide in patients using Propecia (finasteride) for male pattern hair loss, Health Canada completed a review of the risk of suicidal ideation and potential risks of suicide and self-injury with the use of finasteride. The purpose of the current review was to consider recent information and determine if additional measures were warranted. A review of the available information found a possible link between the use of finasteride and the risks of suicidal ideation and self-injury. At this time, there is not enough information to establish a link between the use of
 
 
finasteride and the risk of suicide. Therefore, strengthening of warning statements on the risks of suicidal ideation and self-injury was warranted and Health Canada is working on it.
Furthermore, the most recent Vigilyze statistics related to the finasteride and Standard MedDRA Query(SMQ) selected Depression and suicide/self-injury study identified 2,995 reports and 471 reports specifically with suicidal ideation. The larger portion of the reactions in known gender occurred in males (31.9%, and 45.6% in individuals aged between 18 and 44 years respectively, with the broader SMQ and specifically suicidal ideation. Significant disproportionality signals for suicidal ideation (reporting odds ratio [ROR], 10.6) and SMQ (ROR, 4.5) were identified.
Therapeutic Good(s) Affected:Name:  Finasteride. 

Finasteride is indicated for the treatment of benign prostatic hyperplasia and androgenic alopecia.
Action in PakistanAccordingly, the case of the potential risk of suicidal ideation/thoughts & self-injury with finasteride was discussed in the 2nd  meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP), which decided as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 that registration holders should update prescribing information/safety specification of finasteride containing drugs by strengthening the warning statements on the risks of suicidal ideation and self-injury, and to include information about patient screening for psychiatric risk factors before starting treatment.
Advice for healthcare professionals:Healthcare professionals are informed that mood alterations including depression and, less frequently, suicidal ideation have been reported in patients treated with finasteride and are hereby advised to consider the potential risk of psychological adverse events when assessing the benefit-risk of finasteride for their patients. Healthcare professionals should also advise their patients to consult their doctors at the earliest when such thoughts are developed.
Advice for patients:Patients are advised to immediately consult their doctors if they experience mood alterations including depression and less frequently, suicidal ideation or self-injury etc.
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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
    35-Safety-Alert-of-Potential-risk-of-suicidal-ideation-thoughts-self-injury-with-FinasterideDownload

    Drug Safety Alert: Risk of complex sleep behaviours with Zolpidem

    Asad Ullah Safety Alerts
    { border: 1px solid black; padding: 10px;

    Drug Safety Alert

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

    Date:11th of April, 2023
    Target Audience:• Manufacturers and importers of Zolpidem
    • Healthcare Professionals; and
    • Patients, consumers or caregivers.
    Background:The Ministry of Health Labour and Welfare (MHLW) and the Pharmaceutical and Medical Device Agency (PMDA) of Japan in July, 2022 have announced that the product information for triazolam, zolpidem, zopiclone and eszopiclone should be revised to include the risk of abnormal behaviour as parasomnia. In addition, the use of triazolam, zolpidem or zopiclone is to be contraindicated in patients who have experienced abnormal behaviour such as parasomnia. Based on the published literature on the pharmacological mechanisms of parasomnia and cases of parasomnia reported in Japan, it was concluded the four drugs can increase the risk of abnormal behaviour as parasomnia, which may lead to serious self/other injuries or accidents. Also, a contraindication is considered necessary for triazolam, zolpidem and zopiclone in patients with a history of drug-induced parasomnia due to the risk of recurrence. Regarding eszopiclone, careful administration is still required but it is not a contraindication at this time, as there have been no reports of parasomnia in Japan for this drug.
    Previously, the United States Food and Drug Administration (US-FDA) in April 2019 announced that rare but serious injuries have occurred with some medicines used to treat insomnia such as eszopiclone (Lunesta®), zaleplon (Sonata®) and zolpidem (Ambien®.). The
     
    injuries are a result of sleep behaviours which include: sleepwalking, sleep driving and engaging in other activities while not fully awake. These complex sleep behaviours have also resulted in deaths. Serious injuries and death from complex sleep behaviours have occurred in patients with and without a history of such behaviours, even at the lowest recommended doses, and the behaviours can occur after just one dose. These behaviours can occur after taking these medicines with or without alcohol or other central nervous system depressants that may be sedating such as tranquillizers, opioids, and anti-anxiety medicines. As a result, FDA required information about this risk to be added to the Boxed Warning, the FDA’s prominent warning and also to the contraindication (strongest warning) to avoid use in patients who have previously experienced an episode of complex sleep behaviour with eszopiclone, zaleplon, and zolpidem.
    Therapeutic Good(s) Affected:Name:  Zolpidem. 

    Zolpidem tartrate is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
    Action in PakistanAccordingly, the case of the risk of complex sleep behaviours with Zolpidem was discussed in the 2nd  meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP), which decided as per Rule 10 (1) (h) (ii), (iv) and (vi) of Pharmacovigilance Rules, 2022 that registration holders should update the prescribing information/safety specification of zolpidem-containing drugs by including information related to complex sleep behaviour in the warning and precaution sections, information related to contraindications in patients who have experienced complex sleep behaviours after taking these drugs in the past, and to create a boxed warning as per the format of Reference Regulatory Authority (RRA).
    Advice for healthcare professionals:Healthcare professionals are requested to ask patients and their families or other caregivers at the time of prescribing or dispensing of zolpidem tartrate as to whether the patients have experienced abnormal behaviour as a symptom of parasomnia after they used these drugs in the past. Examples of abnormal behaviour as a symptom of parasomnia include: walking around indoors or outdoors; driving a car; making or eating a meal; making a phone call; behaving violently or calling out, etc. Most of the abnormal behaviours occur after the use of the drug without being fully awake, and those behaviours are not remembered the next day. Healthcare professionals are also advised to not prescribe zolpidem to patients who have previously experienced complex sleep behaviours after taking this medicine. Also, healthcare professionals should advise all patients that although rare, those behaviours have led to serious injuries or death and that if patients experience an episode of complex sleep behaviour, they should discontinue taking the medicines.
    Advice for patients:Patients should stop taking Zolpidem and contact their healthcare professionals right away if they experience a complex sleep behaviour where a patient is engaged in activities while he/she is not fully awake or if the patient do not remember activities they have done while taking the medicine.
    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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
    }
      34-Safety-Alert-of-Risk-of-complex-sleep-behaviours-with-ZolpidemDownload

      Drug Safety Alert: Risk of serious heart-related events, blood clots, cancer and death with Xeljanz (Tofacitinib)

      Asad Ullah Safety Alerts

      Drug Safety Alert

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

      Date:11th of April, 2023
      Target Audience:• Manufacturers and importers of Tofacitinib;
      • Healthcare Professionals; and
      • Patients, consumers or caregivers.
      Background:Health Canada in September 2022 announced that the product safety information for Janus kinase (JAK) inhibitors (including tofacitinib (Xeljanz®), baricitinib (Olumiant®), upadacitinib (Rinvoq®), abrocitinib (Cibinqo®), ruxolitinib (Jakavi®) and fedratinib (Inrebic®)) have been or will be updated to include the risk of serious heart-related problems, blood clots, cancer and death. Health Canada reviewed the final findings from the clinical research study from 2019 which linked tofacitinib to higher risks of serious heart-related problems, cancer and death, and confirmed the initial findings of an increased risk of blood clots. Health Canada also reviewed the interim findings from a 2021 observational study with baricitinib (Olumiant®), which showed increased rates of serious heart-related problems and blood clots with its use. Given the similar mechanisms of action and indications, Health Canada’s review concluded that a drug class effect for the risks of serious heart-related problems, blood clots, cancer and death cannot be excluded with JAK inhibitors used for the treatment of chronic inflammatory diseases, including upadacitinib, abrocitinib, ruxolitinib and fedratinib in addition to tofacitinib and baricitinib.

      Back in October, 2021, the Medicine and Health Product Regulatory Agency (MHRA) of the United Kingdom announced that the product information for tofacitinib will be updated with the information that tofacitinib should not be used in patients older than 65 years of age, people who are current or past smokers, or individuals with other cardiovascular (e.g., diabetes or coronary artery disease) or malignancy risk factors unless there are no suitable alternative treatments. The MHRA reviewed the results of a clinical safety trial (ORAL Surveillance) to evaluate the safety of tofacitinib compared with TNF blockers and identified these risk factors. In 2021, the final results from this study showed tofacitinib to be associated with an increased incidence of non-fatal myocardial infarction and malignancies, particularly lung cancer and lymphoma.

      Likewise, the Ministry of Health Labour and Welfare (MHLW) and Pharmaceutical and Medical Device Agency (PMDA) of Japan had also in October 2021 announced that the package inserts for tofacitinib should be revised to include the risk of cardiovascular events, such as myocardial infarction. The MHLW and the PMDA also reviewed the results of a clinical safety trial to evaluate the safety of tofacitinib compared with TNF blockers and identified.
      Similarly, the United States Food and Drug Administration (US-FDA) on 1st September 2021 through a Drug Safety Communication announced that based on a review of a large randomized safety clinical trial, the agency concluded that there is an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots, and death with arthritis and ulcerative colitis medicines Xeljanz (tofacitinib). This trial compared Xeljanz with another type of medicine used to treat arthritis called tumour necrosis factor (TNF) blockers in patients with rheumatoid arthritis. The trial’s final results also showed an increased risk of blood clots and death with the lower dose of Xeljanz. FDA recommended revisions to the Boxed Warning, FDA’s most prominent warning, for Xeljanz to include information about the risks of serious heart-related events, cancer, blood clots, and death.
        
      Previously, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) in June, 2021 recommended an update to the product information for tofacitinib (Xeljanz®) to include a new recommendation for its use due to the risk of cardiovascular events and cancer. The PRAC reviewed the data from a study conducted in patients who were 50 years of age or older with at least one additional cardiovascular risk factor and advised healthcare professionals that tofacitinib should only be used in patients over 65 years old, patients who are current or past smokers, patients with other cardiovascular risk factors and patients with other malignancy risk factors if no suitable treatment alternative is available.
      Therapeutic Good(s) Affected:Name:  Xeljanz (tofacitinib)

      Xeljanz (tofacitinib) is used to treat certain serious, chronic, and progressive inflammatory conditions. It is approved to be used alone or with other drugs to treat rheumatoid arthritis (RA), a condition in which the body attacks its own joints, causing pain, swelling, joint damage, and loss of function. Xeljanz is also approved to treat psoriatic arthritis, a condition that causes joint pain and swelling; ulcerative colitis, which is a chronic inflammatory disease affecting the colon; and polyarticular course juvenile idiopathic arthritis, a type of childhood arthritis. Xeljanz works by decreasing the activity of the immune system; an overactive immune system contributes to RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.
      Action in PakistanThe National Pharmacovigilance Centre (NPC) of the Drug Regulatory Authority of Pakistan had already issued Safety Alert No. 16, dated 10th September 2021, titled “Risk of serious heart-related events, cancer, blood clots, and death with Tofacitinib” in light of US-FDA drug safety communication. As other stringent regulatory authorities have also updated their label/product information, therefore, the case was again submitted to Pharmacovigilance Risk Assessment Expert Committee (PRAEC).

      Accordingly, the case of the potential risk of serious heart-related events, cancer, blood clots, and death with Tofacitinib was discussed in the 2nd  meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP), which decided as per Rule 10 (1) (h) (iv) and (vi) of Pharmacovigilance Rules, to update the prescribing information/safety specification of Tofacitinib containing medicines by including information related to heart attack or stroke, cancer, blood clots, and death in the warning and precaution section and to create a Boxed warning as per format of Reference Regulatory Authority (RRA).
      Advice for healthcare professionals:Healthcare professionals should consider the benefits and risks for the individual patient before initiating or continuing therapy with tofacitinib (Xeljanz®). This is particularly the case in patients who are current or past smokers, those with other cardiovascular risk factors, or those who develop a malignancy, and those with a known malignancy other than a successfully treated non-melanoma skin cancer. Reserve this medicine for patients who have had an inadequate response or intolerance to one or more TNF blockers. Counsel patients about the benefits and risks of these medicines and advise them to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot.
      Advice for patients:Those patients who are taking Xeljanz should tell their healthcare professionals if they are current or past smokers, or have had a heart attack, other heart problems, stroke, or blood clots in the past as these may put them at higher risk for serious problems with the medicine. Patients starting this medicine should also tell their healthcare professionals about these risk factors.

      Patients should seek emergency help right away if they have any symptoms that may signal a heart attack, stroke, or blood clot, including:

      –   Discomfort in the centre of your chest that lasts for more than a few minutes, or that goes away and comes back
      –   Severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw
      –   Unusual pain or discomfort in your arms, back, neck, jaw, or stomach
      –   Shortness of breath with or without chest discomfort
      –   Breaking out in a cold sweat
      –   Nausea or vomiting
      –   Feeling lightheaded
      –   Weakness in one part or on one side of your body
      –   Slurred speech
      –   Drooping on one side of your mouth
      –   Swelling of a leg or arm
      –   Leg pain or tenderness, or red or discoloured skin in the painful or swollen leg or arm.

      Treatment with this medicine is associated with an increased risk of certain cancers including lymphoma and lung cancer, so patients should inform their healthcare professional if they experience signs and symptoms such as swelling of lymph nodes in the neck, armpits, or groin; constantly feeling tired; fever; night sweats; persistent or worsening cough; difficulty breathing; hoarseness or wheezing; or unexplained weight loss.
      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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
        33-Safety-Alert-of-Risk-of-serious-heart-related-events-blood-clots-cancer-and-death-with-XeljDownload

        Drug Safety Alert: Potential Risk of Abuse, Dependence and Withdrawal with Benzodiazepines

        Asad Ullah Safety Alerts

        Drug Safety Alert

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

        Date:10th of April, 2023
        Target Audience:• Manufacturers and importers of Benzodiazepines containing medicines;
        • Healthcare Professionals; and
        • Patients, consumers or caregivers.
        Background:The Medsafe of Newzealand in June 2022 reminded prescribers about the update to the product information for benzodiazepines regarding the potential risks of abuse, dependence and withdrawal, even when taken at recommended dosages. As per information, the dispensing data of New Zealand showed that diazepam and lorazepam are the most dispensed benzodiazepines. The total amount of these medicines that were dispensed for all indications increased in the period between 2016 and 2020 which suggested frequent and/or long-term use. As per data shared, between August 1969 and March 2022, the Centre for Adverse Reactions Monitoring (CARM) received 23 case reports of withdrawal and/or dependence with the use of benzodiazepines. Clonazepam (nine cases) was the most frequently reported benzodiazepine, followed by lorazepam (five), diazepam (three) and triazolam (three). Therefore, Medsafe advised healthcare professionals to counsel patients about the risks of benzodiazepines when initiating treatment, regularly review the ongoing need for treatment, and gradually taper benzodiazepines following continuous or high-dose use to reduce the risk of withdrawal reactions.
        Back in September 2020 and also through Podcast in January 2022, the United States Food and
         
        Drug Administration (US-FDA) through a Drug Safety Communication informed that the agency is requiring Boxed warnings of all benzodiazepines drugs to include information about the risk of abuse, misuse, addiction, physical dependence and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioid pain relievers, alcohol, or illicit drugs. Physical dependence can occur when benzodiazepines are taken steadily for several days to weeks, even as prescribed. Stopping these medicines abruptly or reducing the dosage too quickly can result in withdrawal reactions, including seizures, which can be life-threatening. The boxed warning also states that concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Therefore, these medicines may be reserved concomitant prescribing for use in patients for whom alternative treatment options are inadequate.
        Therapeutic Good(s) Affected:Name: Benzodiazepines such as Diazepam, Alprazolam, Clonazepam, Lorazepam, Bromazepam etc.

        Benzodiazepines are indicated to treat generalized anxiety disorders, insomnia, seizures, social phobia and panic disorders.
        Action in PakistanAccordingly, the case of the potential risk of abuse, dependence and withdrawal with benzodiazepines was discussed in the 2nd meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP) which after detailed deliberation and discussion decided as per Rule 10 (1) (h) (iv) & (vi) of Pharmacovigilance Rules, 2022 to update the prescribing information/safety specification of benzodiazepines containing medicines by including information related to abuse, misuse, addiction and withdrawal in the warning and precaution section and  to create a boxed warning as per FDA format.
        Advice for healthcare professionals:Healthcare professionals are advised to assess each patient’s risk for abuse, misuse, and addiction before prescribing and throughout treatment. Likewise, caution should be taken when prescribing benzodiazepines to patients with a history of alcohol or drug abuse. When prescribing a benzodiazepine for anxiety or insomnia, it must be ensured that the patient understands that these medicines are intended for short-term use (2-4 weeks). Ongoing use of benzodiazepines may lead to dependence that increases with the dose and duration of treatment and in patients with a history of alcohol or drug abuse or a marked personality disorder. Therefore, healthcare professionals should regularly review the ongoing need for treatment, particularly if the patient is at high risk of dependence.  Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may lead to withdrawal reactions. The likelihood and degree of severity of withdrawal depend on the duration of treatment, dose and degree of dependency. Sudden cessation of benzodiazepines that have been used continually and/or at high doses is associated with serious withdrawal reactions, such as convulsions, delirium or psychosis.

        Therefore, healthcare professionals should inform patients of these risks and advise them to consult their doctor before decreasing the dose or abruptly stopping the medicine. Patients should also be advised that stopping treatment requires an individualized tapering schedule which is supervised by their doctor.
        Advice for patients:Patients are advised to inform healthcare professionals about all the prescription and over-the-counter (OTC) medicines that the patient are taking or any other substances the patient is using, including alcohol. Benzodiazepines should be taken exactly as prescribed by healthcare professionals. If there is a need to discontinue the medicines, discuss a plan for slowly decreasing the dose and frequency of benzodiazepine(s) with your healthcare professional. A healthcare professional should be immediately contacted if any withdrawal symptoms are experienced.
        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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
          32-Safety-Alert-of-Potential-Risk-of-Abuse-Dependence-and-Withdrawal-with-BenzodiazepinesDownload

          Drug Safety Alert: Risk of dental problems with orally dissolved Buprenorphine

          Asad Ullah Safety Alerts

          Drug Safety Alert

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

          Date:10th of April, 2023
          Target Audience:• Manufacturers and importers of Buprenorphine medicines;
          • Healthcare Professionals; and
          • Patients, consumers or caregivers.
          Background:The United States Food and Drug Administration (US-FDA) on 12th of January, 2022 through a drug safety communication warned that dental problems have been reported with medicines containing buprenorphine that are dissolved in the mouth. Dental problems, including tooth decay, cavities, oral infections, and loss of teeth have been reported, even in patients with no prior history of dental issues. The buprenorphine medicines that are associated with dental problems are tablets and films that are dissolved under the tongue or placed against the inside of the cheek. There are also buprenorphine products for pain and opioid use disorder (OUD) delivered by other routes such as a skin patch and injection, but FDA has not identified a concern for dental health related to these other forms.
          Therapeutic Good(s) Affected:Name: Buprenorphine medicines that are orally dissolved.

          Buprenorphine is an opioid used to treat opioid use disorder (misuse of prescribed opioid medications) and pain. The comprehensive approach of buprenorphine combined with counselling and other behavioural therapies is often one of the most effective ways to treat OUD. At proper doses, buprenorphine also decreases the pleasurable effects of other opioids, making misuse of them less appealing.
          Action in PakistanAccordingly, the case of risk of dental problems with orally dissolved Buprenorphine was discussed in the 2nd  meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP) which after detailed deliberation and discussion decided
           
           
          as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 to update the prescribing information/safety specification of buprenorphine medicines that are dissolved in the mouth by including information related to the risk of dental issues, pre-prescribing assessment of patients and guidelines of taking extra steps after use in the warning and precaution sections.
          Advice for healthcare professionals:Healthcare professionals are advised to be aware that the benefits of buprenorphine medicines still clearly outweigh the risks in treating OUD patients and should ask patients about their oral health history before prescribing treatment with the transmucosal/oral buprenorphine medicines. Healthcare professionals should also counsel patients about the potential for dental problems and the importance of taking extra steps after the medicine has completely dissolved, including to gently rinse their teeth and gums with water and then swallow and to wait at least 1 hour before brushing their teeth.
          Advice for patients:Patients are advised to continue taking buprenorphine medicine as prescribed and not to stop it suddenly as it could lead to serious consequences including withdrawal symptoms. Patients are also advised to take extra steps to reduce the risk of serious dental problems such as rinsing their mouth with water and waiting at least 1 hour before brushing their teeth after buprenorphine medicines are dissolved to avoid damage to their teeth.
          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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
            31-Safety-Alert-Risk-of-dental-problems-orally-dissolved-BuprenorphineDownload
            Minutes of 2nd Meeting of Pharmacovigilance Risk Assessment Expert Committee (PRAEC) held on March 07, 2023

            Drug Safety Alert: Risk of Hypersensitivity Reactions with Pegaspargase (Peg L Asparaginase)

            Asad Ullah Safety Alerts

            Drug Safety Alert

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

            Date:10th of April, 2023
            Target Audience:• Manufacturers and importers of Peg L Asparaginase;
            • Healthcare Professionals; and
            • Patients, consumers or caregivers.
            Background:The National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP) received six cases of hypersensitivity reactions from Indus Hospital Karachi with Pegaspargase (Peg L Asparaginase) with different batches having the same importer i.e. M/S Lab Diagnostic System and same manufacture i.e. Jiangsu Hengrui Medicine Co Ltd, China. The drug was prescribed for Acute Lymphoid Leukemia/ Leukemia with a dose of 2500 IU/m2 in children. The events of hypersensitivity reactions including swelling of lips, nausea, rash, vomiting, swelling of the tongue, itching all over the body, shivering, red eyes and abdominal pain were noted in the six cases after administration of Pegaspargase (Peg L Asparaginase) 3750IU. The time to onset of reactions was one day. The Pegaspargase was withdrawn in all cases except one case where the status is unknown and the patients recovered in all those cases. The causality assessment of all six cases was performed by the Causality Assessment Group of the National Pharmacovigilance Centre (NPC) and classified all six cases to have a possible relationship with drug intake.
             
            Further assessment was carried out at the National Pharmacovigilance Centre (NPC), Drug Regulatory Authority of Pakistan (DRAP), where the signal was confirmed from the approved label of Peg L Asparaginase of United States Food and Drugs Administration (US-FDA) and Summary of Product Characteristics (SmPC) of Medicine and Health Products Agency (MHRA) and from the published research articles of hypersensitivity reactions with the drug. There was also significant disproportionality and potential association of hypersensitivity with Pegaspargase as per statistical tool available in VigiLyze of the Uppsala Monitoring Centre, Sweden.
             
             The case was therefore discussed in the 2nd meeting of the Pharmacovigilance Risk Assessment
            Expert Committee (PRAEC) of the NPC, DRAP which after detailed deliberation, decided to update the prescribing information/ safety specification/ label of Pegaspargase injection with the inclusion of information related to hypersensitivity reactions and its monitoring in the warning and precaution section and information on treatment modification as per the grade of hypersensitivity reactions in dosage and administration sections. Registration holder was also directed to introduce an educational training programme for healthcare professionals on proper preparation, administration and monitoring of Pegaspargase and to ensure that resuscitation equipment are available at the treatment sites.
            Therapeutic Good(s) Affected:Name: Pegaspargase (Peg L Asparaginase)

            Pegaspargase is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of pediatric and adult patients with Acute Lymphoid Leukaemia (ALL) and hypersensitivity to native forms of L-asparaginase.
            Advice for healthcare professionals:Healthcare professionals are informed that hypersensitivity reactions to Pegaspargase, including life-threatening anaphylaxis, can occur during therapy, including in patients with known hypersensitivity to E. coli-derived asparaginase formulations. Other hypersensitivity reactions can include angioedema, lip swelling, eye-swelling, erythema, decreased blood pressure, bronchospasm, dyspnoea, pruritus and rash. Premedicate patients 30-60 minutes before administration of pegaspargase. As a routine precautionary measure, the patient should be monitored for an hour after administration and resuscitation equipment and other appropriate means for the treatment of anaphylaxis such as epinephrine, oxygen, intravenous steroids, etc should be available at the treatment sites. Pegaspargase should be discontinued in patients with serious hypersensitivity reactions. Monitoring of patients and modification of treatment is recommended as per the following schedule: reduce the infusion rate by 50% in case of Grade 1 hypersensitivity reaction; interrupt the infusion, treat the symptoms, when symptoms resolved, resume the infusion and reduce the infusion rate by 50% in case of Grade 2 hypersensitivity reaction; and for Grade 3 to 4 hypersensitivity reactions permanently discontinue the pegaspargase.
            Advice for patients:Patients are informed that hypersensitivity reactions with Pegaspargase injection can occur during chemotherapy of Acute Lymphoid Leukaemia (ALL). Talk to your doctor if you have a history of hypersensitivity with conventional asparaginase formulations.
            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 2nd meeting of Pharmacovigilance Risk Assessment Expert Committee.
              30-Safety-Alert-of-Hypersensitivity-Reactions-with-Pegaspargase-Peg-L-Asparaginase.Download

              Safety Alert: WHO Global Alert on Tetracycline Hydrochloride Ophthalmic Ointment USP 1%

              Asad Ullah Recall Alerts, Regulatory Updates, Safety Alerts

              Safety Alert

              Update from WHO Global Surveillance and Monitoring System

              Date:28th February 2023
              Target Audience:· Healthcare Professionals- Physicians, Pharmacists, and Nurses at hospitals and clinics etc.
              · International travelers/General Public
              · NGO’s/Supply Donations/Humanitarian Medicines
              Problem or IssueWorld Health Organization (WHO) issued Medical Product Alert No. N°2/2023 dated 22nd February 2023 which refers to the batches of Tetracycline Hydrochloride Ophthalmic Ointment USP 1%, manufactured by Galentic Pharma (India) Pvt. Ltd, located at R-673, T.T.C. MIDC Rabale, Thane- Belapur Road, Navi Mumbai – 400701, Maharashtra, India Supplied in various countries under various labels.
              Visual examination of random samples had shown a range of quality issues with the random samples of the product batches e.g. particles ranging in color, size and shape on the nozzle, in the cap and in the ointment inside each tube, black spots and brown splotches on the inner foil layer of the tube, and phase separation.
              DRAP has never authorized sale of any products from Galentic Pharma (India) Pvt. Ltd (Thane Belapur Road, Navi Mumbai, India). These products are neither registered nor available on Pakistan market, however these may have been carried for personal use while visiting other countries.
              The manufacturer has initiated a voluntary recall for several batches. The manufacturer has indicated that other batches may be included in the voluntary recall
              Potential Hazards:There is currently no established evidence of any adverse events from the affected batches of TETRACYCLINE HYDROCHLORIDE OPHTHALMIC OINTMENT USP 1%. Redness and swollen eyes are common reactions to general use of tetracycline eye ointment. There is currently no indication that the above-mentioned quality issues may give rise to adverse events that are not listed in the product labelling. The affected TETRACYCLINE HYDROCHLORIDE OPHTHALMIC OINTMENT USP 1% is supplied in bulk and as a component of various medical kits supplied by some international organizations providing humanitarian assistance.
              Advice for healthcare professionals:DRAP requests increased vigilance within the supply chains of institutions/pharmacies/healthcare facilities likely to be affected by this affected batch of product. Adverse reactions or quality problems experienced with the use of any product shall be reported to the National Pharmacovigilance Centre(NPC), DRAP using Adverse Event Reporting Form or online through this link.  Further information of reporting problems to DRAP is available on this link.
              Advice for patients:Consumers should stop using this product bearing the affected batch number(s) and shall contact to 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 Drug Regulatory Authority of Pakistan/ National Pharmacovigilance Centre.
                Safety-Alert-for-TetracyclineDownload

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

                Drug Safety Alert: Risk of Kidney Injury and Death due to Hydroxyethyl-Starch Solutions for Infusion.

                Asad Ullah Pharmacovigilance, Regulatory Updates, Safety Alerts

                Drug Safety Alert

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

                Date:29th of November, 2022
                Target Audience:• Manufacturers and importers of hydroxyethyl-starch solutions for infusion.
                • Healthcare Professionals; and
                • Patients, consumers or caregivers.
                Background:The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicine Agency (EMA) on 11th February, 2022 recommended that the market authorization of hydroxyethyl-starch (HES) solutions for infusion should be suspended across the European Union. These solutions for infusion products are indicated as an addition to other treatments for plasma volume replacement following acute (sudden) blood loss.
                The safety of these solutions for infusion was reviewed in 2013, and a number of restrictions and measures to minimise the risk of kidney injury and death in certain patients (those critically ill, with burn injuries or with sepsis, a bacterial infection in the blood) were put in place at that time.

                Likewise, as a result of a third review conducted in 2018, the use of HES solutions for infusion was further restricted to only accredited hospitals, and healthcare professionals prescribing or administering the medicines had to be trained in their appropriate use. In addition, further warnings were introduced to remind healthcare professionals that these medicines must not be used in patients with sepsis or kidney impairment or in other vulnerable patients such as the critically ill in order to ensure these solutions for infusion were not used in patients who were at increased risk of harm. Market authorization holders of HES solutions for infusion were also requested to conduct a drug utilization study to check that the restrictions were adhered to in clinical practice.

                The PRAC of the EMA accordingly reviewed the results of the study, which show that HES solutions for infusion are still being used outside the recommendations included in the product information and concluded that the further restrictions introduced in 2018 have not sufficiently ensured that the medicines are used safely and that HES solutions were continually used in certain groups of patients in whom serious harm has been demonstrated. In view of the serious risks that certain patient populations were still exposed to, the PRAC recommended the suspension of the marketing authorizations for HES solutions for infusion in the European Union. Accordingly, the European Commission on 24th May, 2022 issued a legal decision confirming the suspension of the market authorization of HES solution for infusion.
                Therapeutic Good(s) Affected:Name: Hydroxyethyl-Starch solutions for infusion.

                These solutions for infusion products are indicated as an addition to other treatments for plasma volume replacement following acute (sudden) blood loss.
                Action in PakistanAccordingly, the case of the risk of kidney injury and death due to hydroxyethyl-starch solutions for infusion was discussed in the 1st meeting of the Pharmacovigilance Risk Assessment Expert Committee (PRAEC) of the National Pharmacovigilance Centre (NPC), Division of Pharmacy Services, Drug Regulatory Authority of Pakistan (DRAP). The PRAEC-DRAP after detailed deliberation and discussion and as per Rule 10 (1) (h) (v) of Pharmacovigilance Rules, 2022 (reliance mechanism) decided to recommend to the Registration Board of the DRAP to suspend the registration of Hydroxyethyl-Starch (HES) solutions in Pakistan subject to the availability of alternative treatment options.
                Advice for healthcare professionals:Healthcare professionals are informed that the National Pharmacovigilance Centre, DRAP is working with the Registration Board and manufacturers/importers of hydroxyethyl-starch solutions for infusion to suspend the registration of these solutions in Pakistan. Therefore, healthcare professionals are reminded that there are alternative solutions for infusion available in the Pakistani market for the treatment of plasma volume replacement following acute (sudden) blood loss and the same must be considered as the treatment in these conditions.
                Advice for patients:Patients are informed that the National Pharmacovigilance Centre, DRAP is working with the Registration Board and manufacturers/importers of hydroxyethyl-starch solutions for infusion to suspend the registration of these solutions in Pakistan. Therefore, talk with your doctor before initiation of treatment with those solutions as alternative treatment options are available in the market.
                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 1st meeting of Pharmacovigilance Risk Assessment Expert Committee.
                European Medicine Agency update regarding hydroxyethyl-starch solutions for infusion recommended for suspension from the market.
                  29_Safety_Alert_of_Risk_of_Kidney_Injury_and_Death_due_Hydroxyethyl-Starch_Solutions_for_Infusion.Download