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

Drug Safety Alert

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

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

Drug Safety Alert: Risk of Respiratory Failure and Sepsis with Terlipressin.

Drug Safety Alert

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

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

Drug Safety Alert: Risk of Tendon Disorders with Third-Generation Aromatase inhibitors

Drug Safety Alert

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 PakistanThe case was discussed in the 3rd meeting of PRAEC, held on the 8th of September, 2023, which decided as per Rule 10 (1) (h) (iv) of Pharmacovigilance Rules, 2022 that registration holders of 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

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 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 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.

Drug Safety Alert: Risk of Kidney Damage with Oral Anticoagulants

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.

Drug Safety Alert:Risk of Potentially Life-threatening Toxicity with Fluorouracil and Capecitabine in Di-hydropyrimidine Dehydrogenase (DPD) Deficient Patients.

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.

Drug Safety Alert: Potential risk of suicidal ideation/thoughts & self-injury with Finasteride

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.

Drug Safety Alert: Risk of complex sleep behaviours with Zolpidem

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

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.

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

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.