ADR reporting system and ICSRs
Individual case safety reports are received by the Department from health care professionals, patients, and from the MAH. Between September 2014 and August 2016, 16,500 reports were entered into the PV central database. Of these reports, 94.3%were submitted by pharmaceutical companies (MAH and importers), 5.5% were submitted by health care professionals from medical institutions, and only 0.2% of the reports have been submitted by patients and the general public. In addition to the electronic reports received in the database, health care professionals also reported adverse events via mail or by phone and patients reported them as complaints or questions via the drug information call center or ADRs patients’ Forum, a web-based service offered by the PV department to the public (more than 130 per year). 40% of the ADR reports in the database, were defined as serious, 59% defined as non-serious, and for the other 1% seriousness was not specified.
Individual case safety reports can be submitted to the Pharmacovigilance and Drug Information Department by sending a standard International Conference on Harmonization (ICH) E2B format, an electronic format facilitated by the ICH for transmission of ADR reports. This method of transmission is currently used mainly by the industry (mostly MAH but also by some importers of unlicensed drugs which may be used in Israel due to drug shortages). Additionally the Department developed a designated electronic form allowing for an online reporting of ADRs by the general public, health care professionals as well as from QPPVs at various MAH/importers who do not have ICH E2B reporting system [10]. The form enables a structured method for reporting and filing an adverse event. The form is based on the WHO guidelines for effective and valid report. The minimum information for a valid report includes at least one patient identifier (initials, age, or gender), an identifiable reporter, at least one reaction, and at least one suspect drug. Individual case safety reports in both formats are received and displayed in the PV system described above.
Over the course of the assessment period, 50% of the reports were submitted via the online government form and 50% were submitted via E2B format. We performed an analysis of the ICSRs in our database according to Anatomical Therapeutic Chemical (ATC) classification – a classification of the suspected drug or active substance, according to the organ or system on which they act and their therapeutic, pharmacological and chemical properties [11]. The most frequently reported medication group was the immunosuppressant drugs (categorized by ATC -3). This is also the most frequent reported group in the WHO ICSRs database (VigiLyze).
During the assessment period, the top 10 ATC-3 medication groups, which account for 68% of all ADRs reported to the department were immunosuppressant drugs (L04A), antineoplastic agents (L01X), parathyroid hormones and analogues (H05A), antithrombotic agents (B01A), blood glucose lowering drugs (excluding insulin; A10B), hypothalamic hormones (H01C), direct acting antivirals (J05A), hormonal contraceptives for systemic use (G03A), immunostimulant drugs (L03A), and all other therapeutic products (V03A). The latter medication group consists of antidotes, iron chelating agents, drugs for hypercalcemia, hyperkalemia and hyperphosphatemia, detoxifying agents, tissue adhesives, drugs for embolization, medical gases, nalfurafine, diazoxide, cobicistat and ethanol. Figure 1 presents the 10 most common ATC-3 medication groups as percentage, of the total number of reports received in database from September 2014 through August 2016.
Signal management and regulatory actions
Signal detection is often based on a review of ICSRs. In the Pharmacovigilance and Drug Information Department, pharmacists and clinical pharmacists, specializing in PV, perform a case by case assessment to detect signals.
Additional sources for signals are reports of medication misuse and/or quality concerns arising from medical staff, industry-operated patient support programs, observational studies, clinical trials, ADRs patients’ forum, scientific literature, periodic safety reports/periodic benefit risk evaluation reports (a document submitted by the MAH to regulatory agencies), and safety communications from other health authorities (whose websites are monitored on daily basis). In order to confirm a signal, it is cross referenced with various sources of data. This process of signal detection, evaluation and prioritization takes into consideration factors such as frequency of the ADR, its severity, impact on public health, and the feasibility of counteract measures.
Additional factors taken into consideration include signals that involve serious, unexpected ADR, with reasonable causal association to the suspected drug, or a new aspect of a known association involving new product or new formulation. Moreover, the Department prioritizes signals derived from ADR reports that can indicate national safety issues such as a local quality concern and unusual frequency of a known ADR. Another important resource used by the Department to evaluate ADRs, signals, and other safety issues is an independent experts advisory committee appointed by the MOH for this purpose. Comparable committees exist at other regulatory agencies such as the FDA and EMA. The advisory committee consists of representatives from a variety of health disciplines, including clinical pharmacologists, pharmacists, and other specialists.
In addition, Israel has signed agreements with several leading medicines agencies, such as Swissmedic and the FDA. These memorandums of understanding include PV data sharing. Overall, when needed, the Department communicates safety dilemmas with other regulatory agencies, mainly the EMA, FDA and Swissmedic. Following an internal assessment process and additional consultation with other regulatory agencies (if needed), the Department concludes whether the evidence is sufficient to support a safety concern to the public and determines what steps should be taken to manage and minimize this potential risk.
Since 2014 until the end of 2016, 850 signals have been identified from all sources. Following evaluations that took into account the impact on public health and the feasibility of counteract measures, it was determined that 430 signals required inquiry or follow-up and 420 of the signals required additional regulatory actions. Forty percent of the signals originated from ADR reports.
Among the PV activities initiated following the signal detection were: initiating leaflets and label updates, informing health care providers and the public regarding safety concerns, and in special cases –withdrawing a drug from the market, recalls or inventory holds of specific products or batches. Figure 2 represents the distribution of PV activities initiated in response to signals (n = 850).
In addition to the described activities, as of 2015 the Pharmacovigilance and Drug Information Department takes proactive risk management process to minimize potential risks associated with the use of medications by implementing risk minimization plans (RMPs) with the MAHs. RMPs are key regulatory tool for characterization, assessment, mitigation, and minimization of risks associated with use of a medicinal products. A procedure that sets the guidelines for submitting RMPs to the Pharmaceutical Division was published in March 2016. Since 2015 to date, 30 RMPs were implemented in Israel.
Examples of PV activities based on signal detection from ADR reports and/or other sources
Increased frequency of labeled ADRs
In 2014 the Department received 11 reports in a period of 10 days regarding urticaria, which presented as intense itchy skin rash, and developed during or minutes to hours after the infusion of a specific batch of an immunoglobulin product. In the prescribing information, urticaria is listed as an uncommon adverse reaction of immunoglobulin products. An investigation was initiated which revealed no quality issues that may have caused the above ADR. Nevertheless, due to the unexplained unusual frequency of these serious drug events, the Department decided to hold the marketing of this batch. Following this hold, there were no additional reports.
Rare and severe ADRs
Three spontaneous reports of death associated with intramuscular administration of benzathine benzylpenicillin (penicillin G benzathine) had been received by the Department during a period of 9 months (2014–2015). The 3 cases involved elderly female patients aged 91, 77 and 70 years with underlying cardiac disease but in stable clinical condition. The patients were treated for erysipelas, with monthly intramuscular injections of the benzathine benzylpenicillin diluted with lidocaine. In each of the cases, shortly after the intramuscular injection of Benzathine benzylpenicillin, the patient lost consciousness with respiratory and cardiac arrest. After a thorough investigation among the 4 HMOs, 3 more cases of severe adverse reactions to benzathine benzylpenicillin during occurring within the last 3 years were identified; one of which was fatal. The benzathine benzylpenicillin was imported from different manufacturers and was from different batches. Chemical analysis of the suspected products revealed no quality issues. In all cases the benzathine benzylpenicillin was diluted with a small amount of lidocaine 1% in order to minimize the pain associated with the injection but the amount of lidocaine injected could not explain this adverse reaction. In each case, the drug was administered for at least several months prior to the event and therefore an evaluation performed by the PV expert advisory committee concluded that anaphylaxis was not a reasonable explanation for the events. It should be noted that the product leaflet contains strict administration instructions for the drug. Specifically, it states that the drug may only be administered by deep intramuscular injection and that intravenous administration of penicillin G benzathine has been associated with cardiopulmonary arrest and death. After considering the available data, it was determined that a possible explanation of the events might have been cardiopulmonary arrest due to embolism after inadvertent intravascular injection. Considering the benefit to risk evaluation, the MOH decided that the risk outweighs the benefit when administering this agent for most indications. In 2015, the MOH issued a communication regarding the restriction of using benzathine benzylpenicillin for a limited number of infections such as syphilis, where other alternative therapies are not suitable [12].
External sources of information received from other regulatory agencies
In June of 2016, the FDA issued a communication that emphasized the existing warning about acute kidney injury with the sodium glucose transporter 2 (SGLT2) inhibitors canagliflozin and dapagliflozin, which are used for treatment of diabetes mellitus [13]. A question has been raised about the third member of the SGLT2 inhibitors, empagliflozin. The FDA communication was based on recent reports regarding the aforementioned drugs. Empaglifozin was not included in the FDA review or in a similar review conducted by Health Canada [14], most likely due to the fact that it was new in the market. The Pharmacovigilance and Drug Information Department communicated this dilemma to its colleagues in Swissmedic and the EMA. Neither agency planned to issue a similar communication regarding a similar risk with empagliflozin. Following a review of the safety data from clinical trials, post-marketing data, and the medical literature, the Department and the advisory committee concluded that the information regarding volume depletion, renal adverse reactions and the necessity to monitor renal function that is currently mentioned in the Israeli product leaflets for all 3 agents is sufficient and that there was no need to issue further communication similar to the FDA and Health Canada to the health care providers in Israel.
Drug-Lab interactions
Fulvestrant is indicated for the treatment of breast cancer. Due to a structural similarity between fulvestrant and estradiol, fulvestrant may interfere with antibody-based estradiol assays and may result in falsely increased levels of estradiol. Following a report on an unnecessary surgical procedure performed in a patient who was treated with fulvestrant which resulted in falsely elevated estradiol levels, the MOH ordered the company to issue a communication letter to health care professionals regarding this cross reactivity. The letter emphasized the importance of informing the laboratory performing the estradiol immunoassay about the treatment with fulvestrant and viewing the results of the estradiol levels in correlation with the clinical status of the patient. The product leaflets will be updated accordingly.
Emerging crisis due to pharmaceutical compounding
In July 2014, the Department received 3 reports of infection with Pantoea in children treated with total parenteral nutrition (TPN) prepared by the largest compounding pharmacy in Israel. After a special request that was made to the medical institutions for similar reports regarding pantoea infections in TPN users, additional 8 validated cases were received. The MOH with the compounding pharmacy collected the suspected batches and initiated a comprehensive investigation including examination of manufacturing process, equipment, and the sterility of each component. Medical institutions were instructed to switch patients to alternative products and to report adverse events related to TPN treatment. This crisis was managed by multidisciplinary team from various professions, expertise, and institutions. Following corrective activities, the compounding pharmacy resumed its routine manufacturing. Since this crisis, as a preventive measure, the MOH instructed the preparation centers to check sterility of samples from each prepared batch.
Initiating and deploying a national risk minimization plan
The MOH receives numerous reports of hemorrhagic events involving new oral anticoagulants (NOACs). Many of these events are serious and some are partially preventable. Because of these reports and in light of safety communications issued by some regulatory agencies, in 2014 the Department decided to initiate a risk minimization plan in collaboration with MAHs of NOAC products. The plan included prescriber guides, patient cards, and education plans for health care professionals. These educational materials were designed to emphasize the most important safety information, contraindications, main risk factors for bleeding, recommendations for conversion from vitamin K antagonists, recommendations for dosing adjustments, and more. The plans were implemented successfully in Israel in 2015.
Increased reporting due to previous high profile ADR event
Following the Eltroxin incident, the MOH supported the registration of additional levothyroxine products in order to provide therapeutic alternatives to patients with hypothyroidism in Israel. Two new products were registered in 2013. Since then, a few clusters of ADR reports for levothyroxine products were received by the Department. One of these clusters was received in 2014 and involved the alteration of the external packaging information of a specific product. As a response to that cluster, the Department initiated an inquiry, involving the MAH and the Institute for Standardization and Control of Pharmaceuticals of the MOH. The inquiry did not reveal any quality issues, changes in the formulation, or deviation from specifications. According to the MAH there has been no a change in the manufacturing site or the manufacturing process. It seems that the change in the information on the packaging triggered the ADR reports. Prior to its registration, the product was marketed in Israel with a US label and after its registration, it was marketed with a Canadian label. After completing the investigation, a communication was issued to health care providers informing them about the inquiry findings and the differences in labeling that were due to different labeling requirement of the 2 regulatory authorities.
In 2015 a second cluster of ADR reports including chest pain, gastrointestinal complaints, headache, and general “bad feeling” was received concerning a specific batch of levothyroxine. The Department initiated a new inquiry. Samples from new packages and used packages from different batches were examined by the Institute for Standardization and Control of Pharmaceuticals of the MOH. This inquiry also did not reveal any quality problem, changes in the formulation, or deviations from specifications. Following a clinical consultation with the advisory committee, no causal association was found between the medication and the complaints. No further action was required.
In 2016, a MAH of levothyroxine announced a change in the external packaging for marketing reasons. As a preventive measure, a communication about the change was issued to health care professionals and patients. The communication stressed the fact that no other change was made. Nevertheless, since this communication another cluster of ADR reports was received. The Department continues to monitor and evaluate these reports and will take actions as needed.
