Pharmacovigilance - PDF

PHARMACOVIGILANCE  Content: 1. Introduction 8. Severity of ADRs 2. Aims of PV 9. Reporting of ADRs 3. History and Need of PV 10. Collection of reports 4. Terminology 11. Follow-up of reports 5. ADR classification 12. Data manage...

PHARMACOVIGILANCE  Content: 1. Introduction 8. Severity of ADRs 2. Aims of PV 9. Reporting of ADRs 3. History and Need of PV 10. Collection of reports 4. Terminology 11. Follow-up of reports 5. ADR classification 12. Data management 6. Possible causes of ADRs 13. Special situations 7. Examples of drug recalls 14. Reporting of ICSR’s  PHARMACO + VIGILANCE medicine to watch Greek pharmakon; drug Latin vigilare; to be awake or alert, to keep watch DRUG SAFETY  Pharmacovigilance The science and activities relating to the; Detection Evaluation Understanding Prevention of adverse drug reactions or any other drug-related problems. Recently, its concerns have been widened to include herbals, traditional and complementary medicines, blood products, biologcal devices and vaccines.  early detection of unknown safety problems detection of increases in Aims of frequency Pharmacovigilance identification of risk factors quantifying risks preventing patients from being affected unnecessarily  Why do we need pharmacovigilance? Thalidomide Tragedy Thalidomide first entered the German market in 1957 as an over-the-counter remedy, based on the maker’s safety claims. They advertised their product as “completely safe” for everyone, including mother and child, “even during pregnancy,” as its developers “could not find a dose high enough to kill a rat.” By 1960, thalidomide was marketed in 46 countries, with sales nearly matching those of aspirin. Thalidomide Tragedy Around this time, Australian obstetrician Dr. William McBride discovered that the drug also alleviated morning sickness. He started recommending this off-label use of the drug to his pregnant patients, setting a worldwide trend. Birth defect; phocomelia In 1961, McBride began to associate this so-called harmless compound with severe birth defects in the babies he delivered. The drug interfered with the babies' normal development, causing many of them to be born with phocomelia, resulting in shortened, absent, or flipper-like limbs. March of 1962, the drug was banned in most countries where it was previously sold. Application for thalidomide contained incomplete and insufficient data on its safety and effectiveness. Among her concerns was the lack of data indicating whether the drug could cross the placenta, which provides nourishment to a developing fetus. Despite its harmful side effects, thalidomide is FDA-approved for two uses today—the treatment of inflammation associated with Hansen’s disease (leprosy) and as a chemotherapeutic agent for patients with multiple myeloma. dispensing of thalidomide is regulated by the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program. The S.T.E.P.S. program, designed by Celgene pharmaceuticals and carried out in pharmacies where thalidomide prescriptions are filled, educates all patients who receive thalidomide about potential risks associated with the drug.  WHO Programme Members additional monitoring 1. Humanitarian Concern 2. Ethics ❖Insufficient evidence of safety from clinical trials Known to cause harm and not narrow population (age & sex specific) informing the patient is unethical. narrow indications (only specific disease) short duration Should report serious reactions ❖Tests in animals are insufficient to predict 3. Safe use of medications human safety It has been suggested that ADRs ❖Safety profile in special groups (elderly, parous, women, children) inadequate / may cause 197,000 deaths per incomplete. year in EU. 4. ADRs are expensive 5. Promoting rational use of Cost of drug related morbidity and medicines and adherence mortality exceeded 177.4 billion dolar in 2000 in USA. 6. Ensuring public confidince ADR related cost exceeds the cost of medications themselves. 7. To protect patients from unnecessary harm Many ADR’s are preventable. Terminology Adverse Drug Any harm associated with the use of given drugs at a normal dosage during normal use. Reaction ADRs may occur following a single dose or prolonged administration of a drug or (ADR) result from the combination of two or more drugs. Adverse Drug Any untoward medical occurrence that may present during treatment with a medicine but which does not necessarily have a causal relationship with this Event (ADE) treatment. Any unintended effect of pharmaceutical product occurring at doses normally used by a patient which is related to the pharmacological properties of drug. Side Effect The meaning of ADR differs from the meaning of "side effect ", as this last expression might also imply that the effects can be beneficial. Unexpected An adverse reaction, the nature of severity of which is not consisted with Adverse Drug domestic labelling or market authorisation, or expected from characteristics of Reaction the drug.  Results in persistent or significant disability / Congenital incapacity Abnormalities Life- Serious threatening Adverse Drug Results in death Reaction Requires intervention to prevent Requires inpatient permanent hospitalization or damage prolongation of existing hospitalization Causality ; The definition of an adverse reaction implies at least a reasonable possibility of a causal relationship between a suspected medicinal product and an adverse event. An adverse reaction, in contrast to an adverse event, is characterized by the fact that a casual relationship between a medicinal product and an occurrence is suspected. For the purposes of reporting to TÜFAM (Türkiye Farmakovijilans Merkezi / Pharmacovigilance Centre of Turkey), if an event is spontaneously reported, even if the relationship is unknown or unstated, it meets the definition of an adverse reaction. Therefore all spontaneous reported notified by healthcare professionals, patients or consumers are considered suspected adverse reactions, unless the reporter specifically states that they believe the events to be unrelated or that a casual relationship can be excluded. Classification of ADRs 1. Type A: Augmented pharmacologic effects (dose dependent and predictable) 2. Type B: Bizarre effects (dose independent & unpredictable) 3. Type C: Chronic effects 4. Type D: Delayed effects 5. Type E: End-of-treatment effects 6. Type F: Failure of therapy 7. Type G: Genetic reactions Possible Causes of ADRs 1. Intrinsic Idiosyncrasy Mutagenicity Carcinogenicity Teratogenicity 2. Extrinsic Adulterations, contamination 3. Underlying medical conditions 4. Interactions 5. Wrong use Examples; 1. Thalidomide (1965) Phocomelia 2. Practolol (1975) Sclerosing peritonitis 3. Phenformin (1982) Lactic acidosis 4. Rofecoxib (2004) cardiovascular effects 5. Veralipride (2007) Anxiety, depression, movement disorders 6. Rosiglitazone (2010( Increased risk of MI and death from CV causes Severity of ADRs No need of therapy, antidote, or Minor hospitalization Requires drug change, specific Moderate treatment, hospitalization Potentially life threatening, permenant Severe damage, and prolonged hospitalization Directly or indirectly lead to death Lethal Reporting ADRs ICSR; individual case safety report This is an adverse drug reaction report, involving the reporting of one or several suspected adverse reactions in relation to a medicinal product that occur in a single patient at a specific point of time. A valid report should include 4 minimum criteria !!! Identifiable reporter Identifiable patient 4 min criterion One suspect medicinal Suspect adverse reaction product Primary source; The primary source of the information on a suspected adverse reaction(s) is the person who reports the event. Collection of reports Reports Spontaneous reports Literature reports originating from Reports from other sources unsolicited Information on suspected adverse reactions from the Internet or digital sources media Reports originating from solicited sources Spontaneous Reports A spontaneous report is an unsolicited communication by a healthcare professional or consumer to the Agency or the marketing authorization holder that describes one or more suspected adverse reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organized data collection program. Reports that follow a direct healthcare professional communication, publication in the press, questioning of healthcare professionals by company representatives, including product promotion representatives, communication from patients’ organizations to their members, or class action lawsuits should be considered spontaneous reports. Literature Reports The scientific and medical literature is a significant source of information for the monitoring of the safety profile and of the risk-benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues. So; marketing authorization holders are responsible from adverse reactions in journals. Reports from other sources If a marketing authorization holder becomes aware of a report of suspected adverse reactions originating from a non- medical source (e.g. the press or other media), it should be handled as a spontaneous report. Every attempt should be made to follow-up the case to obtain the minimum information that constitutes a valid ICSR. Information on suspected adverse reactions from the Internet or digital media Marketing authorization holders should regularly screen the Internet/digital media under their management or responsibility, such as web sites, web pages, blogs, vlogs, social networks, Internet forums, chat rooms, or health portals, for potential reports of suspected adverse reactions. Reports originating from solicited sources Solicited reports of suspected adverse reactions are those derived from organized data collection systems, which include clinical trials, non- interventional studies, registries, off-label or named patient use, other patient support and disease management programs, surveys of patients or healthcare providers, compassionate use programs or information gathering on efficacy or patient compliance. Follow-up of reports When first received, the information in suspected adverse reactions reports may be incomplete. These reports should be followed-up as necessary to obtain supplementary detailed information significant for the scientific evaluation of the cases. This is particularly relevant for monitored events of special interest, prospective reports of pregnancy, cases notifying the death of a patient, cases reporting new risks or changes in the known risks. For suspected adverse reactions relating to biological medicinal products, the definite identification of the concerned product with regard to its manufacturing is of particular importance. Therefore, all appropriate measures should be taken to clearly identify the name of the product and the batch number. Data Management Electronic data and paper reports of suspected adverse reactions should be stored and treated in the same way as other medical records with appropriate respect for confidentiality rules regarding patients’ and reporters’ identifiability. Confidentiality of patients' records including personal identifiers (if provided) should always be maintained. Identifiable personal details of reporting healthcare professionals should be kept in confidence. However, if this information is included in the reports that the marketing authorization holder will be making to TÜFAM, the reporter’s identifiable personal details and contact details should be submitted. With regards to patient’s and reporter’s identifiability, transmission of case report information from TÜFAM to the marketing authorization holder should respect the confidentiality rules. Special Situations Pregnancy Reports, where the embryo or fetus may have been exposed to medicinal products should be followed-up in order to collect information on the outcome of the pregnancy and development of the child after birth. When an active substance or one of its metabolites has a long half-life, this should be taken into account when assessing the possibility of exposure of the embryo, if the medicinal product was taken before conception. When pregnant women or healthcare professionals contact marketing authorization holders to request information on the teratogenicity of a medicinal product or experience of use during pregnancy, reasonable attempts should be made to obtain information on any possible medicinal product exposure to the embryo or fetus and to follow-up on the outcome of the pregnancy. Reports of exposure to medicinal products during pregnancy should contain as many detailed elements as possible in order to assess the causal relationships between any reported adverse events and the exposure to the suspected medicinal product. Individual cases with an abnormal outcome associated with a medicinal product following exposure during pregnancy are classified as serious reports and should be reported. This especially refers to: ❖ reports of congenital anomalies or developmental delay, in the fetus or the child; ❖ reports of fetal death and spontaneous abortion; and ❖ reports of suspected adverse reactions in the neonate that are classified as serious. Phenytoin use in pregnancy (cleft lip) Use of a medicinal product in the pediatric or elderly population The collection of safety information in the pediatric or elderly population is important. Reasonable attempts should therefore be made to obtain and report the age or age group of the patient when a case is reported by a healthcare professional, or consumer in order to be able to identify potential safety signals specific to a particular population. Reports of overdose, abuse, off-label use, misuse, medical error or occupation exposure Medication error refers to any unintentional error in the prescribing, dispensing, or administration of a medicinal product. Reports of overdose, abuse, off-label use, misuse, medication error or occupational exposure with no associated adverse reaction should not be reported as ICSRs. They should be considered in periodic safety update reports as applicable.  Suppose a drug has two pharmaceutical forms, iv and sc, and Medication Error they are similar to each other in terms of packaging. The pharmacist may worry about he/she can give the wrong drug because of the similarity. Off-label Colchicine is indicated for the treatment and prevention of gout, though it is also generally considered first-line treatment for acute pericarditis which is an off-label use. Occupational exposure Adverse events observed in exposure to chemotherapy in nurses Lack of therapeutic efficacy Reports of lack of therapeutic efficacy should be recorded, followed-up if data is incomplete, and reported to the Agency. Special care should be taken with reports involving medicinal products used in critical conditions or for the treatment of life-threatening diseases, vaccines, contraceptives are examples of such cases. This applies unless the reporter has specifically stated that the outcome was due to disease progression and was not related to the medicinal product. Reporting timeframes In general, the reporting of serious valid ICSRs is required as soon as possible, but in no case later than 15 calendar days after initial receipt of the information by any personnel of the marketing authorization holder, including product promotion representatives or other contractors. This applies to initial and follow-up information. Where a case initially reported as ‘serious’ becomes ‘non-serious,’ based on new follow-up information, this information should still be reported within 15 days. Biosimilars A biotechnological product which is similar in terms of quality, safety and eficacy to an already licensed reference biotherapeutic product. Very important according to PV!! http://www.titck.gov.tr/Ilac/Farmakovijilans  Pharmaceutical Patient Company Physician or Pharmacist TÜFAM World Health Organisation Examples; 1. A 57 y-old patient hospitalized due to headache, blurred vision, insomnia and high blood pressure (210 / 120 mm-Hg). In the hospital, parenteral nitroprusside administered to the patient. You were at the hospital at the same time and you noticed a turbidity in the ampoule. What action would you take for this case? 2. Your patient came to the pharmacy, she is in 19th week of pregnancy and she is suffering from thromboembolism. The physician prescribed Aspirin. What action would you take for this case? 3. A physician consulted you about a metastatic breast cancer patient treated with trastuzumab resulted in unexpected progression of the disease. What would you do in such a situation? 4. One of your patient’s daughter came to your pharmacy, she shared her mother’s death with you. Her mother was died in a car accident a week ago. You know her mother, she is always taking her medications from your pharmacy. You know she is suffering from diabetes and using GLP-1 analogs, barbiturates and low dose aspirin. What would you do in such a situation? 5. When you are talking to your colleagues, one of your friend shared his concerns about the preparation of benzamycin. He said there is no sufficient information about the preparation of the drug in short product information and he has doubts about making the wrong application. What would you do in this situation? 6. 32 years old, female patient wants to take propranolol for preventing anxiety before her presentation in office. What action would you take for this case? 7. A 36-year-old female, living in Sydney, presented with hyperpigmented plaques on the face, scalp, arms, hands, buttocks, legs, and feet. She has had similar lesions over the past fifteen years and described them as burning, itchy, and painful. There were dermal papules on the perinasal and periocular areas. The blood work revealed positive antinuclear antibodies (ANA) by ELISA and positive anti-(ds-DNA), with normal C3 and C4, anti-smith and anti-phospholipid antibodies were negative. She diagnosed with Systemic Lupus Ertyhematosus and started therapy 400 mg/day hydroxychloroquinine for 5 years, 7.5 mg/day prednisolone during the attack and naproxen on need. A week ago, she experienced blurred vision, scotomata and in visual fluid examination the physician described her situation as retinal toxicity and change her medication. 8. JM is a 64-year-old woman with a PMH of pancreatitis, uncontrolled gout, severe psoriasis, recurrent infections requiring hospitalization. Her current medications include 40 mg/ day rosuvastatin for a year, methylprednisone lotion for 2 months, and 300 mg/ day allopurinol for 5 years. 0.6 mg during attack Colchicine was also added a few days ago for a gout exacerbation. She reports severe muscle pain and fatigue. She started using paracetemol for pain but it’s not recovered. After that, she consulted her physician and decided to stop rosuvastatin. After discontinuation to statin therapy, her pain started decreasing. References PaI S., WHO; Quality Assurance and Safety of Medicines, Pharmacovigilance TİTCK, İyi Farmakovijilans Uygulamaları Modülleri Pharmacovigilance team, Quanticate CRO, The History of Pharmacovigilance Infographic Fintel B., Samaras A.T., Carias E., The Thalidomide Tragedy: Lessons for Drug Safety and Regulation FDA Adverse Event Reporting System Ernst FR & Grizzle AJ, 2001: J American Pharm. Assoc.