Drug Allergies and Adverse Drug Reactions (PDF)

PHARMACY FOUNDATIONS PART 2 CHAPTER CONTENT .. Background... Adverse Drug Reactions Type A Reactions Type B Reactions FDA Tools to Reduce Adverse Drug Reactions Boxed Warnings Contraindications, Warnings and Precautions Adverse Reactions Risk Evaluation and Mitigation Strategies Medication Guides...

PHARMACY FOUNDATIONS PART 2 CHAPTER CONTENT .. Background... Adverse Drug Reactions Type A Reactions Type B Reactions FDA Tools to Reduce Adverse Drug Reactions Boxed Warnings Contraindications, Warnings and Precautions Adverse Reactions Risk Evaluation and Mitigation Strategies Medication Guides Assessing Causality of an Adverse Drug Reaction Characterizing an Adverse Drug Reaction — - —. — — Drugs Commonly Associated 1005 with Severe Skin Reactions .1005 Drug Allergies Anaphylaxis.... ... 1005 1006 Epinephrine Auto-Injector Administration 1006 Drugs Commonly Associated with Allergic Reactions - - — rt * — • •*»*• » M« " Heparin Biologies NSAIDs Contrast Media Peanuts and Soy tgg * Skin Testing and Desensitization Penicillin Skin Testing Induction of Drug Tolerance ( Desensitization) 1006 ... 1007 1007 1007 1007 1007 1007 1007 1007 1007 1008 1008 1008 « DEFINITIONS Mild or Severe Reactions to Histamine Release Urticaria (hives) A rash with red/pinkish raised patches. The patches have varied shapes and sizes. Pruritis (itching) Any rash or reaction that causes itching can be referred to as with pruritus. Contraction of respiratory ways Itchiness CHAPTER 77 DRUG ALLERGIES & ADVERSE DRUG REACTIONS BACKGROUND Adverse drug reaction (ADR ) is a term that encompasses all unintended pharmacologic effects of a drug when it is administered correctly and used at recommended doses. ADRs should not be confused with medication errors, which can include overdose and administration mistakes, and are discussed in the Medication Safety & Quality Improvement chapter. ADRs result in substantial morbidity and mortality, and reports are increasing; over one million reports with serious outcomes were logged with the FDA in 2018 ( including 197, 060 deaths). Although side effects or adverse effects can occur in anyone, some patients are more susceptible than others. For example, some degree of renal damage can occur with use of an aminoglycoside for longer than seven days. However, in patients with underlying renal impairment, nephrotoxicity is more likely to occur and may happen after a shorter duration. ADVERSE DRUG REACTIONS VS. ERRORS Erythema Redness on skin from superficial (near the surface) capillaries, often due to inflammation, often with pruritis. When pressed down, the red skin that is due to erythema will blanch (whiten) temporarily because the blood flow is blocked. Erythematous refers to an area on the skin, such as a patch, with erythema. Angioedema Swelling caused by edema in the deeper dermal, cutaneous and sub-mucosal tissue. Morbilliform Macular or maculopapular (or both), with 1-10 mm lesions. In between the lesions is healthy skin. Adverse Drug Reaction ( ADR) Effects from a drug when it is administered correctly. ADRs are typically dose - related; the ADR severity increases with higher doses/reduced clearance. Medication Error Someone did something wrong, such as giving a medication dose to the wrong person. The new drug you are taking causes ’urinary retention’ which means it can take longer to pee when you use the restroom. Bring a magazine. Did you just say that Dr. Savage cut off the wrong leg??!! Oh no! Hi Mrs. Apple Cake! Dr. Savage sent over a prescription for you for Celebrex for joint pain. CONTENT LEGEND l Antigen — —— Sulfa Drugs Opioids Blood vessels to r dilate # .. » Beta - Lactams A Penicillin Allergy, Or Not? secretion 1001 1001 1001 1001 1001 1001 1002 1002 1002 1002 1003 ADR Reporting ••••••••••••••••••• Intolerances, Sensitivities and Idiosyncratic Reactions 1003 1003 Stomach Upset / Nausea , 1003 Intolerance or Allergy ?. 1004 Mild Rash 1004 Photosensitivity Drugs Most Commonly Associated 1004 with Photosensitivity Thrombotic Thrombocytopenic Purpura 1004 1004 Drugs Commonly Associated with TTP 1004 Severe Skin Reactions • Gastric acid 1000 1001 Study Tip G ^l , ^9 Weren't you hospitalized recently for a stroke? = * Key Drug Guy V Jl . RxPrep Course Book | RxPrep © 2019 RxPrep © 2020 ADVERSE DRUG REACTIONS ADRs are categorized into two types: predictable (Type A ) and unpredictable (Type B ) reactions. TYPES OF ADRS Type B reactions Idiosyncratic - not predictable from drug's pharmacology Examples: rash with lamotrigine, rash with abacavir, Stevens -Johnson Examples: hemolytic anemia and thrombocytopenia Type III reactions: immune -complex reactions; occur 3-10 hours after drug exposure. Example: drug - induced lupus erythematosus hypersensitivity reactions; can occur anywhere from 48 hours to several weeks after drug exposure. Example: PPD skin test for tuberculosis ( peaks at 48 - 72 hours) Type IV reactions: delayed Type A reactions (most ADRs) Dose- dependent and predictable based on the drug’s pharmacology Can be influenced by patient -specific factors Type II reactions: minutes to hours after drug exposure. Mr . Bean, you are starting doxazosin for prostate enlargement. It will make your blood pressure drop when you stand up. This will make you dizzy. We will Increase the dose slowly. Start by taking the medication at bedtime. Mr. Mortensen, you are going to take Plavix to keep the arteries to your heart open so blood can get through. Plavix can cause a severe rash called TTP. This rash is not common, but if it happens, call your doctor right away. Syndrome TYPE A REACTIONS Type A reactions are dose - dependent, related to the known pharmacologic actions of the drug, can occur in any patient and range from mild to severe. Type A reactions are the most common and account for an estimated 80% of ADRs. An example of a Type A reaction is orthostatic hypotension with doxazosin. If a patient starts doxazosin at 1 mg QHS, they will have much less orthostatic hypotension and dizziness than if the medication is started at a 4 mg dose. Because of this risk , the dose should be slowly titrated upward. TYPE B REACTIONS Type B reactions are generally not dose -dependent, are unrelated to the pharmacologic actions of the drug and can be influenced by patient -specific factors. Type B reactions include: Drug allergies Pseudoallergic reactions (e .g., redman syndrome with rapid vancomycin infusion , itching after opioid administration ) Drug intolerances (e.g., nausea with codeine ) Idiosyncratic reactions (e.g., Stevens-Johnson syndrome) Drug allergy refers to an immune - mediated response to a medication or excipient (inactive ingredient ). True drug allergies, or hypersensitivity reactions, are classified into four types: r~ This is the classic -type of IgE - mediated allergic reaction. \y Type I reactions: immediate Mostly due to histamine basophils. (within 15-30 minutes of drug release from exposure). bronchospasm, include Reactions urticaria, angioedema and anaphylaxis ^ Severity ranges from minor inconvenience to death FDA TOOLS TO REDUCE ADVERSE DRUG REACTIONS BOXED WARNINGS A boxed warning indicates a risk of death or permanent disability from a drug (e.g. increased risk of venous thromboembolism and death from stroke with raloxifene) . f The risk of fatality can be due to prescribing or dispensing errors. For example, conventional amphotericin b deoxycholate has a boxed warning not to exceed 1.5 mg / kg. Fatalities have been caused by using the lipid amphotericin dosing ( typically 3 - 6 mg / kg) for conventional amphotericin. CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS Contraindications indicate that the drug Mrs. Jones, you cannot cannot be used in that patient. The risk get Evista because you had a DVT in the past will outweigh any possible benefit (e.g., a history of venous thromboembolism is a contraindication to the use of raloxifene ). If there are no known contraindications for a drug, the section will state “ None.” include Mrs. Smith , you could get a DVT from Evista serious reactions that can result in death, because you sleep on the couch all day. hospitalization, medical intervention disability or teratogenicity (e.g., raloxifene has a warning for venous thromboembolism ). Warnings and precautions may or may not change a prescribing decision. Warnings and precautions . ADVERSE REACTIONS Mrs. Ngo, you are Adverse reactions refer to undesirable, starting Evista . You uncomfortable or dangerous effects from might get hot flashes and achy joints. a drug (e.g., arthralgia from raloxifene). The risk- benefit assessment is patient -specific (e.g., arthralgia from raloxifene will be more of a concern in an unfit patient with chronically sore joints, versus a fit patient with no sore joints) . 77 | DRUG ALLERGIES & ADVERSE DRUG REACTIONS RISK EVALUATION AND MITIGATION STRATEGIES MEDICATION GUIDES Risk Evaluation and Mitigation Strategies ( REMS) are risk management plans required by the FDA for some drugs. They are developed by the manufacturer and approved by the FDA to ensure the benefits of a drug outweigh the risks. REMS programs can include a Medication Guide or Patient Package Insert, communication plan , Elements to Assure Safe Use ( ETASU) or an Implementation System. REMS can include a variety of approaches. For example, the REMS for a drug could require physicians or pharmacies to have special certification to prescribe or dispense the drug, patients enroll in a registry so that ADRs can be tracked or that lab testing is completed before dispensing. Examples include the clozapine REMS, the iPLEDGE program for isotretinoin and the REMS to reduce the misuse of long acting opioids. The list of REMS drugs continues to grow. When studying from this book, note the many drugs that have REMS requirements. Medication Guides ( or MedGuides) present important adverse events that can occur with over 300 medications. MedGuides are FDA-approved patient handouts that are written in non- technical language and are considered part of the drug's labeling. If a medication has a MedGuide, it should be dispensed with the original prescription and with each refill. Some medications dispensed while inpatient require MedGuides and these should be available to the patient or family upon request. It is not necessary to dispense them to inpatients routinely because the patient is being monitored. MedGuides are required for many individual agents and some entire classes of medications ( including anticonvulsants, antidepressants, long-acting opioids, NSAIDs, ADHD stimulants and atomoxetine ). - ASSESSING CAUSALITY OF AN ADVERSE DRUG REACTION When an ADR occurs, the Naranjo Scale (a validated causality assessment scale) can help determine the likelihood that a drug caused an adverse reaction. Based on the questionnaire, a probability score is calculated. A score > 9 = definite ADR; 5 - 8 = probable ADR; 1 - 4 = possible ADR; 0 = doubtful ADR. QUESTION YES NO DO NOT KNOW Are there previous conclusive reports on this reaction? +1 0 0 Did the adverse event appear after the suspected drug was given? +2 -1 0 Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given? +1 0 0 Did the adverse reaction appear when the drug was readministered? +2 -1 0 Are there alternative causes that could (on their own) have caused the reaction? -1 +2 0 Did the reaction reappear when a placebo was given? -1 +1 0 Was the drug detected in any body fluid in toxic concentrations? +1 0 0 Was the reaction more severe when the dose was increased or less severe when the dose was decreased? +1 0 0 Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 Was the adverse event confirmed by any objective evidence? +1 0 0 CHARACTERIZING AN ADVERSE DRUG REACTION When patients report an adverse drug reaction, pharmacists must ask the right questions in order to determine whether an adverse reaction is an intolerance or drug allergy: What reaction occurred (e.g., a mild rash, a severe rash with blisters, trouble breathing) ? When did it occur? About how old were you? Can you use similar drugs in the same class? For example, if a penicillin allergy is reported, ask if the patient has ever used Keflex. Do you have any food allergies or a latex allergy? Some food allergies (e.g.f soy, peanut ) have implications for certain drugs or formulations. Latex allergies should be collected because some drugs require tubing, have latex vial stoppers or require gloves for administration. All allergies should be noted in the patients record . RxPrep Course Book | RxPrep 02019, RxPrep 02020 ADR REPORTING Side effects, adverse events and allergies should be reported to the FDAs Med Watch program , which is called the FDA Adverse Event Reporting System ( FAERS) , that provides a centra] collection point for problems caused by drugs. Vaccines are an exception and are reported under a different program called VAERS. See Immunizations chapter for more information. The FDA can require Phase IV ( post - marketing safety surveillance programs) for approved drugs and biologies, and collects and analyzes the reports to better understand the drug safety profile in a real world setting. When drugs are studied in trials, high - risk patients are typically excluded. Yet in real life settings, some high -risk patients will receive the medication. Post - marketing reports also help identify side effects that occur less frequently. If a drug causes a reaction in 1 out of every 3,000 people, the problem may not be apparent in a smaller clinical trial. For this reason, community - based adverse event reporting is critical. EXAMPLE: ADR INCIDENCE IN REAL LIFE VS. CLINICAL TRIAL When spironolactone was studied in heart failure patients during the RALES trial, patients with renal insufficiency or elevated potassium levels were excluded due to the known risk of additional hyperkalemia from the use of spironolactone. The drug was found to have benefit in advanced heart failure patients and doctors in the community began to use it in their heart failure patients. In this real life setting, patients with renal insufficiency or elevated potassium were occasionally prescribed spironolactone, and arrhythmias and sudden death due to hyperkalemia were reported. Reporting is voluntary but has important implications for safe medication use. Healthcare professionals and patients can report adverse events to the drug manufacturer, who is required by law to send the report to the FDA. The MedWatch form used for reporting can be found online. Reports can also be made by calling the FDA directly. MedWatch is also used for reporting problems with biologies, medical devices, some dietary supplements and cosmetics. If the FDA receives enough reports that a drug is linked to a particular problem, the manufacturer can be required to update the labeling (e.g., package insert ). In especially risky cases, a drug safety alert is issued to prescribers, usually before the labeling is changed. EXAMPLE: ADR REPORTS LEAD TO FDA REQUIREMENT FOR SAFETY LABELING CHANGES Oseltamivir (Tamiflu ) was initially released without any warning of unusual behavior in children. The FDA received enough reports that they issued a warning to prescribers in 2006. After many more reports, in 2008, the FDA required the manufacturer to update the prescribing information to include a precaution about hallucinations, confusion and other strange behavior in children. Example of a Posting on the FDA Website of Phase IV Monitoring DRUG USAGE Dulaglutide Diabetes mellitus type 2 (Trulicity ) . ADVERSE EVENT REPORTS Serious hypersensitivity reactions NOTES FDA is evaluating the need for regulatory action. INTOLERANCES, SENSITIVITIES AND IDIOSYNCRATIC REACTIONS STOMACH UPSET/NAUSEA Stomach upset or nausea is often incorrectly reported as an allergy. It should be listed on the patient profile because the drug bothered the patient and, if possible, should be avoided in the future, but this is not an allergy and should not prevent drugs in the same class from being used. This is more accurately categorized as an intolerance. Electronic medical records allow for documentation of intolerances separate from allergies. An example of an intolerance is the patient who has stomach upset with codeine (but not hydrocodone or other drugs in the morphine class) or from erythromycin ( but not azithromycin or other macrolides). INTOLERANCE OR ALLERGY ? Gather enough information to determine the type of reaction. Example: A patient reports getting a stomach ache from Chantix . Possibilities: I did not eat anything until dinner because Chantix made me nauseous. ( Intolerance) I got nauseous , I felt dizzy and I had trouble breathing. ( Allergy ) Intolerances are less serious complaints, such as nausea or constipation. As the drug bothers the patient, it should be avoided, if possible. Allergies are an immune system response, and range from mild (e.g., pruritus) to severe (e.g., Stevens Johnson syndrrome). Allergies can affect multiple areas: Facial swelling, bronchoconstriction with a severe drop in BP Weakness, fever and severe rash EXAMPLE: INTOLERANCE REPORTED INCORRECTLY AS A DRUG ALLERGY CG received acetaminophen 300 mg/codeine 30 mg (Tylenol #3) for pain relief after a dental extraction. She got very nauseated from the medicine. When she was admitted to the hospital several years later for a left hip replacement, she reported to the intake coordinator that she was “allergic " to codeine. The intake coordinator did not attempt to clarify the reaction. The hospital’s pain management protocol calls for hydromorphone in a patient-controlled analgesic device for postoperative pain control. The physician used a less desirable option for pain control due to the reported allergy.