Drug Allergies and Adverse Drug Reactions PDF

77 | DRUG ALLERGIES & ADVERSE DRUG REACTIONS MILD RASH SPOTS AND RASHES Opioids cause a non-allergic release of histamine from mast cells in the skin, causing itching and hives in some patients. This is particularly problematic in the inpatient setting after surgery, when opioid - naive patients...

77 | DRUG ALLERGIES & ADVERSE DRUG REACTIONS MILD RASH SPOTS AND RASHES Opioids cause a non-allergic release of histamine from mast cells in the skin, causing itching and hives in some patients. This is particularly problematic in the inpatient setting after surgery, when opioid - naive patients receive the medication or when non- naive patients receive higher -than -normal doses. Pruritus due to this or other causes, if not severe, can be reduced or avoided if the patient is pre - medicated with an antihistamine, such as diphenhydramine. PHOTOSENSITIVITY Photosensitivity can occur when sunlight reacts with a drug in the skin and causes tissue damage that looks like a severe sunburn on sun -exposed areas; this occurs within hours of sun exposure. A type IV (delayed hypersensitivity ) reaction can also occur with sun exposure and some medications. It appears as a red , itchy rash that can spread to areas that were not exposed to sun and occurs within days of sun exposure. When dispensing medications that can cause photosensitivity, it is important to advise the patient and /or their caregivers to limit sun exposure and to use sunscreens that block both UVA and UVB radiation ( these are labeled broad spectrum). See Key Drugs Guy below. DRUGS MOST COMMONLY ASSOCIATED WITH PHOTOSENSITIVITY KEY DRUGS Amiodarone Diuretics (thiazide and loop) Methotrexate Oral and topical retinoids Quinolones St. John’s wort Others: Antihistamines (1st generation) Carbamazepine Chloroquine Coal Tar Fluorouracil Griseofulvin NSAIDs Sulfa antibiotics Quinidine Tacrolimus Tigecycline Tetracyclines Voriconazole THROMBOTIC THROMBOCYTOPENIC PURPURA Thrombotic Thrombocytopenic Purpura (TTP) is a blood disorder in which clots form throughout the body. The clotting process consumes platelets and leads to bleeding under the skin and the formation of purpura ( bruises) and petechiae (dots) on the skin. TTP can be fatal and should be treated immediately with plasma exchange. Common drugs that can cause TTP are listed in the Key Drugs Guy on the right. Macules Flat spots Papules Raised spots Purpura Red /purple skin spots (lesions) due to bleeding underneath the skin. Purpura includes small and large spots: Petechiae Smaller lesions Larger lesions Ecchymoses < 3 mm > 5 mm Purpura , with petechiae and ecchymoses (TTP rash) Hematoma A collection of blood under the skin due to trauma (injury) to a blood vessel, resulting in blood leaking into the surrounding tissue. Drugs that can cause hematoma include heparin, low molecular weight heparin (LMWH), some other anticoagulants and phytonadione (vitamin K) if given mistakenly as . an IM injection Hematoma DRUGS COMMONLY ASSOCIATED WITH TTP KEY DRUGS % Others: Acyclovir Clopidogrel Famciclovir Sulfamethoxazole Quinine Valacyclovir SEVERE SKIN REACTIONS There are several severe skin reactions that can be caused by drugs, including Stevens-Iohnson syndrome (SJS) , toxic epidermal necrolysis (TEN ) , and drug reaction with eosinophilia and systemic symptoms ( DRESS ). All of these can be life - threatening and require prompt treatment. Although the OTC analgesics acetaminophen and ibuprofen are generally considered to be safe, cases of severe reaction have been reported , which highlights the unpredictable nature of these reactions. Drugs most commonly associated with these severe skin reactions are listed in the Key Drugs Guy on the following page. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis SJS and TEN involve epidermal detachment and skin loss that is equivalent to third degree burns. SJS and TEN generally occur 1 - 3 weeks after drug administration, and almost always more than 72 hours after drug administration. These Patient with Stevens Johnson Syndrome . RxPrep Course Book | RxPrep © 2019 RxPrep © 2020 reactions can result in severe mucosal erosions, a high body temperature, major fluid loss and organ damage (eyes, liver, kidney, lungs). SJS and TEN are commonly classified by the percent of skin detachment. The key to treating both is to stop the offending agent as soon as possible. In addition , patients will receive fluid and electrolyte replacement, wound care and pain medications. Systemic steroids are contraindicated in TEN, but may be used in SJS, though benefit is controversial. Due to the severity of the mucosal involvement, antibiotics are often necessary to prevent or treat an infection. Drug Reaction with Eosinophilia and Systemic Symptoms DRESS can include a variety of skin eruptions accompanied by systemic symptoms such as fever, hepatic dysfunction, renal dysfunction and lymphadenopathy, but rarely involves mucosal surfaces. Treatment consists of stopping the offending agent, although symptoms may continue to worsen for a period of time after the agent has been discontinued. DRUG ALLERGIES Some drugs are more commonly associated with drugallergies than others. Penicillins and sulfonamides are two classes that cause the most drug allergies. For a true drug allergy to occur, the person must have taken the drug previously. Initial exposure will cause a Type I hypersensitivity reaction, resulting in IgE production, which primes the body to release excessive histamine at the next drug exposure. This section describes drug allergy reactions and treatment, but keep in mind that similar treatment can be used for non -drug allergies. A pharmacist who is dispensing an epinephrine auto-injector for other types of allergies will provide the same instructions. Some medications (e.g., phytonadione, contrast media ) are associated with a pseudoallergic reaction, sometimes called an anaphylactoid reaction. It is not IgE - mediated , but the clinical appearance and treatment are similar to that of anaphylaxis. A reaction without breathing difficulty can sometimes be treated by simply stopping the offendingdrug. Antihistamines can be used to counteract the histamine release that causes itching, swelling and rash. Systemic steroids, and sometimes NSAIDs, can be used to decrease swelling. Severe swelling may necessitate a steroid injection. Epinephrine is used to reverse bronchoconstriction if the patient is wheezing or has other signs of trouble breathing. ANAPHYLAXIS Anaphylaxis is a severe, life - threatening allergic reaction that occurs within seconds to minutes of drug exposure. Anaohvlaxis can occur after an initial exposure and DRUGS COMMONLY ASSOCIATED WITH SEVERE SKIN REACTIONS SJS / TEN Clopidogrel Terbinafine Amiodarone Darunavir Tiagabine Bupropion Deferasirox Varenicline Caspofungin Etravirine Voriconazole Celecoxib Fosphenytoin Zonisamide Clindamycin Hydroxychloroquine KEY DRUGS Abacavir Allopurinol Carbamazepine Ethosuximide * Tf Ibuprofen DRESS Isavuconazonium Doxycycline Isoniazid Fosphenytoin Macrolides Gabapentin Metronidazole Lacosamide Minocycline Minocycline Oseltamivir Olanzapine Oxcarbazepine Oxcarbazepine Peramivir Sulfasalazine Modafinil Phenobarbital Terbinafine Nevirapine Piroxicam Valproate Penicillins Quinine Quinolones Vancomycin Lamotrigine Phenytoin Sulfamethoxazole subsequent immune response, but some drugs can cause anaphylaxis with the first exposure. A patient experiencing anaphylaxis may have generalized urticaria ( hives ) , swelling of the mouth and throat , difficulty breathing or wheezing sounds, abdominal cramping and hypotension ( which can cause dizziness, lightheadedness or loss of consciousness) . Symptoms can develop quickly, within seconds or minutes; treatment must be administered immediately. Anyone with serious allergies to food , drugs or serious medical conditions (including hypoglycemia that may require glucagon ) should wear a medical identification bracelet. This will alert emergency responders and many can be linked to the patient s health profile that is accessible through a 24hour information center. Anaphylaxis Treatment An anaphylactic reaction requires immediate emergency medical care. The patient or family should be instructed to call 911 if anaphylaxis occurs. Treatment includes epinephrine injection ± diphenhydramine ± steroids ± IV fluids. To avoid blocking the airway, nothing should be placed under the head or in the mouth. Swollen airways can be quickly fatal; patients who have had such a reaction should carry a single use epinephrine auto-injector ( EpiPen, EpiPen Jr, Auvi -Q , Adrenaclick , Symjepi or generic equivalent ) as they may be at future risk. These are generally available as epinephrine 1 mg / mL ( previously labeled as 1:1000 ) in dosages of 0.3 mg (adult dose ) or 0.15 mg ( pediatric dose ) of epinephrine. The 0.15 mg dose is for patients 15 - 30 kg ( EpiPen Jr dose). 77 | DRUG ALLERGIES & ADVERSE DRUG REACTIONS EPINEPHRINE AUTO- INJECTOR ADMINISTRATION For EpiPen: Remove from the carrying case and pull off the blue safety release. Keep thumb, fingers and hand away from the orange (needle) end of the device. Inject into the middle of the outer thigh only at a 90 degree angle. Hold the needle firmly in place while counting to 3. Remove the needle and massage the area for 10 seconds. After injection, the orange tip will extend to cover the needle. If the needle is visible, it should not be reused. For all epinephrine auto- injectors: It is normal to see liquid remaining in the device after injection. Call for emergency help because additional care may be needed. A second dose (in the opposite leg) may be given if needed prior to arrival of medical help. Refrigeration is not required. All products can be injected through clothing. Check the device periodically to make sure the medication is clear and not expired. Symjepi is only available in 0.3 mg ( indicated for patients 30 kg and up) , and Auvi -Q is also available in 0.1 mg ( for patients weighing 7.5 - 14 kg) . The patient 's emergency kit should also include emergency contact information and diphenhydramine tablets ( 25 mg x 2) , which should be taken only if there is no tongue /lip swelling. Patient Counseling for Epinephrine Auto- Injectors Tell your family, caregivers and others where you keep your epinephrine auto- injector and how to use it, as you may not be able to speak in an allergic emergency. It is important to keep the thumb, fingers and hand away from the needle end of the device, as injection can cause vasoconstriction and necrosis. When injecting an uncooperative child, hold leg firmly to avoid bending or breaking the needle. Skin infections can occur after injection. Report any prolonged redness, swelling, warmth or tenderness at the injection site. For Adrenaclick : Remove the two gray end caps while keeping the thumb, fingers and hand away from the red tip. Inject in the middle of the outer thigh, hold needle firmly in place on the thigh for 10 seconds, then massage area for 10 seconds. After injection, examine the red tip. If the needle is visible, the dose has been received. If the needle is not visible, repeat the injection step. When complete, place the cap over the needle. For Symjepi: Pull off cap, holding the syringe with the fingers (avoiding the needle ). Inject in the middle of the outer thigh, hold needle firmly in place on the thigh for two seconds, then massage area for 10 seconds. After injection, slide the safety guard out over the needle. For Auvi - Q: Pull off the outer case, then follow the voice instructions to administer. Hold needle firmly in place on the thigh for five seconds. DRUGS COMMONLY ASSOCIATED WITH ALLERGIC REACTIONS While any drug can lead to an allergic reaction, some are known to do so more than others. These are discussed below. Often the drug that caused a reaction can be replaced with another drug. Patch testing by an allergist is the most reliable way to determine if a person is truly allergic to a drug, but it does not provide any information regarding certain types of rashes (e.g., SJS or TEN ). BETA- LACTAMS Penicillin is a beta - lactam antibiotic and there are many related compounds in this family, including nafcillin, ampicillin, piperacillin and others. Anyone who is allergic to one of the penicillins should be presumed to be allergic to all penicillins and should avoid the entire group, unless they have been specifically evaluated for this problem. Cephalosporins are structurally related to penicillin. People with a history of penicillin allergy have a small risk of also having an allergic reaction to a cephalosporin or carbapenem. Risk of cross- reactivity is low, but it is prudent on the NAPLEX exam to avoid any beta - lactam with a stated allergy to another, unless there is no acceptable alternative agent. A notable exception is in acute otitis media (AOM ) ; the American Academy of Pediatrics recommends use of 2 nd or 3rd generation cephalosporins in patients with a non - severe penicillin allergy, due to toxicities and decreased efficacy of alternative AOM therapies in children. Aztreonam (a monobactam ) is considered safe in patients with penicillin allergies. . RxPrep Course Book | RxPrep © 2019 RxPrep © 2020 BIOLOGICS A PENICILLIN ALLERGY, OR NOT ? About 10% of people report they have a penicillin “allergy,” but the CDC reports the true incidence of an IgG -mediated (Type I hypersensitivity) reaction to penicillin is ~1%, When a "penicillin allergy" is reported, broad-spectrum antibiotics are often used, which increases resistance and cost *4 *4 It can be best to test: a negative skin test result should be followed by an oral drug. Give an oral drug “challenge" dose before the full treatment dose. For a positive test or a past severe skin reaction (SJS/ TEN, DRESS, etc), don’t give the drug. Remember: if penicillin allergy AND syphilis in pregnancy or HIV: Must test, and if positive, desensitize. Penicillin is the only acceptable treatment. Good news report! Many cephalosporins can be safely tolerated despite a penicillin allergy in acute otitis media infection (e.g , allergy to penicillin/amoxicillin, give cefdinir, cefpodoxime, ceftriaxone or cefuroxime) Biologies (e.g., rituximab) can cause hypersensitivity reactions, among other ADRs. Desensitization is possible for some agents in patients who need a biologic but have had a prior poor reaction. See the following page for more information regarding desensitization processes. NSAIDS Reactions to NSAIDs, including aspirin , can either be a drug sensitivity or a true allergic reaction. A drug sensitivity can cause rhinitis, mild asthmatic-type reactions, or skin reactions. If a true allergy is present, the patient will experience urticaria, angioedema and occasionally anaphylaxis. COX- 2 selective NSAIDs may be used in practice, but on the NAPLEX exam it is prudent to avoid all NSAIDs. . . SULFA DRUGS with most commonly reported are Reactions sulfamethoxazole (in Bactrim ), and the patient should avoid using sulfasalazine, sulfadiazine and sulfisoxazole. The package labels for “ non-arylamine” sulfonamides [thiazide diuretics, loop diuretics (except ethacrynic acid ) , sulfonylureas, acetazolamide, zonisamide and celecoxib], as well as cidofovir, darunavir ( Prezista ) , fosamprenavir and tipranavir contain warnings or contraindications for use in patients with sulfa allergy, although they usually do not cross react with a sulfamethoxazole allergy. The risk of cross- reactivity with sulfamethoxazole, thiazides and loop diuretics is very low, and in clinical practice the reaction is usually not considered significant when these drugs are needed. Even so, the patient should be aware to watch for a possible reaction. Some other sulfa - type groups also have low risk of cross- reactivity. On the NAPLEX exam you should recognize the possible interaction. Sulfite or sulfate allergies do not cross react with sulfonamides. The rotigotine patch , orphenadrine injection, the Rowasa mesalamine enema , some dobutamine formulations and some eye drops contain sulfites. OPIOIDS Opioid intolerance due to histamine release is common; however, true opioid allergy is uncommon. See Pain chapter for information on opioid allergy and treatment options. HEPARIN See Anticoagulation chapter for information on heparin induced thrombocytopenia (HIT). CONTRAST MEDIA Contrast media ( used in CT scans) can cause anaphylactoid reactions and delayed skin reactions. Systemic steroids and antihistamines are sometimes used to prevent reactions if contrast media is needed in a patient who has had a prior reaction. PEANUTS AND SOY It is important for the pharmacist to be aware if a patient has a peanut allergy. Peanuts and soy are in the same family and can have cross- reactivity. Soy is used in some medications. Parents of children with peanut allergies should be CPRtrained and have ready access to an epinephrine autoinjector. Most likely, a reaction will be due to consuming peanuts or soy unknowingly in food products. Drugs to avoid with peanut or soy allergy: clevidipine (Cleviprex ) , propofol ( Diprivan) , progesterone in Prometrium capsules. EGGS If a patient has a true allergy to eggs, they cannot use clevidipine ( Cleviprex ) , propofol ( Diprivan ) or Yellow Fever vaccine (chicken eggs are used in vaccine production ) . For influenza vaccine, ACIP states that even patients who have had more severe symptoms when consuming eggs (such as wheezing, requiring epinephrine, hypotension or cardiovascular changes ) can receive any indicated inactivated vaccine. Administration should be supervised by a healthcare provider who is able to recognize and treat severe allergic reactions. Flublok , which is made using recombinant techniques and contains no egg protein , is one option in patients with severe reactions to consuming eggs, but is not preferentially recommended by ACIP. If a severe reaction to an influenza vaccine occurs, regardless of which ingredient is suspected , that patient should not receive further doses of any influenza vaccine formulation. 77 | DRUG ALLERGIES & ADVERSE DRUG REACTIONS SKIN TESTING AND DESENSITIZATION PENICILLIN SKIN TESTING A penicillin allergy is the most common drug allergy in the U.S., reported in about 10% of the general population. A true penicillin allergy has been found to be present in only about 10% of those that are reported. Some patients report a penicillin ' allergy ” when their reaction was more properly categorized as an intolerance (e.g., nausea or diarrhea ) . In other cases, patients may have had a true allergic reaction to penicillin in the past , but over time, the antibodies can wane and the patient may be able to safely receive penicillins. Due to concerns of cross- reactivity with cephalosporins and carbapenems, a penicillin allergy can severely limit the selection of antibiotics available to treat infectious diseases. Patients who report a penicillin allergy have been shown to more often receive broad -spectrum antibiotics that cause more collateral damage, such as quinolones, and antibiotics with greater toxicity potential, such as vancomycin. The goal of penicillin skin testing is to identify patients who are at the greatest risk of a Type I hypersensitivity reaction if exposed to a systemic penicillin. The penicillin skin test uses the components of penicillin that most often cause an immune (allergic) response. Pre - Pen ( benzylpenicilloyl polylysine injection ) contains the major determinants of penicillin allergy and is used with very dilute solutions of penicillin G. A step- wise skin test is done: a skin prick test followed by intradermal testing. A localized reaction around the Pre - Pen or penicillin G test site indicates a high risk of a reaction to systemic penicillin and the patient should not receive it. A patient with a negative skin test, ( no reaction to the test solutions) can be considered to be at the same risk as a patient in the general population who does not report a penicillin allergy. Skin testing only predicts an IgEmediated reaction. Regardless of skin test results, a patient should never be re -challenged with an agent that caused SJS or TEN. INDUCTION OF DRUG TOLERANCE (DESENSITIZATION) In many cases when a drug allergy is present, an alternative medication can be chosen. When no acceptable alternative is available, induction of drug tolerance (often referred to as desensitization ) may be recommended. For example, if a pregnant patient has syphilis and a penicillin allergy, the CDC recommends desensitization and penicillin treatment, rather than using second -line agents (see Infectious Diseases II chapter) . Desensitization is a step-wise process that begins by administering a very small dose of the medication and then incrementally increasing the dose at regular time intervals up to the target dose. This modifies the patient 's response to the medication and temporarily allows safe treatment . The desensitization procedure must take place in a medical setting where emergency care can be provided if a serious reaction occurs. Treatment with the agent must start immediately following the desensitization procedure and must not be interrupted. If doses are missed , the drug-free period allows the immune system to re-sensitize to the drug and serious hypersensitivity reactions ( including anaphylaxis) could occur with subsequent doses. Induction of drug tolerance is a more accurate term than desensitization, because the process does not "cure” the patient of an allergy, and the reaction should not be removed from the patient's medical record. If the drug is required on a separate occasion, the process must be repeated. Desensitization protocols exist for a number of antimicrobial agents, some biologies and a few other medications (such as aspirin ) . Desensitization should never be attempted if an agent has previously caused SJS or TEN. Select Guidelines/ References Food and Drug Administration MedWatch program http:// www.fda.gov/ Safety/ MedWatch / (accessed 2019 Apr 5) Drug Allergy: An Updated Practice Parameter. Ann Allergy Asthma Immunol . 2010 Oct;105:259 - 273.